Bioengineering Transla Med - 2022 - Chopade - Alzheimer S and Parkinson S Disease Therapies in The Clinic

Received: 14 February 2022 Revised: 31 May 2022 Accepted: 6 June 2022
DOI: 10.1002/btm2.10367
REVIEW ARTICLE
Alzheimer's and Parkinson's disease therapies in the clinic
Puja Chopade1 | Neha Chopade1 | Zongmin Zhao2 | Samir Mitragotri3,4 |

Rick Liao3,4 | Vineeth Chandran Suja3,4
1
Bob Jones High School, Madison,
Alabama, USA Abstract
2
Department of Pharmaceutical Sciences, Alzheimer's disease (AD) and Parkinson's disease (PD) are the most prevalent neurodegen-
College of Pharmacy, University of Illinois at
erative diseases, affecting millions and costing billions each year in the United States alone.
Chicago, Chicago, Illinois, USA
3
School of Engineering and Applied Sciences, Despite tremendous progress in developing therapeutics that manage the symptoms of
Harvard University, Cambridge, these two diseases, the scientific community has yet to develop a treatment that effec-
Massachusetts, USA
4
tively slows down, inhibits, or cures neurodegeneration. To gain a better understanding of
Wyss Institute for Biologically Inspired
Engineering, Cambridge, Massachusetts, USA the current therapeutic frontier for the treatment of AD and PD, we provide a review on
past and present therapeutic strategies for these two major neurodegenerative disorders
Correspondence
Vineeth Chandran Suja, School of Engineering in the clinical trial process. We briefly recap currently US Food and Drug Administration-
and Applied Sciences, Harvard University,
approved therapies, and then explore trends in clinical trials across the variables of therapy
Cambridge, MA 01234, USA.
Email: vinny@g.harvard.edu mechanism of disease intervention, administration route, use of delivery vehicle, and out-
Rick Liao and Vineeth Chandran Suja, School come measures, across the clinical phases over time for “Drug” and “Biologic” therapeu-
of Engineering and Applied Sciences, Harvard
tics. We then present the success rate of past clinical trials and analyze the intersections in
University, Cambridge, MA 01234, USA.
Email: rickliao@g.harvard.edu and vinny@ therapeutic approaches for AD and PD, revealing the shift in clinical trials away from thera-
g.harvard.edu
pies targeting neurotransmitter systems that provide symptomatic relief, and towards anti-
Funding information aggregation, anti-inflammatory, anti-oxidant, and regeneration strategies that aim to inhibit
John A Paulson School of Engineering &
the root causes of disease progression. We also highlight the evolving distribution of the
Applied Sciences, Harvard University
types of “Biologic” therapies investigated, and the slowly increasing yet still severe under-
utilization of delivery vehicles for AD and PD therapeutics. We then briefly discuss novel
preclinical strategies for treating AD and PD. Overall, this review aims to provide a succinct
overview of the clinical landscape of AD and PD therapies to better understand the field's
therapeutic strategy in the past and the field's evolution in approach to the present, to bet-
ter inform how to effectively treat AD and PD in the future.
KEYWORDS
Alzheimer's Disease, clinical trials, delivery vehicles, drug administration routes, outcome
measures, Parkinson's Disease, therapy mechanisms
1 | INTRODUCTION
Alzheimer's disease (AD) and Parkinson's disease (PD) are the two
Puja Chopade and Neha Chopade contributed equally to this study.
most common neurodegenerative disorders. AD and PD afflict around
Rick Liao and Vineeth Chandran Suja contributed equally to this study and are joint senior
authors. 6 million and 1 million patients, respectively, in the United States
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2022 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of American Institute of Chemical Engineers.
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2 of 23 CHOPADE ET AL.
alone,1,2 placing heavy financial and emotional burdens on patients as landscape of AD therapies, Section 5 details the clinical landscape of
well as their caregivers. Between direct medical costs and indirect PD therapies, Section 6 details the clinical intersections between AD
costs such as caregiver burden and disability income, AD and PD cost and PD therapies, and Section 7 discusses novel preclinical strategies.
around $305 billion and $51.9 billion, respectively, in the Finally, we conclude the article in Section 8 detailing the future
United States annually.2,3 Furthermore, as the population grow and prospects in the field.
lifespans increase, neurodegenerative diseases will become more
widespread. Globally, AD and PD currently afflict around 50 million
and 10 million people, respectively, and are projected to increase to 2 | C UR R E NT L Y A P P RO V E D T H E R A PIE S
150 million and 12 million people, respectively, by the year 2050.1,4,5
Despite decades of research and investment, there are no clinically 2.1 | Alzheimer's disease
approved therapies that slow down or prevent the progression of
these diseases. Instead, available treatments only mitigate symptoms. AD is the most common neurodegenerative disorder that affects cog-
However, many experimental therapies have succeeded in preclinical nitive function, leading to dementia, confusion, and general mental
animal models and are currently under investigation in clinical trials. decline. Classic AD symptoms occur due to brain atrophy and dis-
The US Food and Drug Administration (FDA) made the rupted neuronal signaling in areas essential for cognition and memory,
clinicaltrials.gov database publicly available in 2000 to document and such as the hippocampus and cerebral cortex.7 AD is characterized at
display information about currently ongoing and completed clinical tri- the cellular level by the accumulation of two types of insoluble protein
als.6 This database is aimed towards helping patients, health care pro- aggregates throughout the brain: extracellular amyloid-beta (Aβ) pla-
fessionals, researchers, and the public easily access clinical studies for ques and intraneuronal and extracellular tau neurofibrillary tangles.8,9
any disease. Patients are able to explore and register for clinical trials While the cause of AD has not been confirmed, the well-known “amy-
that involve therapies targeting the health conditions they are facing. loid hypothesis” theorizes that these Aβ aggregates play the primary
The clinicaltrials.gov database is the largest registry of its kind and role in the pathogenesis and progression of AD.10,11 However, there
contains a comprehensive list of details for each clinical trial including is growing concern that the field should move beyond the “amyloid
a brief summary of the study as well as a description of the study hypothesis” and shift focus onto other potential pathogenesis hypoth-
design, aims and interventions, key outcome measures, and eligibility eses.12 Still, the “amyloid hypothesis” is not yet ruled out, with poten-
criteria for the trial. Its scope was expanded greatly in 2007 when all tial clinical failures attributed to administering therapies too late in AD
non-phase 1 interventional clinical trials were required to report development to elicit any therapeutic effect.13 For example, the A4
6
results and adverse effects to the database. Despite its value to study coordinated by the University of Southern California's Alzhei-
patients seeking entry into specific trials investigating experimental mer's Therapeutic Research Institute seeks to preemptively treat older
therapies, the clinicaltrials.gov database lacks a concise cumulative individuals at risk of AD with Aβ aggregate-reducing therapies to
display of information for researchers to glean understanding of the determine whether proactive treatment prevents AD development.14
current state of the clinical frontier for a given disease or disorder. While AD is extensively researched, much remains to be discovered
To address this limitation, here we report the clinical trial frontier about this clinically devastating and biologically complex disease.
for the two major neurological disorders: Alzheimer's disease and Par- Figure 1 displays therapy mechanisms utilized by currently FDA-
kinson's disease. We begin by first summarizing current clinically approved therapeutics for AD and PD and Table 1 lists the specific
approved therapies. To gain a better understanding of the clinical approved therapies. Several therapies have been approved by the FDA
landscape of potential upcoming AD and PD treatments, we have to relieve the symptoms, but not progression of AD. The main limitation
sorted through AD and PD clinical trials to succinctly summarize the of these symptomatic therapies is their inability to slow, stop, or
therapeutic intervention mechanism, administration route, delivery reverses the progression of the disease. These therapies include the
vehicle, and outcome measures of these investigations across clinical acetylcholinesterase inhibitors galantamine hydrobromide (Razadyne,
phases and therapy types for past and active registered interventional approved in 2001), donepezil hydrochloride (Aricept, approved in 2006),
trials. We provide analyses that present the success rate of past clini- and rivastigmine tartrate (Exelon, approved in 2007), and previously tac-
cal trials and highlight the directions and trends in the clinical land- rine hydrochloride (Cognex, approved in 1993), which was withdrawn in
scape across past and active clinical trials. We finally close with a 2013 due to hepatotoxicity.15 These therapies manage symptoms of
critical analysis of clinical intersections in therapeutic intervention dementia and mental decline via preserving acetylcholine (ACh) levels in
strategies and a brief discussion of novel preclinical strategies for the synaptic gaps between neurons by preventing its degradation by
these two most prevalent neurodegenerative diseases. This analysis acetylcholinesterase.15 Memantine hydrochloride (Namenda, approved
also emphasizes how the field can benefit from more widely adopting in 2003) is another FDA-approved symptomatic treatment for AD.16
advanced drug delivery strategies utilizing delivery vehicles such as Memantine hydrochloride is an N-methyl-D-aspartate receptor
nanoparticle or cellular carriers to enhance therapeutic delivery and (NMDAR) antagonist that aims to prevent excess glutamate from over-
hence efficacy. The rest of the article is organized as follows. Section 2 stimulating neurons and causing damage from excitotoxicity.16 Suvorex-
details the approved therapies, Section 3 details the methodology fol- ant (Belsomra), originally a dual orexin receptor antagonist used for
lowed for selecting the clinical trial data, Section 4 details the clinical insomnia, was approved in 2020 to treat sleep disorders in AD.17
CHOPADE ET AL. 3 of 23
F I G U R E 1 Schematic showing therapy mechanisms utilized by approved AD and PD drugs. a, b, and c, respectively, show therapy
mechanisms specific to AD, common overlapping therapy mechanisms, and therapy mechanisms specific to PD. AD, Alzheimer's disease; PD,
Parkinson's disease
In 2021, Aducanumab (Aduhelm), an anti-Aβ monoclonal anti- 2.2 | Parkinson's disease

body, became the first Aβ plaque-reducing therapy for AD to be
granted FDA approval.18 However, the efficacy of aducanumab is PD is the second most common neurodegenerative disorder with
highly controversial since phase III clinical trials were inconclusive in characteristic motor symptoms including tremor, rigidity, bradykinesia,
demonstrating clinical benefits, namely improvements in cognitive and postural instability. PD patients may also experience nonmotor
function and reduction of dementia.18 Patients in one study experi- symptoms including sleep disturbances, psychotic symptoms, sensory
enced a reduction in AD-related cognitive decline while those in disorders, mood disturbances, and cognitive impairment. PD occurs
another study did not experience a statistically significant reduction. after the loss of dopaminergic neurons in the pars compacta of the
Clinical limitations of aducanumab include the several treatment- substantia nigra, associated with the presence of intracellular aggre-
emergent adverse events (TEAEs) reported during early phase clinical gates of misfolded alpha-synuclein.35,36 The exact cause of PD
19
trials investigating its safety. Totally, 41.3% of patients in the remains unknown, but several implicated processes include
EMERGE and ENGAGE clinical trials experienced amyloid-related neuroinflammation,37,38 mitochondrial dysfunction,39–41 oxidative
imaging abnormalities (ARIA), the most common type of TEAE stress,42 and defective protein homeostasis.43,44
observed, including brain edema, sulcal effusion, and hemosiderin Table 1 shows a list of key approved therapies for PD. The most
deposits from brain hemorrhage, and 26% of these patients experi- prominent approved treatments for the motor symptoms of PD are
enced associated symptoms.20 All cases of symptomatic ARIA were medications containing levodopa and carbidopa, such as Sinemet,
reported as serious adverse effects. However, no patients were hospi- Paracopa, Rytary, and Duopa. Levodopa is a dopamine precursor,45
talized due to ARIA, and most ARIA cases resolved within 4– and carbidopa is a dopa-decarboxylase inhibitor that reduces extracer-
12 weeks.21 The FDA granted accelerated approval of aducanumab ebral metabolism of levodopa before it has crossed the protective
due to its consistent success with reducing Aβ levels in AD patients, blood-brain barrier (BBB),46 enhancing levodopa brain bioavailability.
suggesting a “reasonable likelihood” for clinical improvement, while Another class of FDA-approved treatments is catechol-o-methyl-
requiring phase IV clinical trials to prove clinical benefit by February transferase (COMT) inhibitors (such as Comtan, Tasmar, Ogentys),
of 2030.22 If this deadline is not met, FDA approval for aducanumab which have achieved success when used in conjunction with carbi-
will be withdrawn. While the clinical benefit of aducanumab has not dopa/levodopa medication. These drugs function by inhibiting the
yet been verified, its availability on the market is a major milestone for enzyme COMT, thus preventing extracerebral degradation of levo-
AD therapeutic development as it is the first available drug with the dopa and increasing levodopa plasma concentration.47 Dopamine ago-
potential to slow the progression of AD. Despite these advancements, nists can cross the BBB and mimic the effect of dopamine by binding
the existing therapies available for the treatment of AD, while offering to dopamine receptors,48 reducing dyskinesia. Carbidopa and COMT
significant improvement in management of AD symptoms, are either inhibitors reduce the required dosage of levodopa. The current FDA-
disputable in efficacy or restricted to providing solely symptomatic approved drugs that act as dopamine agonists are Mirapex, Requip,
relief. AD patients are yet to gain access to a fully approved drug that Apokyn, Kynmobi, and Neupro. Monoamine Oxidase Type B (MAO-B)
can reliably slow or stop the progression of AD. By analyzing data is an enzyme that breaks down dopamine in the brain.49 MAO-B
from completed and ongoing AD clinical trials, this study will enable inhibitors such as Eldepryl, Zelapar, Azilect, and Xadago have suc-
researchers to comprehend the current clinical frontier for AD thera- ceeded in gaining FDA approval. NMDA glutamate receptor antago-
peutic development. nists including Symmetrel, Gocovri, and Osmolex have been approved
TABLE 1 All FDA-approved therapies for AD and PD
Approval
No. Name Disease Therapy Mechanism Year Notes
1 Razadyne (Johnson & AD Neurotransmitter system (iii) 2001 Acetylcholinesterase inhibitor15
Johnson)
2 Namenda (Abbvie) AD Anti-excitotoxicity (ii) 2003 NMDA receptor antagonist16
3 Aricept (Eisai/Pfizer) AD Neurotransmitter system (iii) 2006 Acetylcholinesterase inhibitor15
4 Exelon (Novartis) AD Neurotransmitter system (iii) 2007 Acetylcholinesterase inhibitor15
5 Belsomra (Merck) AD Neurotransmitter system (ii) 2020 Dual orexin receptor antagonist17
6 Aduhelm (Biogen) AD Anti-aggregation (i) 2021 Anti-amyloid beta monoclonal antibody18
7 Cogentin (Merck) PD Neurotransmitter system (ii) 1954 Anticholinergic23
8 Eldepryl (Somerset) PD Neurotransmitter system (iii) 1988 Monoamine oxidase inhibitor23
9 Mirapex (Pharmacia) PD Neurotransmitter system (iv) 1997 Dopamine agonist24
10 Requip (GlaxoSmithKline) PD Neurotransmitter system (iv) 1997 Dopamine agonist23
11 Tasmar (Hoffman-La Roche, PD Neurotransmitter system 1998 COMT inhibitor23
Inc)
12 Comtan (Novartis) PD Neurotransmitter system 1999 COMT inhibitor23
13 Stalevo (Novartis) PD Neurotransmitter system (v) 2003 Combination of carbidopa, levodopa, and COMT
inhibitor23
14 Symmetrel (Endo PD Anti-excitotoxicity (ii) 2003 NMDA glutamate receptor antagonist23
Pharmaceuticals)
15 Artane (Wyeth-Ayers PD Neurotransmitter system (ii) 2003 Anticholinergic23
Research)
16 Parcopa (Schwarz Pharma) PD Neurotransmitter system (v) 2004 Combination of carbidopa and levodopa25
17 Apokyn (Brituswip) PD Neurotransmitter system (iv) 2004 Dopamine agonist23
18 Zelapar (Valeant PD Neurotransmitter system (ii) 2006 Monoamine oxidase inhibitor23
Pharmaceuticals)
19 Azilect (Teva PD Neurotransmitter system (ii) 2006 Monoamine oxidase inhibitor23
Pharmaceuticals)
20 Neupro (Schwarz PD Neurotransmitter system (iv) 2006 Dopamine agonist26
BioSciences, Inc)
21 Requip XL (GlaxoSmithKline) PD Neurotransmitter system (iv) 2008 Dopamine agonist23
22 Mirapex ER (Boehringer PD Neurotransmitter system (iv) 2010 Dopamine agonist24
Ingelheim)
23 Sinemet (Merck) PD Neurotransmitter system (v) 2014 Combination of carbidopa and levodopa27
24 Sinemet CR (Merck) PD Neurotransmitter system (v) 2014 Combination of carbidopa and levodopa27
25 Rytary (Impax) PD Neurotransmitter system (v) 2015 Combination of carbidopa and levodopa23
26 Duopa (AbbVie) PD Neurotransmitter system (v) 2015 Combination of carbidopa, levodopa, and COMT
inhibitor23
27 Xadago (Newron PD Neurotransmitter system (ii) 2017 Monoamine oxidase inhibitor28
Pharmaceuticals)
28 Gocovri (Adamas PD Anti-excitotoxicity (ii) 2017 NMDA glutamate receptor antagonist29
Pharmaceuticals)
29 Inbrija (Acorda Therapautics) PD Neurotransmitter system (v) 2018 Inhaled levodopa30
30 Osmolex (Osmotica) PD Anti-excitotoxicity (ii) 2018 NMDA glutamate receptor antagonist31
31 Nourianz (Kyowa Kirin, Inc) PD Neurotransmitter system (ii) 2019 Adenosine A2A receptor antagonist32
32 Ongentys (Neurocrine PD Neurotransmitter system 2020 COMT inhibitor33
Biosciences)
33 Kynmobi (Sunovion) PD Neurotransmitter system (iv) 2020 Dopamine agonist34
Note: The roman numerals in parentheses refer to mechanisms illustrated in Figure 1. COMT inhibitors and carbidopa act systemically and hence are not
represented in the above schematic.
Abbreviations: AD, Alzheimer's disease; COMT, catechol-O-methyl-transferase; FDA, US Food and Drug Administration; NMDA, N-methyl-D-aspartate;
PD, Parkinson's disease.
by the FDA to treat dyskinesia. Adenosine 2A antagonists such as allocated antibodies, peptides, proteins, natural products, and micro-
Nourianz show neuroprotective effects in PD patients. Anticholinergic bial products under the “Biologic” classification. Natural products
drugs such as Artane and Cogentin have been approved for their abil- refer to plant extracts that contain a cocktail of molecules, such as
ity to relieve tremors by correcting the imbalance between ACh and ginkgo biloba extract. However, if a single molecule was isolated from
dopamine in PD patients. It is worth noting that all the approved ther- a natural source, such as resveratrol or curcumin, we classified it as a
apies are symptomatic therapies. small molecule and therefore under the “Drug” classification. Figure 2
displays the total number of clinical trials in each clinical phase as a
function of trial completion years and therapeutic type (“Drug” and
3 | C L I N I C A L T R I A L DA TA SE T “Biologic”) for AD and PD since 2000, with “Biologic” trials stacked in
ORGANIZATION green. Active investigations include all clinical trials that were active
as of January 2021, when the clinical trial date of completion data set
All clinical trials analyzed were originally sourced from data available was analyzed.
from the clinicaltrials.gov database. We eliminated “observational” tri-
als to focus our analysis on “interventional” trials. Within “interven-
tional” trials, we further eliminated trials that were device-, diagnostic, 4 | A LZ HE I M ER ' S D I S E A S E T H E R A P I E S I N
surgical procedure-, implant-, behavioral-, and radiation-based, con- T H E CL I N I C
centrating on therapeutic interventions namely drug- and biologic-
based therapies. Starting with 2603 AD and 2933 PD clinical trials, Figure 3 and Figure 4 show a total of 948 clinical trials that are
we reduced the data set to 1005 AD and 938 PD clinical trials after respectively dissected into active (179 trials) and past (769 trials).
the aforementioned eliminations. Among these, 57 AD and 40 PD did Note as mentioned in Figure 3, 57 trials (out of 1005) were excluded
not report the trial phase, and hence were not included in analyses from the analysis presented in this section due to unreported clinical
that broke up trials across phases. Following the convention of phase. Considering all the clinical trials represented in figures, we find
clinicaltrials.gov, we grouped therapy types into either “Drug” or “Bio- that there are more trials in the early phases 1 (27% of trials) and
logic” with minor adjustments for consistency with the FDA definition 2 (40% of trials), involving basic safety and preliminary efficacy test-
of biologics. In addition to cell- and protein-based systems, we ing, than the later phases 3 (24% of trials) and 4 (9% of trials). Small
F I G U R E 2 All AD and PD interventional trials fitting the criteria detailed in Section 3. One thousand and five AD trials and 938 PD trials are
plotted as a function of the clinical phase and completion year. In the stacked bars, orange color indicates “Drug” and green color indicates
“Biologic” therapies. “Biologic” therapies are becoming more popular and are increasingly more successful through the clinical phases. AD,
Alzheimer's disease; PD, Parkinson's disease
F I G U R E 3 Summary of active AD clinical trials. (a) Therapy mechanism, (b) administration route, (c) delivery vehicle, and (d) outcome
measures utilized by 179 active AD trials are plotted as a function of clinical phase. In the stacked bars, orange color indicates “Drug” and green
color indicates “Biologic” therapies. The definition of key terms is available in Table A1. Note that liposomes-based delivery vehicles are binned
under micro/nanoparticle category in this article. AD, Alzheimer's disease
molecule drug trials make up the majority of clinical trials (76%) in all trials consist of variations of the currently FDA-approved small mole-
phases, but account for an even greater proportion of clinical trials cule therapies, namely galantamine hydrobromide, donepezil hydro-
(87%) in phases III and IV than biologic therapies. Biologic therapies chloride, and rivastigmine tartrate, and are being tested for efficacy
for AD are relatively newer and more experimental than small mole- across varied patient populations or in combination with other thera-
cule therapies for AD and therefore have a relatively smaller number pies. Table 2 presents 10 currently active clinical trials for AD utilizing
of completed and ongoing clinical trials. However, biologic therapies a broad range of therapeutic strategies to give an idea of the wide
are increasing in popularity, with biologics accounting for 33% of variety of therapeutics under investigation. In the rest of this
active trials versus 21% of past trials. Furthermore, several AD clinical section we analyze the clinical landscape focusing on the therapy
F I G U R E 4 Summary of past AD clinical trials. (a) Therapy mechanism, (b) administration route, (c) delivery vehicle, and (d) outcome measures
utilized by 769 past AD trials are plotted as a function of clinical phase. In the stacked bars, orange color indicates “Drug” and green color
indicates “Biologic” therapies. The definition of key terms is available in Table A1. AD, Alzheimer's disease
mechanisms, drug administration routes, drug delivery vehicles, and leveraged by AD trials, namely anti-aggregation, neurotransmitter system
outcome measures as a function of clinical phase and therapy type. (NTS), anti-inflammatory, anti-oxidant, anti-excitotoxicity, anti-apoptotic,
and regeneration. While many neurological disease processes are inter-
twined, such as inflammation, oxidative stress, and excitotoxicity,61 we
4.1 | Therapy mechanisms categorized therapy mechanism based on their primary intervention
target.
Figures 3a and 4a respectively show the therapeutic mechanisms lever- Therapies targeting NTS dominate the overall clinical landscape,
aged by active and past trials. There are seven main therapy mechanisms accounting for 34% of past and 14% of active trials. For NTS
8 of 23
TABLE 2 Examples of active AD clinical trials that represent the diverse therapy approaches pursued currently
Therapy Administration Delivery Outcome

Name Phase Therapy Type Mechanism Route Vehicle Measures Trial Number Notes
LX1001 (Lexeo Therapeutics) 1 Biologic: Gene Other Intrathecal Viral Safety, NCT03634007 Adeno-associated virus delivery of
therapy biochemical, human apolipoprotein E2 (APOE2)
psychiatric cDNA50
Canakinumab/Ilaris (Novartis) 2 Biologic: Anti-inflammatory Subcutaneous No carrier Psychiatric, NCT04795466 Human anti-IL-1β monoclonal
Antibody pharmacokinetics antibody51
MSC-Exos (Cell Biomedicine 2 Biologic: Cell Regeneration Intranasal Cellular Safety, psychiatric NCT04388982 Allogenic adipose mesenchymal stem
Group) therapy cell exosomes52
ACI-35.030 & JACI-35.054 (AC 2 Biologic: Anti-aggregation Intravenous Micro/nano Safety, NCT04445831 Anti-phosphorylated tau vaccine,
Immune SA) Protein/ particle biochemical, peptide loaded into liposome53
peptide psychiatric
ABvac40 (Araclon Biotech) 2 Biologic: Anti-aggregation Subcutaneous Protein Safety, biochemical NCT03461276 Peptide repeat conjugated to keyhole
Protein/ limpet cyanine (KHL) carrier
peptide protein, active vaccine targeting
the Aβ40 peptide C-terminal54
CT1812/Elayta (Cognition 2 Drug: Small Anti-aggregation Oral No carrier Biochemical NCT04735536 Small molecule antagonist of the
Therapeutics) molecule sigma2 receptor that reduces the
affinity of oligomeric Aβ for its
receptor55
Levetiracetam/Keppra (UCB 2 Drug: Small Anti- Oral No carrier Psychiatric, EEG NCT03875638 Binds to synaptic vesicle protein
Pharmaceuticals) molecule excitotoxicity SV2A to reduce neurotransmitter
vesicle release rate56,57
AC-1204 Caprylic triglyceride/ 3 Drug: Small Anti-apoptotic Oral No carrier Safety, psychiatric NCT04187547 Induce mild chronic ketosis to
Tricaprilin (Cerecin) molecule improve mitochondrial
metabolism58
AVP-786/Deudextromethorphan 3 Drug: Small Anti- Oral No carrier Safety, psychiatric NCT02446132 Dextromethorphan is a weak
Hydrobromide-Quinidine (Avanir molecule excitotoxicity antagonist of NMDA receptors and
Pharmaceuticals) an agonist of sigma 1 receptors;
quinidine increases bioavailability59
NE3107 (BioVie) 3 Drug: Small Anti-inflammatory Oral No carrier Psychiatric, NCT04669028 BBB permeable insulin sensitizer that
molecule biochemical binds ERK, to inhibit ERK and
NFKB inflammation60
Abbreviations: AD, Alzheimer's disease; BBB, blood-brain barrier; NMDA, N-methyl-D-aspartate.

CHOPADE ET AL.
intervention, AD therapies mainly targeted the cholinergic system therapies previously and anti-aggregation therapies presently domi-
(211), with other therapies targeting the dopaminergic (30), serotoner- nate the majority of clinical trials, with a lower percentage of therapies
gic (71), GABAergic (7), and norepinephrinergic (5) systems. Choliner- targeting one or more of the following disease mechanisms: apoptosis,
gic NTS trials refer to therapies that affect the neurotransmitter excitotoxicity, inflammation, and oxidative stress.
ACh. ACh is vital to neuronal signaling involved in several cognitive In AD animal models, Aβ has been shown to induce apoptosis of
functions including learning, short-term memory, and attention.62 neurons.69,70 However, its pro-apoptotic role has not been clearly
Drug therapies targeting the cholinergic system typically aim to proven in human studies, and its precise molecular mechanism in pro-
increase ACh levels, which are lowered in AD. This leads to some moting apoptosis remains unclear.71 Additional research on the spe-
symptomatic relief from the cognitive symptoms of AD. These thera- cific role of the disialoganglioside GD3, a potential target of anti-
pies include acetylcholinesterase inhibitors which stop the enzyme- apoptotic therapies, is also needed in order to improve therapeutic
mediated breakdown of ACh in the synaptic gaps between neurons, strategy.72 Several anti-apoptotic therapies have shown positive
nicotinic acetylcholine receptor α7 agonists, and several other medica- results in early clinical trials, but further investigation is needed to
tions designed to increase ACh levels.62 Also, a large proportion of confirm these results.71
therapies target the neurotransmitters serotonin and dopamine which Anti-excitotoxic therapies target NMDARs and their ligand, the
are connected to several psychological symptoms of AD including excitatory neurotransmitter glutamate. Excitotoxicity occurs when
apathy and depression.63 These other NTS therapies are also aimed NMDARs are overstimulated, allowing excess sodium and calcium
towards providing symptomatic relief rather than stopping or slowing ions to enter the neuron, generating excessive levels of reactive oxy-
the progression of AD. gen species (ROS), exhausting ATP stores in attempt to reestablish
Anti-aggregation therapies dominate the active clinical trial land- ionic equilibrium, and ultimately inducing necrosis or apoptosis.73,74
scape accounting for 30% of active trials increasing from just 14% of Many anti-excitotoxic therapies are unable to pass the early stages of
past trials. Anti-aggregation therapies utilize a variety of mechanisms clinical trials due to the adverse effects caused by a widespread block-
to stop the production, accumulation, and toxicity of hyperphosphory- ing of NMDAR activity which is essential to normal neuronal func-
64
lated neurofibrillary tau tangles and Aβ plaques. These therapies tion.75 Successful anti-excitotoxic therapies should block NMDAR
typically aim to increase clearance by targeting Aβ or tau with mono- overstimulation at injured brain regions without impeding essential
clonal antibodies such as aducanumab, or reduce Aβ production with NMDAR functioning.76 For this reason, competitive antagonists of
β-secretase 1 inhibitors such as Verubecestat and Lanabecestat,65 or glutamate and glycine are prone to causing TEAEs and are not viable
γ-secretase inhibitors such as Begacestat, 66
to prevent Aβ plaque for- options for AD patients. Some noncompetitive antagonists such as
mation. A greater proportion of clinical trials target Aβ rather than tau, MK-801 act allosterically to block the ion channel, but blockage for an
but the proportion of clinical trials targeting tau is greater for “Drug” extended period also leads to TEAEs.77 However, antagonists that
trials than “Biologic” trials. must first be activated by an agonist before allosteric binding to
A small percentage (7%) of “Biologic” trials investigate regenera- NMDARs only block NMDAR channels in conditions of excitotoxicity
tion therapies, mostly consisting of mesenchymal stem cell (MSC) thus providing clinical benefit without TEAEs. One such antagonist is
transfusion for promoting neuronal growth and regeneration. We also memantine hydrochloride (Namenda), which was approved by the
included the category Multiple for clinical trial therapies that inter- FDA in 2003.78
vened via more than one of the seven approaches. Pleiotropic drugs Chronic inflammation can damage brain tissue in AD patients due
fall in the category of Multiple as these therapeutics often exert multi- to excess release of cytokines from overactive microglia, astrocytes,
ple effects in concert, such as ginkgo biloba which has anti-aggrega- and invading peripheral leukocytes.79 Aβ activates the complement
tion, anti-oxidant, anti-inflammatory, and cholinergic modulation cascade, releasing anaphylatoxins, increasing levels of amyloid precur-
67,68
properties. The therapy mechanism Other encompasses all other sor protein (APP), and producing free radicals.80 Clinical trials investi-
therapeutic approaches that do not fit within the seven outlined cate- gating anti-inflammatory therapies are complicated by the lack of
gories. Other therapy mechanisms include drugs that modulate the inflammatory biomarker detection methods to monitor the success of
microbiome, hormonal systems, neurovascular system, or glucose these therapies. Studies on inflammatory markers have produced con-
metabolism. troversial results due to their inconsistent sampling times and patient
Anti-aggregation approaches have been commonly used in past populations.81 Current therapeutic strategies targeting inflammation
clinical trials, and have increased in popularity among currently active include reducing the concentration and inhibiting the action of cyto-
trials. Anti-aggregation was the most common approach in phase kines, and manipulating microglia to phagocytose Aβ plaques.82 Stud-
2, and second most common approach in phase 1 and 3 clinical trials ies investigating the preventive effect of non-steroidal anti-
in the past, and is currently the most common therapy mechanism in inflammatory drugs on AD have shown mixed results, with naproxen
phase 1 and 2 trials. NTS therapies heavily dominated past clinical tri- (Aleve) and celecoxib (Celebrex) appearing to increase AD risk.83
als as the most common approach in phases 1, 2, and 4, but have con- Oxidative stress occurs due to the buildup of ROS and contrib-
siderably decreased in numbers among currently active trials, utes to the development of AD. Anti-oxidant therapies aim to mitigate
especially for newer phase 1 and 2 investigations. Overall, NTS damage caused by oxidative stress, which is pronounced in brain
regions most affected by AD.84 Although several substances that 4.4 | Outcome measures
scavenge ROS have been investigated in AD animal models, most
anti-oxidant therapies are unable to significantly lower oxidative Figures 3d and 4d show the distribution of clinical trials categorized
stress and have overall shown limited success in human patients.85 by the outcome measures utilized by active and past clinical trials,
Furthermore, some anti-oxidant therapies such as vitamin E may respectively. Outcome measures can be organized into the categories
increase oxidative stress under various conditions.86 When adminis- of Safety, Psychiatric, Biochemical, Sleep, Pain, Volume, Other, and
tered in high dose, anti-oxidant therapies have the potential to disrupt Multiple. Volume refers to the percent change of hippocampal or
the body's natural anti-oxidant defense system.87 The majority of clin- whole brain volume. Most outcome measures categorized as Safety
ical trials for anti-oxidant therapies are currently confined to earlier involve the identification of TEAEs. Common Biochemical outcome
stages and more research is needed to verify clinical benefit for AD measures include cerebrospinal fluid or serum measurements of con-
88
patients. centrations of various biomarkers, such as Aβ, tau, or inflammatory
In addition to anti-aggregation approaches, alternative therapy cytokines. While biochemical outcome measures are often used for
mechanisms are gaining in prevalence among currently active clinical preliminary demonstration that an AD therapy is achieving a signifi-
trials. Most NTS drug therapies for AD aim to provide symptomatic cant effect by showing target interaction or some disease-modifying
relief, reducing the emotional burden of patients and caregivers capability, clinical benefit must be proven via psychiatric outcome
affected by severe memory loss, persistent confusion, and other cog- measures for long-term FDA approval. Common psychiatric outcome
nitive, behavioral, and psychological symptoms caused by AD. In con- measures for cognition for AD clinical trials include the mini-mental
trast, clinical trials not targeting NTS more often aim to slow or stop status examination,90 Alzheimer's disease cognitive scale,91 neuropsy-
the progression of AD as they target potential root causes of neuronal chiatric inventory,92 Alzheimer's disease cooperative study-activities
death in AD, namely inhibition of aggregation, apoptosis, inflamma- of daily living,93 and changes from baseline cognitive performance in
tion, excitotoxicity, and oxidative stress. Therapies targeting these working memory, processing speed, and learning abilities. These
alternative disease mechanisms may have potential for success in mit- methods assess the patients' clinical improvement, or lack thereof, in
igating AD progression as further research is conducted in these less response to each AD therapy. Psychiatric assessments are the primary
explored areas. outcome measures for both past and present trials for both “Drug”
and “Biologic” therapies. Safety and then Biochemical are the next
most common outcomes assessed. Many currently active phase 2 and
4.2 | Administration route 3 trials observe Multiple outcome measures, mainly composed of Psy-
chiatric, Safety, and Biochemical outcomes.
Figures 3b and 4b show the distribution of AD therapies by adminis-
tration route for active and past clinical trials, respectively. The major-
ity of “Drug” therapies are delivered orally. Because small molecule 5 | P A R K I N S O N ' S TH E R A P I E S I N T H E
drugs can bypass gastrointestinal barriers, oral delivery is favored as CLINIC
the least invasive mode of administration with high patient compli-
ance and convenience.89 In contrast, “Biologic” therapies are deliv- Figure 5 and Figure 6 show a total of 898 PD clinical trials that are
ered through an injection, most commonly via intravenous (IV), respectively dissected into active (158 trials) and past (740 trials).
intramuscular, or subcutaneous (SC) administration. Oral delivery Note as mentioned in Figure 3, 40 trials (out of 938) were excluded
dominates past and present clinical trials, but IV and SC delivery has from the analysis presented in this section due to unreported clinical
gained in prominence among currently active phase 1 and 2 trials. phase. Considering all the clinical trials represented in the figures, we
find that the majority of active clinical trials are in phase 2 (44%), fol-
lowed by phase 3, 1, and 4, which account for 22%, 22%, and 12% of
4.3 | Delivery vehicle the total active trials, respectively. A similar ordering is observed in
the past clinical trials with phase 2, 3, 1, and 4 accounting for 36%,
Figures 3c and 4c show the distribution of clinical trials by delivery 27%, 21%, and 16%, respectively. Unsurprisingly, small molecule
vehicle for active and past clinical trials, respectively. A very limited “Drug” therapies account for the lion's share of the therapy type
proportion of clinical trials use drug carriers. While “Biologic” thera- accounting for 66% and 78% of the active and current trials respec-
pies have a slightly more diverse distribution of delivery vehicles than tively. “Drug” therapies also have a significantly larger proportion of
that of “Drug” trials, both heavily underutilize delivery vehicles, with a therapies that have advanced to phase 3 and phase 4 clinical trials,
vast majority of therapies using no carrier. Increased utilization of indicating that they are nearing FDA approval or have already been
delivery vehicles offers potential to improve therapeutic efficacy for approved for general use. “Biologic” therapies are increasingly becom-
AD treatment, as elaborated in Section 6.4. Delivery vehicle ing popular with protein/peptide-based, cell-based, and antibody ther-
approaches are increasing in number among currently active phase apies leading the way by accounting for 28%, 24%, and 21%,
1 and 2 trials. respectively of active “Biologic” therapies (see Section 6 for more
F I G U R E 5 Summary of active PD clinical trials. (a) Therapy mechanism, (b) administration route, (c) delivery vehicle, and (d) outcome
measures utilized by 158 active PD trials are plotted as a function of clinical phase. In the stacked bars, orange color indicates “Drug” and green
color indicates “Biologic” therapies. The definition of key terms is available in Table A1
details). The majority of “Biologic” therapies remain in Phase 1 and 5.1 | Therapy mechanisms
Phase 2 as they are relatively new, and target less-explored mecha-
nisms of PD pathology that are mainly still being evaluated for safety. Figures 5a and 6a, respectively, show the same therapeutic mecha-
Table 3 presents 10 currently active clinical trials for PD utilizing a nisms utilized by active and past clinical trials organized into seven
broad range of therapeutic strategies to give an idea of the wide vari- main categories, namely Anti-aggregation, NTS, Anti-inflammatory,
ety of therapeutics under investigation. As with AD, in the rest of this Anti-oxidant, Anti-excitotoxicity, Anti-apoptotic, and Regeneration.
section we analyze the clinical landscape focusing on the therapy Majority of PD “Drug” therapies (69.5%) target NTS, accounting
mechanisms, drug administration routes, drug delivery vehicles, and for 47% of active and 72% of past trials. Among these, the neuro-
outcome measures as a function of clinical trial phases and therapy transmitter dopamine is unsurprisingly the most popular with many
types. trials testing varied doses of levodopa/carbidopa, COMT inhibitors,
F I G U R E 6 Summary of past PD clinical trials. (a) Therapy mechanism, (b) administration route, (c) delivery vehicle, and (d) outcome measures
utilized by 740 past PD trials are plotted as a function of clinical phase. In the stacked bars, orange color indicates “Drug” and green color
indicates “Biologic” therapies. The definition of key terms is available in Table A1
and AADC inhibitors that reduce levodopa breakdown, and therapies that can cross the protective BBB, are also tested for their effects on
that act as dopamine agonists of D2 or D1/D5 receptors. Other targeted motor and nonmotor symptoms of PD.32 Therapies targeting metabotro-
neurotransmitters include serotonin that is employed by drugs that com- pic glutamate include NMDAR blockers that have been used to reduce
bat nonmotor symptoms of PD, particularly reduction in sleep quality.104 dyskinesia.32 Adenosine a2a receptor agonists are also being explored
ACh has been targeted in therapies aimed at treating motor PD symp- for their neuroprotective effects and are being used as add-on therapies
toms such as dyskinesia as well as nonmotor symptoms such as overac- to shorten off time for patients on carbidopa/levodopa.32,105 Therapies
23
tive bladder. Trials with histamine assess its effect on daytime that target the neurotransmitter GABA are also tested for their effect on
sleepiness in PD patients. Prodrugs of norepinephrine such as Droxidopa sleep quality and motor symptoms.
CHOPADE ET AL.
TABLE 3 Examples of active PD clinical trials that represent the diverse therapy approaches pursued currently
Therapy Administration Delivery Outcome

Name Phase Therapy type mechanism route vehicle measures Trial number Notes
AAV2-GDNF (Brain 1 Biologic: Gene Regeneration Intracerebral Viral Safety NCT04167540 Adeno-associated virus delivery of glial cell
Neurotherapy Bio, Inc.) therapy line-derived neurotrophic factor94
UB-312 (Vaxxinity) 1 Biologic: Anti-aggregation Subcutaneous No carrier Safety NCT04075318 Peptide-based vaccine targetting alpha-
Protein/ synuclein95
peptide
Prasinezumab (Hoffmann-La 2 Biologic: Anti-aggregation Intravenous No carrier Motor, psychiatric NCT03100149 Humanized IgG1 monoclonal antibody
Roche) Antibody directed against aggregated
α-synuclein96
Exenatide (AstraZeneca) 2 Biologic: Anti- Subcutaneous No carrier Biochemical NCT04305002 Analog of the incretin hormone glucagon-
Protein/ inflammatory like peptide (GLP-1), previously FDA
peptide approved for T2D97
HB-adMSCs (Hope 2 Biologic: Cell Multiple Intravenous Cellular Motor, safety, NCT04928287 Autologous adipose-derived mesenchymal
Biosciences) therapy biochemical stem cells98
TAK-071 (Takeda) 2 Drug: Small Neurotransmitter Oral No carrier Motor, NCT04334317 Muscarinic acetylcholine receptor 1
molecule system pharmacokinetics positive allosteric modulator99
Rifaximin (UC San Francisco) 2 Drug: Small Anti- Oral No carrier Other NCT03575195 Antibiotic targeting gut microbiota100
molecule inflammatory
Cannabidiol (University of 2 Drug: Small Anti-oxidant Oral No carrier Motor NCT03582137 Extract from the Cannabis sativa plant101
Colorado) molecule
UCB0599 (UCB Biopharma 2 Drug: Small Anti-aggregation Oral No carrier Motor, psychiatric NCT04658186 Small-molecule α-synuclein aggregation
SRL) molecule inhibitor102
Apomorphine (US 3 Drug: Small Neurotransmitter Subcutaneous No carrier Motor NCT02339064 Non-ergoline dopamine D2 agonist
WorldMeds LLC) molecule system indicated to treat hypomobility103
Abbreviation: PD, Parkinson's disease.

13 of 23
Other therapy mechanisms leveraged by PD clinical trials include dopamine agonists, are also administered subcutaneously or transder-
anti-aggregation therapies such as myeloperoxidase inhibitor mally via patches and topical creams. “Biologic” therapies are mostly
AZD3241 that are tested for effectiveness against the toxic aggrega- delivered via IV administration, whereas those in the form of natural
tion of alpha-synuclein, known as Lewy body formation.106 Anti- products are commonly administered orally. A large number of “Bio-
apoptotic therapies such as TCH346 are tested for their efficacy in logic” therapies are delivered intracerebrally through direct implanta-
delaying loss of dopaminergic neurons.107,108 Anti-excitotoxicity drugs tion into the brain. These therapies tend to be stem cell therapies
such as memantine block glutamate receptors are tested for reducing which involve stem cells that are placed via intraputaminal infusions
involuntary movements (dyskinesias) in PD.109 Anti-inflammatory directly into the area of the brain in which they are needed. Neuro-
therapies such as Omega-3 fatty acid Docosahexaenoic acid are trophic factors are also mostly intracerebrally administered.
tested for reducing neuroinflammation and consequent improvement
in dyskinesia. Small molecule drugs targeting regeneration use neuro-
trophic factors to protect and repair neurons. We also included the 5.3 | Delivery vehicle
category Multiple for clinical trial therapies that intervened via more
than one of the seven approaches. Pleiotropic therapeutics such as Figures 5c and 6c, respectively, show the distribution of delivery vehi-
stem cells fall in the category of multiple, as these therapeutics often cles utilized by active and past trials. “Drug” therapies are mostly
exert multiple effects in concert such as regeneration, anti-apoptosis, administered freely without a carrier. Extended-release micro/nano
and neurotransmitter production. The therapy mechanism Other for particles are also utilized for the continuous delivery of small molecule
PD include therapies that modulate the microbiome, opioid receptors, drugs such as rotigotine, prolonging the effects of the therapy and
hormones such as through antidiuretics, or metabolism. providing sustained improvements in symptoms. Compared to “Drug”
Similar to AD, there is an increased diversity in “Biologic” therapy therapies, “Biologic” therapies leverage more diverse drug delivery
mechanisms in active clinical trials. Anti-aggregation is a popular vehicles. Many “Biologic” therapies have cellular delivery vehicles,
mechanism of action employed by several recent “Biologic” therapies which include therapies utilizing stem cells that will differentiate into
such as UB-312 and Affitope PD01A, which are focused on prevent- dopaminergic neurons. “Biologic” genetic therapies utilize non-
ing Lewy body formation in dopaminergic neurons to prevent their pathogenic viral vectors to transfer healthy copies of genes to the
degeneration.105 Anti-inflammatory therapies such as Exenatide are patient. However, very few “biologic” therapies use microparticles or
currently investigated for their potential to reduce dopaminergic neu- nanoparticles to deliver the therapy, suggesting an area in need of fur-
ron degeneration. Many past and active “Biologic” clinical trials have ther development. The vast majority of past and active clinical trials
utilized Regeneration based therapies. Dopaminergic neurogenesis is across therapy types did not use a delivery vehicle, revealing the
a key goal of these therapies, with many trials employing stem cells untapped potential of using delivery vehicles to optimize efficacy of
which can differentiate into dopaminergic neurons. A significant pro- PD treatment (see Section 6.4 for a more detailed discussion).
portion of Regeneration therapies also test the utility of neurotrophic
factors such as GDNF and neurturin to protect dopaminergic neuron
end terminals.105 “Biologic” therapies also targeted NTS, with 50% of 5.4 | Outcome measures
these targeting dopamine and the remaining 50% targeting ACh.
Overall, there is a clear dominance of NTS therapies across past Figures 5d and 6d, respectively, show outcome measure used to
and active trials. Interestingly, the only exception to this is the active determine success of the therapy across active and past trials. Most
phase 1 trials, which are dominated by Anti-aggregation therapies. of the “Biologic” therapies (which tended to be in early clinical trial
We also see an interesting paradigm shift in the diversity of therapy phases) were being monitored for safety, measuring the occurrence
mechanisms leveraged by “Biologics.” Anti-aggregation, NTS, and TEAEs, or vital sign abnormalities. “Biologic” therapies in phase
Anti-inflammatory therapies in phase 1, which were once dominated 2, mostly NTS and Anti-aggregation therapies, are dominantly evalu-
by small molecule drugs are now completely driven by biologics. The ated for changes in motor symptoms. In contrast, the more estab-
eventual outcome of these promising changes are eagerly awaited. lished “Drug” therapies were being evaluated for improvements in
motor and nonmotor symptoms, commonly using Movement Disor-
ders Society-Unified Parkinson's Disease Rating Scale scores to evalu-
5.2 | Administration route ate efficacy. Other common outcome measures include drug
pharmacokinetics, which is usually obtained via plasma drug concen-
Figure 5b and 6b respectively show the administration routes utilized tration measurements in patients at various intervals, daytime sleepi-
by active and past trials. Overall, there are no significant changes in ness, which is usually evaluated using the Epworth Sleepiness Scale,
the diverse administration routes employed by past and present clini- and pain intensity, which is usually measured using the Visual Analog
cal trials, with oral administration still being the preferred route. The Scale.110 Biochemical outcomes including hematology measures such
vast majority of drug therapies (78%) are delivered orally in the form as basophils to leukocytes ratio, eosinophils to leukocytes ratio, lym-
of tablets, increasing ease for patients to independently administer phocytes to leukocytes ratio, and reticulocytes to erythrocytes ratio
the therapy. A notable fraction of small molecules (12%), especially are also utilized in PD trials.
F I G U R E 7 Clinical outcomes based on therapy mechanism for “Drug” and “Biologic” trials. Success and termination percentiles for (a) AD
and (b) PD clinical trials. A total of 375 out of 769 AD past trials have reported results (either through clinical trials.gov or via supported
publications), whereas 213 out of 740 past PD trials have reported results. The numbers on top of the bars indicate the total number of trials
represented by the bar. AD, Alzheimer's disease; PD, Parkinson's disease
6 | INTERSECTIONS IN CLINICAL publications), whereas 213 out of 740 past PD trials have reported
APPROACHES results. NTS “Drug” clinical trial outcomes for AD and PD reveal simi-
larities with the lowest success rate in phase 2 compared to that of
Despite different etiology of disease for AD and PD, these neurodegen- phases 1 and 3. This is also expected from broad clinical trial success
erative diseases have parallel roots of potential causes of disease onset. rates over the last couple of decades.116–118 However, there are devi-
While AD primarily affects cognitive function and PD primarily affects ations from this expected trend for some other therapy mechanisms
motor function, there are at times a partial overlap in symptoms across for “Drug” and “Biologic” trials. One potential reason for deviations is
the two neurodegenerative diseases, with interrelated pathologenesis as the limited number of clinical trials with reported results for these
well. Both AD and PD are afflicted with protein aggregates, whether other categories. This is especially apparent for categories with 100%
Aβ, tau,8
or α-synuclein,35
dysregulation of NTSs, 63,104,105
neuronal success or 100% failure rate, where <5 clinical trials account for the
death,105,111 inflammation,37,112 oxidative stress,42,113 and excitotoxi- percentile. It is also worth noting a large number of trials also evaluate
city.114,115 Furthermore, similar therapies utilizing memantine hydrochlo- repurposed FDA-approved drugs, which often enter the clinical gaunt-
ride, or cholinergic, dopaminergic, and serotonergic system modulators let at phase 2 or higher. This is the reason for the absence of phase
are explored for both neurodegenerative diseases. As a result, there is a 1 data for PD Anti-excitotocity category. Nonetheless, this analysis
meaningful overlap in the therapeutic approaches and strategies lever- reveals several interesting trends.
aged to treat these diseases (Figure 8a). In the next section, we critically Anti-aggregation clinical studies for AD exhibit a high failure rate
evaluate the success rate of past clinical trials and three emerging of >80% for “Drug” and “Biologic” candidates. Potential explanations
aspects relevant to the AD-PD clinical intersection. include targeting the wrong pathological substrates, administering
treatment too late in disease progression, and other issues as dis-
cussed by Mehta et al.119 Anti-inflammatory “Drug” candidates for
6.1 | Clinical outcomes based on therapy both AD and PD exhibited greater than 80% and 100% failure in
mechanisms phase 3, respectively, which may also possibly be attributed to AD/PD
treatment window. The lone successful phase 3 trial of an anti-
Figure 7 displays the percentiles of successful and terminated clinical inflammatory agent targeting AD is antibiotic Doxycycline, which
studies based on therapy mechanism for past “Drug” and “Biologic” showed promising results,120 but is not yet an approved therapy. The
clinical trials (2001–2020). A total of 375 out of 769 AD past trials apparent success of anti-oxidant therapies for AD stem from investi-
have reported results (either through clinicaltrials.gov or via related gation of vitamin E121 or combination of vitamin E and memantine.
F I G U R E 8 Clinical intersections in the treatment of AD and PD. (a) Alluvial plot showing the intersections in the therapy mechanisms and
drug delivery vehicles. Circular bar charts showing the distribution of clinical trials across the six most common (b) therapy mechanisms and
(c) “Biologic” therapy types over 5-year bins, encompassing all trials that were completed or terminated during that period of time. The radial axis
denotes percentage of total number of AD and PD trials present in a 5-year bin. Note that the completion year was used to date the trials. AD,
Alzheimer's disease; PD, Parkinson's disease
Anti-oxidant therapies, however, have not been successful for tackling 6.2 | The evolving landscape of therapeutic
PD. Furthermore, “Biologic” trials outperformed “Drug” trials in terms mechanisms of disease intervention
of percentile success across all therapy types and mechanisms. This is
notable in the case of PD NTS therapies where protein/peptide based Both AD and PD clinical trials have exhibited a shift in distribution
“Biologic” therapies (e.g., Rimabotulinumtoxinb) have enjoyed consid- away from the predominant NTS therapeutic mechanism approaches
erable success. While “Drug” candidates have not surpassed the clini- to a more varied distribution of therapeutic interventions. This trend
cal trial barrier for curative treatments, “Biologic” therapies offer is most notable and consistent since 2011–2015 until the present.
potential for achieving neuroprotection beyond symptomatic Considering NTS therapies solely manage the symptoms of AD and
improvement. PD, the growth of clinical trials exploring alternative therapeutic
mechanism approaches illustrates researchers' and clinicians' attempts AD, and 3% to 4% to 8% for PD, and Gene therapy trials increased
to combat potential root causes of neurodegenerative diseases to from 1% to 0% to 3% for AD, and 1% to 2% to 3% for PD from 2011–
inhibit disease progression. 2015 to 2016–2020 to present. Interestingly, Natural product “Bio-
There has been widespread investment in cholinergic system logic” therapies exhibited a sharp decrease in percentage after 2005
modulation and anti-Aβ strategies without fruition of a therapeutic for AD and after 2020 for PD clinical trials. Proteins/peptides-based
that effectively mitigates AD progression. Altogether, NTS therapies “Biologic” therapies (note that antibodies are categorized separately)
accounted for 33% of past clinical trials for AD, dominating as the have also gradually decreased in the total percentage of “Biologic”
most common therapy mechanism in all phases (Figure 4a). Mean- clinical trials. Besides, the prevalence of exploring Antibody therapeu-
while, Anti-aggregation approaches increased from 2001–2005 to tics against AD, the shifts in distribution of “Biologic” candidates
2006–2010, and have since remained relatively constant from 2011 being investigated is largely parallel for both AD and PD.
to present (Figure 8b). However, the future is uncertain as to whether
Anti-aggregation approaches will gain or lose popularity as the amy-
loid hypothesis is being carefully scrutinized and alternative hypothe- 6.4 | Leveraging drug delivery vehicles for clinical
ses are explored.13 Reflective of the field's shift in encouraging translation
exploration of alternative therapeutic intervention strategies for AD
treatment, there is an expansion of therapy mechanism approaches Figure 8a presents an alluvial flow diagram that illustrates the distribu-
among currently active clinical trials. The percent of NTS clinical trials tion of clinical trials for AD and PD intervening via the categorized
has reduced over time, while Regeneration, Anti-excitotoxicity, and therapy mechanisms, and additionally ties these trials to the delivery
Anti-inflammatory therapy clinical trials have increased since 2011– vehicle leveraged. Despite drug delivery technologies being heavily
2015 (Figure 8b). These trends are further illustrated in Figure 3a, researched for the past several decades, it is evident that delivery
where Anti-inflammatory and Anti-excitotoxicity therapies occupy the vehicles are underutilized for clinical translation for both AD and
greatest percentage of clinical trials for phase 1, 2, and 4 clinical trials, PD. Clinical trials utilizing delivery vehicles only account for 1.07%
respectively. In combination with lack of clinical success of Anti- and 4.99% of AD and PD clinical trials, respectively. There is a clinical
aggregation and NTS approaches beyond symptomatic relief, expan- need for additional research into the optimization and compatibility of
sion of the fields of cell therapy for anti-inflammation and regenera- delivery vehicles for neurodegeneration therapies. Delivery vehicles
tion with stem cells,122,123 and critical re-examination of excitotoxicity have the potential to increase the efficacy and efficiency of both
and targeting NMDARs after the successes of memantine and rilu- existing and future AD and PD therapies.
zole124 have contributed to the broadening of therapeutic clinical Achieving target site-specific accumulation of therapeutics is
approaches for neurodegenerative diseases. Meanwhile, to a lesser cumbersome, especially for neurological diseases given the multiple
extent, NTS trials for PD have also decreased since 2011–2015. The biological barriers such as the BBB and intraparenchymal diffusion.125
breadth of therapeutic mechanism approaches combating PD has also Advanced drug delivery vehicles of synthetic or biological nature may
expanded as Anti-aggregation, Anti-inflammatory, Anti-oxidant, and improve upon previously and currently explored therapeutics to pro-
Regeneration clinical trials have increased since 2011–2015. Notably, vide greater accumulation in the brain to achieve therapeutic efficacy
in a shift reminiscent of the AD clinical landscape, the active phase with reduced peripheral side effects.
1 trials of PD are dominated by Anti-aggregation therapies (Figure 5a). The lack of a carrier severely limits the types of drugs that can
cross the BBB, where more than 98% of small molecules and essen-
tially 100% of biologics are incapable of bypassing an intact BBB.126
6.3 | The evolving distribution of biologic Drug delivery vehicles may improve brain targeting and expand the
therapeutics types of therapeutics that can achieve brain accumulation, which is
naturally limited to small hydrophobic molecules.73,127 For example,
“Biologic” therapies are becoming more prevalent in clinical trials for nanoparticle vehicle surface conjugation or direct modification of bio-
both AD and PD as evidenced in recent years and especially for cur- logics with BBB-targeting antibodies can leverage receptor mediated
rently active phase 1, 2, and 3 clinical trials. Figure 8c displays the per- transcytosis across the BBB via transferrin, low-density lipoprotein
centage of each type of “Biologic” used for AD and PD. The majority (LDL), and insulin receptors.128,129 Drug incorporation into carriers
of Antibody therapy types are monoclonal antibodies targeting Aβ or also reduces systemic drug clearance and extends drug half-life,130
tau for AD, and targeting α-synuclein for PD. For AD, the investiga- increasing the opportunity for brain accumulation. In addition to fur-
tion of antibodies has remained relatively stable over the last ther extending carrier half-life,131 carrier surface functionalization
20 years, constituting (35%) of “Biologic” therapies. On the other with low affinity materials such as polyethylene glycol can also
hand, Antibody approaches are gaining popularity in PD clinical trials, enhance diffusive ability, enabling the therapeutic to achieve a wider
with percentage of trials doubling from 2011–2015 to 2016–2020, volume of distribution.132 Carrier shape can also affect neurovascular
and then tripling from 2016–2020 to currently active clinical trials. adhesion, as demonstrated by increased brain accumulation of rod-
Cell therapy and Gene therapy “Biologic” therapies have undergone a shaped compared to spherical nanoparticles.133,134 Furthermore,
similar trend. Cell therapy trials increased from 1% to 4% to 11% for many free drugs that manage to cross the BBB are often readily
ejected out of the brain parenchyma by several active efflux trans- (EVs), also known as exosomes or microvesicles depending on size, as
porters including the P-glycoprotein, ATP binding cassette, multidrug biomarkers of disease progression in AD and PD.146,147 EVs from vari-
resistance-associated proteins, and breast cancer resistance proteins ous donor cell origins are also being explored as potential therapeutics
(BCRP).135,136 After entering the brain parenchyma, carriers may due to their complex roles in cell-to-cell communication, and ability to
shield their drug cargo from efflux transporters expressed on the cross the BBB and carry therapeutic cargo.148,149 EVs derived from
abluminal brain endothelium, reducing efflux transport out of the MSCs are of special interest as therapeutic carriers.150 EVs from
brain. Furthermore, cell therapies can deliver therapeutics or them- human teeth stem cells administered intranasally indeed reduced gait
selves act as the therapeutic137 and capitalize on intrinsic chemotactic impairments in a 6-hydroxydopamine (6-OHDA) rat model of PD.151
capabilities to achieve targeted accumulation at injured brain regions With the growing burden of AD and PD with no effective cures yet,
following neuroinflammatory chemokine gradients.138 novelty and innovation in therapeutic mechanism and delivery
One of the challenges in translating drug delivery vehicle strate- approaches is crucial to bringing effective treatments for neurodegen-
gies to the clinic include an increased number of components for the erative diseases to market.
therapeutic, which increases the regulatory hurdles for FDA approval.
Delivery vehicles may also potentially involve more complexity leading
to increased costs for manufacturing, involving multiple biomaterials 8 | CON C LU SION AN D OUT LO OK
and synthesis or conjugation steps. Developing cell biologics also
entails additional considerations adding to production complexity, Clinicaltrials.gov has a wealth of information for gaining insight into
such as obtaining cells from autologous versus allogeneic sources and the clinical frontier of any given disease. By meticulously organizing
ex vivo cell culturing and modification. Nevertheless, considering the data for AD and PD clinical trials, we have generated figures that
there are no currently approved therapeutics that mitigate or stop succinctly provide information about these clinical trials across differ-
neurodegeneration, the benefits of applying these novel delivery ent clinical phases, therapy types, and time. This has enabled the illus-
approaches may still outweigh the challenges towards translation. tration of meaningful trends in clinical trials over the years regarding
Furthermore, if these advanced drug delivery strategies prove suc- the therapy mechanism of intervention, distribution of “Biologic” ther-
cessful, future manufacturing optimization and innovation could make apies explored, and growth of advanced drug delivery strategies.
these therapeutics more competitive for widespread treatment of Although the scientific community has come a long way in terms of
neurodegenerative diseases. Fortunately, there is a growing percent- symptomatic management of AD and PD, therapeutic innovation in
age of trials utilizing delivery vehicles in phase 1 and 2 for both AD the field is branching into new directions to tackle root causes of dis-
and PD among active clinical trials compared to past clinical trials ease progression. Notably, Anti-aggregation therapies are taking over
(Figures 3c, 4c, 5c, and 6c), indicating increased adoption of drug NTS therapies as the most common therapy mechanism. This is
delivery strategies. expected for AD but is also interestingly concurrently happening for
PD. There is also a growing number of AD and PD clinical trials that
are utilizing Anti-inflammatory, Anti-oxidant, and Regeneration strate-
7 | NOVEL PRECLINICAL STRATEGIES FOR gies since 2011. The types of “Biologic” therapies used in the clinical
AD/PD TREATMENT frontier is also changing, with consistent use of Antibody-, reduction
of Natural product-, and proteins/peptides-based therapies, and
In addition to the expansion of using viral vectors and cell therapy increases in Cell therapy and Gene therapy approaches. There is also
including stem cells and various immune cells, there are other exciting a growth in the use of delivery vehicles, although they are still heavily
strategies that are in their infancy of preclinical studies or barely underutilized. Currently, many of the clinical trials investigating alter-
entering clinical trials. One such strategy is the development of neuro- native therapeutic mechanism targets, types of “Biologic” therapies,
degeneration vaccines, where the immune system is primed against and utilization of carriers are currently in phase 1 and 2 trials. The
Aβ or tau in AD,139 and against alpha-synuclein in PD.140 Beyond con- upcoming decades will bring many exciting advances as we witness
ventional antigen/adjuvant strategies, Fessel imagines an mRNA vac- which clinical trials survive running the clinical trial gauntlet to gener-
141
cine strategy for AD, where mRNA self-amplifies Aβ production. ate novel effective therapies on the market that can finally inhibit or
However, the efficacy and safety, in regards to autoimmunity, possibly even cure AD and PD progression.
increased inflammation, and prematurely causing AD, has yet to be
evaluated.141 With promise of CRISPR/Cas9 intervention in Hunting- AUTHOR CONTRIBU TIONS
ton's disease, there is also exploration of CRISPR application in AD Puja Chopade: Data curation (equal); formal analysis (equal); investiga-
and PD.142,143 CRISPR/Cas9 edited sRAGE-MSCs reduced neuronal tion (equal); methodology (equal); writing – original draft (equal). Neha
death and improved movement in a rotenone-induced PD mouse Chopade: Data curation (equal); formal analysis (equal); investigation
model.144 Gyorgy et al. demonstrated deletion of APP Swedish muta- (equal); methodology (equal); writing – original draft (equal). Zongmin
tion with CRISPR/Cas9 adeno-associated viral vectors to reduce Aβ Zhao: Writing – review and editing (equal). Samir Mitragotri: Concep-
levels in transgenic mice overexpressing APP Swedish mutation.145 tualization (equal); resources (equal); supervision (equal); writing –
Another growing field of research is the role of extracellular vesicles review and editing (equal). Rick Liao: Conceptualization (lead); data
curation (equal); formal analysis (equal); investigation (equal); method- 17. Uslaner JM, Herring WJ, Coleman PJ. The discovery of suvorexant:
ology (equal); supervision (equal); validation (equal); visualization lessons learned that can be applied to other CNS drug development
efforts. ACS Pharmacol Transl Sci. 2020;3(1):161-168.
(lead); writing – original draft (lead). Vineeth Chandran Suja: Concep-
18. Dunn B, Stein P, Cavazzoni P. Approval of aducanumab for Alzhei-
tualization (lead); data curation (equal); formal analysis (equal); investi- mer disease—the FDA's perspective. JAMA Intern Med. 2021;
gation (equal); methodology (equal); supervision (equal); validation 181(10):1276-1278.
(equal); visualization (lead); writing – original draft (lead). 19. Padda IS, Parmar M. Aducanumab. StatPearls [Internet]. StatPearls
Publishing; 2021.
20. Salloway S, Chalkias S, Barkhof F, et al. Amyloid-related imaging
CONF LICT OF IN TE RE ST abnormalities in 2 phase 3 studies evaluating aducanumab in
The authors declare that they have no competing interests. patients with early Alzheimer disease. JAMA Neurol. 2022;79(1):
13-21.
21. Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab
DATA AVAI LAB ILITY S TATEMENT
reduces aβ plaques in Alzheimer's disease. Nature. 2016;537(7618):
All data generated or analyzed during this study are included in this 50-56.
published article. 22. Lalli G, Schott JM, Hardy J, De Strooper B. Aducanumab: a new
phase in therapeutic development for Alzheimer's disease? EMBO
Mol Med. 2021;13(8):e14781.
ORCID
23. Kriebel-Gasparro A. Parkinson's disease: update on medication man-
Zongmin Zhao https://orcid.org/0000-0001-8979-844X
agement. J Nurse Pract. 2016;12(3):e81-e89.
Samir Mitragotri https://orcid.org/0000-0002-2459-8305 24. Wilson SM, Wurst MG, Whatley MF, Daniels RN. Classics in chemi-
Rick Liao https://orcid.org/0000-0002-4780-161X cal neuroscience: pramipexole. ACS Chem Neurosci. 2020;11(17):
Vineeth Chandran Suja https://orcid.org/0000-0002-3406-7655 2506-2512.
25. Ondo WG, Shinawi L, Moore S. Comparison of orally dissolving
carbidopa/levodopa (Parcopa) to conventional oral carbidopa/levo-
RE FE R ENC E S dopa: a single-dose, double-blind, double-dummy, placebo-con-
1. Alzheimer's Association et al. 2010 Alzheimer's disease facts and fig- trolled, crossover trial. Mov Disord. 2010;25(16):2724-2727.
ures. Alzheimers Dement. 2010;6(2):158-194. 26. Frampton JE. Rotigotine transdermal patch: a review in Parkinson's
2. Yang W, Hamilton JL, Kopil C, et al. Current and projected future disease. CNS Drugs. 2019;33(7):707-718.
economic burden of Parkinson's disease in the US. NPJ Parkinsons 27. Hansen CA, Miller DR, Annarumma S, Rusch CT, Ramirez-Zamora A,
Dis. 2020;6(1):1-9. Khoshbouei H. Levodopa-induced dyskinesia: a historical review of
3. Wong W. Economic burden of Alzheimer disease and managed care Parkinson's disease, dopamine, and modern advancements in
considerations. Am J Manag Care. 2020;26(8 Suppl):S177-S183. research and treatment. J Neurol. 2022;269:1-18.
4. Rocca WA. The burden of Parkinson's disease: a worldwide perspec- 28. Cruz MP. Xadago (safinamide): a monoamine oxidase B inhibitor for
tive. Lancet Neurol. 2018;17(11):928-929. the adjunct treatment of motor symptoms in Parkinson's disease.
5. GBD 2019 Dementia Forecasting Collaborators et al. Estimation of Pharm Ther. 2017;42(10):622.
the global prevalence of dementia in 2019 and forecasted preva- 29. Paik J, Keam SJ. Amantadine extended-release (GOCOVRI™): a
lence in 2050: an analysis for the global burden of disease study review in levodopa-induced dyskinesia in Parkinson's disease. CNS
2019. Lancet Public Health. 2022;7(2):E105-E125. Drugs. 2018;32(8):797-806.
6. Anderson ML, Chiswell K, Peterson ED, Tasneem A, Topping J, 30. Lipp MM, Hickey AJ, Langer R, LeWitt PA. A technology evaluation
Califf RM. Compliance with results reporting at ClinicalTrials.gov. N of CVT-301 (inbrija): an inhalable therapy for treatment of Parkin-
Engl J Med. 2015;372(11):1031-1039. son's disease. Expert Opin Drug Deliv. 2021;18(11):1559-1569.
7. Sabuncu MR, Desikan RS, Sepulcre J, et al. The dynamics of cortical 31. Aradi SD, Hauser RA. Medical management and prevention of motor
and hippocampal atrophy in Alzheimer disease. Arch Neurol. 2011; complications in Parkinson's disease. Neurotherapeutics. 2020;17(4):
68(8):1040-1048. 1339-1365.
8. Bloom GS. Amyloid-β and tau: the trigger and bullet in Alzheimer dis- 32. McFarthing K, Buff S, Rafaloff G, Dominey T, Wyse RK, Stott SR.
ease pathogenesis. JAMA Neurol. 2014;71(4):505-508. Parkinson's disease drug therapies in the clinical trial pipeline: 2020.
9. Avila J. Intracellular and extracellular tau. Front Neurosci. 2010;4:49. J Parkinsons Dis. 2020;10(3):757-774.
10. Du X, Wang X, Geng M. Alzheimer's disease hypothesis and related 33. St. Onge E, Vanderhoof M, Miller S. Opicapone (ongentys): a new
therapies. Transl Neurodegener. 2018;7(1):1-7. COMT inhibitor for the treatment of Parkinson's disease. Ann Phar-
11. Esposito Z, Belli L, Toniolo S, Sancesario G, Bianconi C, Martorana A. macother. 2021;55(9):1159-1166.
Amyloid β, glutamate, excitotoxicity in Alzheimer's disease: are we 34. Agbo F, Isaacson SH, Gil R, et al. Pharmacokinetics and comparative
on the right track? CNS Neurosci Ther. 2013;19(8):549-555. bioavailability of apomorphine sublingual film and subcutaneous
12. Herrup K. The case for rejecting the amyloid cascade hypothesis. apomorphine formulations in patients with Parkinson's disease and
Nat Neurosci. 2015;18(6):794-799. “OFF” episodes: results of a randomized, three-way crossover,
13. Makin S. The amyloid hypothesis on trial. Nature. 2018;559(7715): open-label study. Neurol Ther. 2021;10(2):693-709.
S4-S7. 35. Martin LJ, Pan Y, Price AC, et al. Parkinson's disease α-synuclein
14. Sperling RA, Rentz DM, Johnson KA, et al. The A4 study: stopping transgenic mice develop neuronal mitochondrial degeneration and
AD before symptoms begin? Sci Transl Med. 2014;6(228):228fs13. cell death. J Neurosci. 2006;26(1):41-50.
15. Marucci G, Buccioni M, Dal Ben D, Lambertucci C, Volpini R, 36. Reddy AP, Ravichandran J, Carkaci-Salli N. Neural regeneration ther-
Amenta F. Efficacy of acetylcholinesterase inhibitors in Alzheimer's apies for Alzheimer's and Parkinson's disease-related disorders. Bio-
disease. Neuropharmacology. 2021;190:108352. chim Biophys Acta - Mol Basis Dis. 2020;1866(4):165506.
16. Robinson DM, Keating GM. Memantine. Memantine Drugs. 2006; 37. Hirsch EC, Vyas S, Hunot S. Neuroinflammation in Parkinson's dis-
66(11):1515-1534. ease. Parkinsonism Relat Disord. 2012;18:S210-S212.
38. Wang Q, Liu Y, Zhou J. Neuroinflammation in Parkinson's disease Alzheimer's disease including agitation. Expert Opin Pharmacother.
and its potential as therapeutic target. Transl Neurodegener. 2015; 2021;22(7):783-795.
4(1):1-9. 60. Reading CL, Ahlem CN, Murphy MF. NM101 phase III study of
39. Bose A, Beal MF. Mitochondrial dysfunction in Parkinson's disease. NE3107 in Alzheimer's disease: rationale, design and therapeutic
J Neurochem. 2016;139:216-231. modulation of neuroinflammation and insulin resistance. Neurodege-
40. Abou-Sleiman PM, Muqit MM, Wood NW. Expanding insights of ner Dis Manag. 2021;11(4):289-298.
mitochondrial dysfunction in Parkinson's disease. Nat Rev Neurosci. 61. Liao R, Wood TR, Nance E. Superoxide dismutase reduces monoso-
2006;7(3):207-219. dium glutamate-induced injury in an organotypic whole hemisphere
41. Exner N, Lutz AK, Haass C, Winklhofer KF. Mitochondrial dysfunc- brain slice model of excitotoxicity. J Biol Eng. 2020;14(1):1-12.
tion in Parkinson's disease: molecular mechanisms and pathophysio- 62. Akıncıo glu H, Gülçin _I. Potent acetylcholinesterase inhibitors: poten-
logical consequences. EMBO J. 2012;31(14):3038-3062. tial drugs for Alzheimer's disease. Mini Rev Med Chem. 2020;20(8):
42. Henchcliffe C, Beal MF. Mitochondrial biology and oxidative stress 703-715.
in Parkinson disease pathogenesis. Nat Clin Pract Neurol. 2008;4(11): 63. Martorana A, Koch G. Is dopamine involved in Alzheimer's disease?
600-609. Front Aging Neurosci. 2014;6:252.
43. Olanow CW, Prusiner SB. Is Parkinson's disease a prion disorder? 64. Espay AJ, Vizcarra JA, Marsili L, et al. Revisiting protein aggregation
Proc Natl Acad Sci. 2009;106(31):12571-12572. as pathogenic in sporadic Parkinson and Alzheimer diseases. Neurol-
44. Klein C, Westenberger A. Genetics of Parkinson's disease. Cold ogy. 2019;92(7):329-337.
Spring Harb Perspect Med. 2012;2(1):a008888. 65. Das B, Yan R. A close look at BACE1 inhibitors for Alzheimer's dis-
45. Lopez A, Munoz A, Guerra M, Labandeira-Garcia J. Mechanisms of ease treatment. CNS Drugs. 2019;33(3):251-263.
the effects of exogenous levodopa on the dopamine-denervated 66. Martone RL, Zhou H, Atchison K, et al. Begacestat (GSI-953): a
striatum. Neuroscience. 2001;103(3):639-651. novel, selective thiophene sulfonamide inhibitor of amyloid precur-
46. Lieberman A, Goodgold A, Jonas S, Leibowitz M. Comparison of sor protein γ-secretase for the treatment of Alzheimer's disease.
dopa decarboxylase inhibitor (carbidopa) combined with levodopa J Pharmacol Exp Ther. 2009;331(2):598-608.
and levodopa alone in Parkinson's disease. Neurology. 1975;25(10): 67. Ramassamy C, Longpre F, Christen Y. Ginkgo biloba extract (EGb
911-916. 761) in Alzheimer's disease: is there any evidence? Curr Alzheimer
47. Müller T. Catechol-O-methyltransferase inhibitors in Parkinson's dis- Res. 2007;4(3):253-262.
ease. Drugs. 2015;75(2):157-174. 68. Nathan P. Can the cognitive enhancing effects of ginkgo biloba be
48. Brooks D. Dopamine agonists: their role in the treatment of Parkin- explained by its pharmacology? Med Hypotheses. 2000;55(6):
son's disease. J Neurol Neurosurg Psychiatry. 2000;68(6):685-689. 491-493.
49. Fernandez HH, Chen JJ. Monoamine oxidase-B inhibition in the 69. Shimohama S. Apoptosis in Alzheimer's disease—an update. Apopto-
treatment of Parkinson's disease. Pharmacotherapy. 2007;27(12 Pt sis. 2000;5(1):9-16.
2):174S-185S. 70. Tanzi RE. Caspases land on APP: one small step for apoptosis, one
50. MW MS. FDA places gene therapy LX1001 on fast track. Alzheimer's giant leap for amyloidosis? Nat Neurosci. 1999;2(7):585-586.
News Today. 2021. https://alzheimersnewstoday.com/2021/05/03/ 71. Obulesu M, Lakshmi MJ. Apoptosis in Alzheimer's disease: an under-
gene-therapy-lx1001-placed-on-fda-fast-track-designation/ standing of the physiology, pathology and therapeutic avenues. Neu-
51. Dhimolea E. Canakinumab. MAbs. Vol 2. Taylor & Francis; 2010: rochem Res. 2014;39(12):2301-2312.
3-13. 72. Copani A, Melchiorri D, Caricasole A, et al. β-Amyloid-induced syn-
52. Guo M, Yin Z, Chen F, Lei P. Mesenchymal stem cell-derived exo- thesis of the ganglioside GD3 is a requisite for cell cycle reactivation
some: a promising alternative in the therapy of Alzheimer's disease. and apoptosis in neurons. J Neurosci. 2002;22(10):3963-3968.
Alzheimers Res Ther. 2020;12(1):1-14. 73. Liao R, Wood TR, Nance E. Nanotherapeutic modulation of excito-
53. Ji C, Sigurdsson EM. Current status of clinical trials on tau immuno- toxicity and oxidative stress in acute brain injury. Nanobiomedicine
therapies. Drugs. 2021;81(10):1135-1152. (Rij). 2020;7:1849543520970819.
54. Lacosta AM, Pascual-Lucas M, Pesini P, et al. Safety, tolerability and 74. Mattson MP. Excitotoxic and excitoprotective mechanisms. Neuro-
immunogenicity of an active anti-aβ40 vaccine (ABvac40) in patients Molecular Med. 2003;3(2):65-94.
with Alzheimer's disease: a randomised, double-blind, placebo-con- 75. Wood PL. NMDA antagonists for stroke and head trauma: current
trolled, phase I trial. Alzheimers Res Ther. 2018;10(1):1-13. status. Expert Opin Investig Drugs. 1998;7(9):1505-1508.
55. Grundman M, Morgan R, Lickliter JD, et al. A phase 1 clinical trial of 76. Chen HSV, Lipton SA. The chemical biology of clinically tolerated
the sigma-2 receptor complex allosteric antagonist CT1812, a novel NMDA receptor antagonists. J Neurochem. 2006;97(6):1611-1626.
therapeutic candidate for Alzheimer's disease. Alzheimers Dement 77. Chen HS, Wang Y, Rayudu P, et al. Neuroprotective concentrations
Transl Res Clin Interv. 2019;5:20-26. of the N-methyl-D-aspartate open-channel blocker memantine are
56. Vossel K, Ranasinghe KG, Beagle AJ, et al. Effect of levetiracetam on effective without cytoplasmic vacuolation following post-ischemic
cognition in patients with Alzheimer disease with and without epi- administration and do not block maze learning or long-term potenti-
leptiform activity: a randomized clinical trial. JAMA Neurol. 2021; ation. Neuroscience. 1998;86(4):1121-1132.
78(11):1345-1354. 78. Olivares D, Deshpande VK, Shi Y, et al. N-methyl-D-aspartate
57. Abou-Khalil B. Levetiracetam in the treatment of epilepsy. Neuropsy- (NMDA) receptor antagonists and memantine treatment for Alzhei-
chiatr Dis Treat. 2008;4(3):507-523. mer's disease, vascular dementia and Parkinson's disease. Curr Alz-
58. Henderson ST, Walker J, Gold M, Morimoto B, Greer S, Davis CS. heimer Res. 2012;9(6):746-758.
P4-211: investigational new Alzheimer's drug tricaprilin: possible 79. Akiyama H, Barger S, Barnum S, et al. Inflammation and Alzheimer's
effects of APOEε4 non-carrier selection and site effects on study disease. Neurobiol Aging. 2000;21(3):383-421.
outcomes in a phase 2/3 study in mild-to-moderate Alzheimer's dis- 80. Blasko I, Veerhuis R, Stampfer-Kountchev M, Saurwein-Teissl M,
ease patients. Alzheimers Dement. 2018;14(7S Part 29):P1521- Eikelenboom P, Grubeck-Loebenstein B. Costimulatory effects of
P1522. interferon-γ and interleukin-1β or tumor necrosis factor α on the
59. Khoury R, Marx C, Mirgati S, Velury D, Chakkamparambil B, synthesis of aβ1–40 and aβ1–42 by human astrocytes. Neurobiol
Grossberg GT. AVP-786 as a promising treatment option for Dis. 2000;7(6):682-689.
81. Heneka MT, Carson MJ, El Khoury J, et al. Neuroinflammation in 102. Genius J, Dastros-Pitei D, Detalle L, et al. Results from a phase 1b
Alzheimer's disease. Lancet Neurol. 2015;14(4):388-405. study of UCB0599, an orally available, brain-penetrant inhibitor of
82. Ozben T, Ozben S. Neuro-inflammation and anti-inflammatory treat- alphasynuclein (ASYN) misfolding in people living with Parkinson's
ment options for Alzheimer's disease. Clin Biochem. 2019;72:87-89. disease (PD) (2025). Neurology. 2021;96(15 Suppl): 2025.
83. Szekely C, Green R, Breitner JC, et al. No advantage of aβ42-lower- 103. Prakash N, McFarthing K, Simuni T. Clinical trial highlights—infusion
ing NSAIDs for prevention of Alzheimer dementia in six pooled therapies. J Parkinsons Dis. 2020;10(1):5-17.
cohort studies. Neurology. 2008;70(24):2291-2298. 104. Wilson H, Giordano B, Turkheimer FE, Chaudhuri KR, Politis M.
84. Frank B, Gupta S. A review of antioxidants and Alzheimer's disease. Serotonergic dysregulation is linked to sleep problems in Parkinson's
Ann Clin Psychiatry. 2005;17(4):269-286. disease. NeuroImage Clin. 2018;18:630-637.
85. Kamat CD, Gadal S, Mhatre M, Williamson KS, Pye QN, Hensley K. 105. Elkouzi A, Vedam-Mai V, Eisinger RS, Okun MS. Emerging therapies
Antioxidants in central nervous system diseases: preclinical promise in Parkinson disease—repurposed drugs and new approaches. Nat
and translational challenges. J Alzheimers Dis. 2008;15(3):473-493. Rev Neurol. 2019;15(4):204-223.
86. Bowry VW, Stocker R. Tocopherol-mediated peroxidation. The 106. Zeuner KE, Schäffer E, Hopfner F, Brüggemann N, Berg D. Progress
prooxidant effect of vitamin e on the radical-initiated oxidation of of pharmacological approaches in Parkinson's disease. Clin Pharma-
human low-density lipoprotein. J Am Chem Soc. 1993;115(14):6029- col Ther. 2019;105(5):1106-1120.
6044. 107. Hashmi RN, Kiram U. Disease modification trials in Parkinsons dis-
87. Dumont M, Lin MT, Beal MF. Mitochondria and antioxidant targeted ease: a review. Pak J Neurol Sci. 2020;15(3):42-59.
therapeutic strategies for Alzheimer's disease. J Alzheimers Dis. 108. Prasad EM, Hung SY. Current therapies in clinical trials of Parkin-
2010;20(s2):S633-S643. son's disease: a 2021 update. Pharmaceuticals. 2021;14(8):717.
88. Feng Y, Wang X. Antioxidant therapies for Alzheimer's disease. Oxi- 109. Miliukhina I, Gracheva E. Effects of akatinol memantine on gait dis-
dative Med Cell Longev. 2012;2012:1-17. turbances at the developed stages of Parkinson's disease. Neurosci
89. Anselmo AC, Gokarn Y, Mitragotri S. Non-invasive delivery strate- Behav Physiol. 2021;51(4):423-429.
gies for biologics. Nat Rev Drug Discov. 2019;18(1):19-40. 110. Myles PS, Troedel S, Boquest M, Reeves M. The pain visual analog
90. Arevalo-Rodriguez I, Smailagic N, Figuls MRI, et al. Mini-mental state scale: is it linear or nonlinear? Anesth Analg. 1999;87(6):1517.
examination (MMSE) for the detection of Alzheimer's disease and 111. Cotman CW, Su JH. Mechanisms of neuronal death in Alzheimer's
other dementias in people with mild cognitive impairment (MCI). disease. Brain Pathol. 1996;6(4):493-506.
Cochrane Database Syst Rev. 2015;2015(3):CD010783. 112. Heppner FL, Ransohoff RM, Becher B. Immune attack: the role of
91. Kueper JK, Speechley M, Montero-Odasso M. The Alzheimer's dis- inflammation in Alzheimer disease. Nat Rev Neurosci. 2015;16(6):
ease assessment scale–cognitive subscale (ADAS-cog): modifications 358-372.
and responsiveness in pre-dementia populations. A narrative review. 113. Christen Y. Oxidative stress and Alzheimer disease. Am J Clin Nutr.
J Alzheimers Dis. 2018;63(2):423-444. 2000;71(2):621S-629S.
92. Kaufer DI, Cummings JL, Ketchel P, et al. Validation of the NPI-Q, a 114. Mironova YS, Zhukova I, Zhukova N, Alifirova V, Izhboldina O,
brief clinical form of the neuropsychiatric inventory. Latypova A. Parkinson's disease and glutamate excitotoxicity. Zh
J Neuropsychiatry Clin Neurosci. 2000;12(2):233-239. Nevrol Psikhiatr Im S S Korsakova. 2018;118(6 Vyp 2):50-54.
93. Cheung YB, Tan HX, Wang VW, et al. Mapping the Alzheimer's dis- 115. Hynd MR, Scott HL, Dodd PR. Glutamate-mediated excitotoxicity
ease cooperative study-activities of daily living inventory to the and neurodegeneration in Alzheimer's disease. Neurochem Int. 2004;
health utility index mark III. Qual Life Res. 2019;28(1):131-139. 45(5):583-595.
94. Van Laar AD, Van Laar VS, San Sebastian W, et al. An update on 116. Van Norman GA. Phase II trials in drug development and adaptive
gene therapy approaches for Parkinson's disease: restoration of trial design. J Am Coll Cardiol Basic Trans Science. 2019;4(3):428-437.
dopaminergic function. J Parkinsons Dis. 2021;11(s2):S173-S182. 117. Thomas DW, Burns J, Audette J, Carroll A, Dow-Hygelund C,
95. Stott SR, Wyse RK, Brundin P. Novel approaches to counter protein Hay M. Clinical development success rates 2006–2015. BIO Ind
aggregation pathology in Parkinson's disease. Prog Brain Res. 2020; Anal. 2016;1(16):25.
252:451-492. 118. Thomas D, Micklus A, LaFever S. Clinical Development Success Rates
96. Pagano G, Boess FG, Taylor KI, et al. A phase II study to evaluate the and Contributing Factors 2011–2020. Pharma Intelligence; 2021.
safety and efficacy of prasinezumab in early Parkinson's disease 119. Mehta D, Jackson R, Paul G, Shi J, Sabbagh M. Why do trials for Alz-
(PASADENA): rationale, design, and baseline data. Front Neurol. heimer's disease drugs keep failing? A discontinued drug perspective
2021;12:705407. for 2010-2015. Expert Opin Investig Drugs. 2017;26(6):735-739.
97. Ntetsika T, Papathoma PE, Markaki I. Novel targeted therapies for 120. Loeb MB, Molloy DW, Smieja M, et al. A randomized, controlled trial
Parkinson's disease. Mol Med. 2021;27(1):1-20. of doxycycline and rifampin for patients with Alzheimer's disease.
98. Fričová D, Korchak JA, Zubair AC. Challenges and translational con- J Am Geriatr Soc. 2004;52(3):381-387.
siderations of mesenchymal stem/stromal cell therapy for Parkin- 121. Sano M, Aisen PS, Andrews HF, et al. Vitamin E in aging persons
son's disease. NPJ Regen Med. 2020;5(1):1-10. with Down syndrome: a randomized, placebo-controlled clinical trial.
99. Kurimoto E, Yamada R, Hirakawa T, Kimura H. Therapeutic potential Neurology. 2016;86(22):2071-2076.
of TAK-071, a muscarinic M1 receptor positive allosteric modulator 122. Alessandrini M, Preynat-Seauve O, De Bruin K, Pepper MS. Stem
with low cooperativity, for the treatment of cognitive deficits and cell therapy for neurological disorders. S Afr Med J. 2019;109(8
negative symptoms associated with schizophrenia. Neurosci Lett. Suppl 1):S71-S78.
2021;764:136240. 123. Hassan AU, Hassan G, Rasool Z. Role of stem cells in treatment of
100. Vizcarra JA, Wilson-Perez HE, Fasano A, Espay AJ. Small intestinal neurological disorder. Int J Health Sci. 2009;3(2):227.
bacterial overgrowth in Parkinson's disease: tribulations of a trial. 124. Granzotto A, Weiss J, Sensi SL. Excitotoxicity turns 50. The death
Parkinsonism Relat Disord. 2018;54:110-112. that never dies. Front Neurosci. 2022;15:831809.
101. Sholler DJ, Huestis MA, Amendolara B, Vandrey R, Cooper ZD. 125. Curtis C, Zhang M, Liao R, Wood T, Nance E. Systems-level thinking
Therapeutic potential and safety considerations for the clinical use for nanoparticle-mediated therapeutic delivery to neurological dis-
of synthetic cannabinoids. Pharmacol Biochem Behav. 2020;199: eases. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2017;9(2):
173059. e1422.
126. Pardridge WM. Blood–brain barrier delivery. Drug Discov Today. 141. Fessel J. A vaccine to prevent initial loss of cognition and eventual
2007;12(1–2):54-61. Alzheimer's disease in elderly persons. Alzheimers Dement Transl Res
127. Liao R, Pon J, Chungyoun M, Nance E. Enzymatic protection and Clin Interv. 2021;7(1):e12126.
biocompatibility screening of enzyme-loaded polymeric nanoparti- 142. Rohn TT, Kim N, Isho NF, Mack JM. The potential of CRISPR/Cas9
cles for neurotherapeutic applications. Biomaterials. 2020;257: gene editing as a treatment strategy for Alzheimer's disease.
120238. J Alzheimers Dis Parkinsonism. 2018;8(3):439.
128. Pulgar VM. Transcytosis to cross the blood brain barrier, new 143. Safari F, Hatam G, Behbahani AB, et al. CRISPR system: a high-
advancements and challenges. Front Neurosci. 2019;12:1019. throughput toolbox for research and treatment of Parkinson's dis-
129. Lajoie JM, Shusta EV. Targeting receptor-mediated transport for ease. Cell Mol Neurobiol. 2020;40(4):477-493.
delivery of biologics across the blood-brain barrier. Annu Rev Phar- 144. Lee J, Bayarsaikhan D, Arivazhagan R, et al. CRISPR/Cas9 edited
macol Toxicol. 2015;55:613-631. sRAGE-MSCs protect neuronal death in Parkinson's disease model.
130. Kadam RS, Bourne DW, Kompella UB. Nano-advantage in enhanced Int J Stem Cells. 2019;12(1):114-124.
drug delivery with biodegradable nanoparticles: contribution of 145. György B, Lööv C, Zaborowski MP, et al. CRISPR/Cas9 mediated
reduced clearance. Drug Metab Dispos. 2012;40(7):1380-1388. disruption of the Swedish APP allele as a therapeutic approach for
131. Shalgunov V, Zaytseva-Zotova D, Zintchenko A, et al. Comprehen- early-onset Alzheimer's disease. Mol Ther Nucleic Acids. 2018;11:
sive study of the drug delivery properties of poly (l-lactide)-poly 429-440.
(ethylene glycol) nanoparticles in rats and tumor-bearing mice. 146. Upadhya R, Shetty AK. Extracellular vesicles for the diagnosis and
J Control Release. 2017;261:31-42. treatment of Parkinson's disease. Aging Dis. 2021;12(6):1438-1450.
132. Nance EA, Woodworth GF, Sailor KA, et al. A dense poly (ethylene 147. Vella LJ, Hill AF, Cheng L. Focus on extracellular vesicles: exosomes
glycol) coating improves penetration of large polymeric nanoparti- and their role in protein trafficking and biomarker potential in Alz-
cles within brain tissue. Sci Transl Med. 2012;4(149):149ra119. heimer's and Parkinson's disease. Int J Mol Sci. 2016;17(2):173.
133. Da Silva-Candal A, Brown T, Krishnan V, et al. Shape effect in active 148. Leggio L, Paternò G, Vivarelli S, et al. Extracellular vesicles as
targeting of nanoparticles to inflamed cerebral endothelium under nanotherapeutics for Parkinson's disease. Biomolecules. 2020;10(9):
static and flow conditions. J Control Release. 2019;309:94-105. 1327.
134. Nowak M, Brown TD, Graham A, Helgeson ME, Mitragotri S. Size, 149. Trotta T, Panaro MA, Cianciulli A, Mori G, Di Benedetto A, Porro C.
shape, and flexibility influence nanoparticle transport across brain Microglia-derived extracellular vesicles in Alzheimer's disease: a
endothelium under flow. Bioeng Transl Med. 2020;5(2):e10153. double-edged sword. Biochem Pharmacol. 2018;148:184-192.
135. Golden PL, Pollack GM. Blood–brain barrier efflux transport. 150. Liew LC, Katsuda T, Gailhouste L, Nakagama H, Ochiya T. Mesen-
J Pharm Sci. 2003;92(9):1739-1753. chymal stem cell-derived extracellular vesicles: a glimmer of hope in
136. Grabrucker AM, Ruozi B, Belletti D, et al. Nanoparticle transport treating Alzheimer's disease. Int Immunol. 2017;29(1):11-19.
across the blood brain barrier. Tissue Barriers. 2016;4(1):e1153568. 151. Narbute K, Piļipenko V, Pupure J, et al. Intranasal administration of
137. Shields CW IV, Evans MA, Wang LLW, et al. Cellular backpacks for extracellular vesicles derived from human teeth stem cells improves
macrophage immunotherapy. Sci Adv. 2020;6(18):eaaz6579. motor symptoms and normalizes tyrosine hydroxylase expression in
138. Tong HI, Kang W, Davy PM, et al. Monocyte trafficking, engraft- the substantia nigra and striatum of the 6-hydroxydopamine-treated
ment, and delivery of nanoparticles and an exogenous gene into the rats. Stem Cells Transl Med. 2019;8(5):490-499.
acutely inflamed brain tissue—evaluations on monocyte-based deliv-
ery system for the central nervous system. PLoS One. 2016;11(4):
e0154022.
139. Marciani DJ. Alzheimer's disease vaccine development: a new strat- How to cite this article: Chopade P, Chopade N, Zhao Z,
egy focusing on immune modulation. J Neuroimmunol. 2015;287: Mitragotri S, Liao R, Chandran Suja V. Alzheimer's and
54-63. Parkinson's disease therapies in the clinic. Bioeng Transl Med.
140. Fleming SM, Davis A, Simons E. Targeting alpha-synuclein via the
2023;8(1):e10367. doi:10.1002/btm2.10367
immune system in Parkinson's disease: current vaccine therapies.
Neuropharmacology. 2022;202:108870.
APPENDIX
TABLE A1 Definition of key terms
Term Definition
Therapy mechanisms
Neurotransmitter Therapies targeting neurochemical signaling between neurons.
system
Anti-aggregation Therapies targeting build of misfolded proteins such as the amyloid beta plaques.
Anti-excitotoxicity Therapies targeting excessive stimulation of neuronal receptors.
Anti-inflammatory Therapies targeting neuronal inflammation.
Anti-oxidant Therapies targeting imbalance between the neuronal production and clearance of reactive oxygen species.
Anti-apoptotic Therapies targeting programmed cell death.
Regeneration Therapies targeting neurogenesis.
Administration route
Intracerebral Drug administration directly into the brain including intracisternal and intraventricular injections.
Intradermal Drug administration via a superficial injection into the dermis.
Transdermal Drug administration via absorption through the skin including using topical creams and patches.
Intestinal Drug administration directly into the duodenum or upper jejunum.
Intraglandular Drug administration directly into the glands including salivary glands.
Delivery vehicle
Cellular Drug delivery utilizing live cells including immune and stem cells
Viral Drug delivery utilizing viral vectors.
Protein Drug delivery utilizing protein-based particles.
Outcome measures
Psychiatric Evaluation of cognitive and behavioral metrics using scales such as the Dementia Severity Rating Scale.
Biochemical Concentration of biomarkers including enzymes such as glucocerebrosidase and proteins such as amyloid beta.
Pain Evaluation of pain perception and nociceptive thresholds using tests such as thermotests.
Sleep Evaluation of sleep quality and daytime sleepiness using metrics such as Epworth Sleepiness Scale and REM Sleep Behavior
Disorders severity scale.
Volume Evaluation of changes in hippocampus and total brain volume.
Motor Evaluation of changes in movement using metrics such as Movement Disorders Society-Unified Parkinson's Disease Rating
Scale.
Pharmacokinetics Evaluation of drug distribution within the body.
Gastrointestinal Evaluation of gut health using metrics such as Bristol stool scale and Nepean dyspepsia index.
Safety Evaluation of treatment-emergent adverse events (TEAE's).
Fatigue Evaluation of feeling of tiredness and weakness using metrics such as the Fatigue Severity Scale.

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Received: 14 February 2022 Revised: 31 May 2022 Accepted: 6 June 2022

Alzheimer's and Parkinson's disease therapies in the clinic

Puja Chopade1 | Neha Chopade1 | Zongmin Zhao2 | Samir Mitragotri3,4 |

Bioeng Transl Med. 2023;8:e10367. wileyonlinelibrary.com/journal/btm2 1 of 23

In 2021, Aducanumab (Aduhelm), an anti-Aβ monoclonal anti- 2.2 | Parkinson's disease

TABLE 1 All FDA-approved therapies for AD and PD

Therapy Administration Delivery Outcome

Abbreviations: AD, Alzheimer's disease; BBB, blood-brain barrier; NMDA, N-methyl-D-aspartate.

Therapy Administration Delivery Outcome

Abbreviation: PD, Parkinson's disease.

TABLE A1 Definition of key terms

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