News feature
https://doi.org/10.1038/s41587-023-01724-9
Personalized medicine is
having its day
From made-to-order genetic therapies to model organisms engineered to be ‘patient avatars’,
the technology exists right now to save patients with rare diseases. By Caroline Seydel
L
ast October, Susannah Rosen, an
8-year-old girl with a devastating
neurodegenerative genetic disease,
took her first dose of a custom-made
genetic medicine. What’s more, she
got it at no cost, provided by the non-profit
foundation n-Lorem. The drug isn’t gene
therapy: it doesn’t change Susannah’s genome
or undo her mutation. It’s an antisense oligo-
nucleotide (ASO), a short sequence of modi-
fied DNA, designed to bind to a problematic
mRNA transcript and stop production of the
disease-causing protein.
Susannah joins a small but growing group
of patients who have received treatments
designed just for them, called ‘N of 1’ thera-
pies. Personalized medicine seemed to be just
around the corner for decades, but in 2018,
nature biotechnology
the corner had finally been turned when a
custom-designed ASO made its clinical debut
at Boston Children’s Hospital. Researchers
there, led by Tim Yu, developed an ASO drug
called milasen to treat a child — Mila — who had
a one-of-a-kind genetic disorder. Incredibly,
that drug was designed, manufactured and
administered in less than a year1.
ASOs are only one approach to design-
ing N-of-1 drugs; CRISPR gene editing, an
inherently customizable tool, is moving suc-
cessfully into the clinic, making it another
promising candidate. Clinical trials underway
for genetic diseases including sickle cell ane-
mia and congenital blindness, though these
are not ultra-rare conditions, nonetheless
have demonstrated that the technique can
be used safely in humans. Some people are
pushing to apply personalized CRISPR thera-
pies more broadly, but regulators remain cau-
tious. Once gene editing is performed, it can’t
be reversed if adverse events arise.
Another way that CRISPR can contribute is
by creating models for drug repurposing stud-
ies. By genetically modifying yeast or other
model organisms to mimic a patient’s muta-
tion, researchers can screen existing drugs to
see whether any address the defect causing a
Credit: PM Images / DigitalVision / Getty
single patient’s disease.
What all these strategies have in com-
mon is the issue of cost. Without a large cus-
tomer base to buy the resulting treatments,
scientists working on rare diseases are
struggling to build new models that enable
access to life-saving treatments for all who
need them.
News feature
Balancing safety with speed
ASOs aren’t new; the US Food and Drug Admin-
istration (FDA) approved the first, fomivirsen,
in 1998. Developed as an antiviral against cyto-
megalovirus retinitis in people with AIDS,
fomivirsen provided a proof-of-concept for
clinical ASOs. It would be 15 years before
antisense drugs began to take off. Since 2013,
however, no fewer than eight ASO drugs have
been green-lighted for use in the United States
or Europe to treat genetic diseases2, including
Spinraza (nusinersen), the first FDA-approved
therapy for spinal muscular atrophy (SMA),
a motor neuron disease that, in its most severe
form, causes death by age two.
Spinraza’s development, like that of so
many therapeutics, was a multi-year odyssey,
beginning in 2004 and not ending until the
drug won approval in 2016. In contrast, the
milasen story showed that the timeline can
be accelerated. Because Mila’s disease was
progressive and fatal, the risks of waiting a
year for animal safety studies outweighed the
danger of possible adverse effects from the
treatment, so Mila began treatment while the
animal safety study was still in progress. Her
treatment was authorized by the FDA under
an expanded-access protocol, which allows
a patient with a life-threatening condition to
be treated with an investigational drug out-
side of clinical trials. However, exactly where
to draw the line between letting a child suf-
fer from a degenerative disease and trying a
potentially harmful experimental treatment
remains a subject of vigorous debate. In a
2019 editorial in the New England Journal of
Medicine, the same issue where the develop-
ment of milasen was published, Janet Wood-
cock and Peter Marks at the FDA raised issues
about how to proceed safely, arguing that
“even in rapidly progressing, fatal illnesses,
precipitating severe complications or death is
not acceptable”3.
Since then, the FDA has published a
non-binding guidance document for investi-
gators developing personalized ASO drugs. It
lays out protocols for dose escalation sched-
ules, regular safety assessments, and the
establishment of stopping criteria in case of
serious adverse events. The document explic-
itly does not address the level of preclinical
data or drug quality requirements needed to
start treating a patient, and it also excludes
drugs intended for commercial marketing.
“You can make a really strongly ethical case
that if something is safe in rats, and a patient
is going to die, or is going to lose neurons, it’s
a better move for that patient to proceed than
to wait for a monkey study, because the risk of
nature biotechnology
not treating outweighs the risk of treating,”
says Jonathan Watts of the RNA Therapeutics
Institute at the University of Massachusetts
Medical School.
Yu points out that the ethical issues around
personalized ASOs aren’t unique. “Through
these guidances, we are seeing concepts that
are already in clinical practice and regulatory
practice in fields like oncology, where patients
who have failed first, second, third, fourth
line therapy are often first subjects in very
early stage, investigational trials of quite new
agents,” Yu says. “Patients and their clinicians
weigh their decisions to participate in these
trials knowing their disease is fatal and other
options have been exhausted.”
Regulatory policies differ between the
United States and Europe, points out Anne-
mieke Aartsma-Rus, a translational geneti-
cist at Leiden University Medical Center in
the Netherlands, and this affects what types
of mutations are eligible for N-of-1 designa-
tion. “There’s two things you can do with ASOs:
restore a protein or reduce the production of
a toxic protein,” she says. An ASO that treats
a disease by reducing a toxic protein could
conceivably work for anyone who makes it,
regardless of the specific mutation. “You can
develop it for one individual, but you know it
applies to others,” explains Aartsma-Rus. “In
the US, you are allowed to say ‘we’re going to
develop this in an N-of-1 setting’, but in Europe,
they would say no, it’s not allowed. You either
do it for everyone who’s eligible, or not at all —
not for one specific patient who happens to be
able to fund that.”
Milasen is an exon-skipping ASO. It is
designed to bind to a mis-spliced section of
the mRNA for MSFD8 that interferes with the
production of a lysosomal transporter protein
needed for neuronal survival in an ultra-rare
form of Batten disease (a late infantile neu-
ronal ceroid lipofuscinosis, CLN7)4. “A cryptic
splicing mutation leads to the inclusion of part
of an intron in the messenger RNA, and that
disrupts protein production,” Aartsma-Rus
explains. “If you can skip that cryptic exon,
the normal transcript is back, you can restore
the normal protein.” A properly designed ASO
can do just that: neutralize a cryptic exon,
restoring the normal transcript. Thus, she
says, these types of mutations are the most
promising avenue for N-of-1 therapies because
cryptic splicing mutations are unique and the
tailor-made ASO will work in only one patient.
However, mutations occurring in introns are
difficult to identify because introns contain a
lot of sequence variability. It’s not always obvi-
ous whether a particular variant is disrupting
the transcript. “People say [cryptic splicing
mutations] are very rare, but the reality is
they’re probably not that rare, it’s just really
difficult to find them,” says Aartsma-Rus.
Aartsma-Rus serves as chair of the Dutch
Center for RNA Therapeutics, a nonprofit
consortium of medical centers developing
personalized RNA therapies. Identifying an
appropriate mutation is just the first issue,
she says (Fig. 1). Ideally, one would want to
apply it to a disease that affects the brain or
the eye — someplace the ASO can be injected
locally. “You can use a very low amount, and
you don’t have to worry about systemic expo-
sure,” she says. She adds that there must be
some hope of benefit to the patient at the time
of treatment. “You can do local injection in the
eye, but if someone is totally blind, you can
restore the protein, but they will stay blind,”
she says. “You’re not going to return function
into the cells. If the disease is too advanced,
the patient won’t benefit.” The ultimate deci-
sion rests with the patient, she emphasizes. It’s
critically important that the patient and the
family understand realistically what benefits
they can expect and the treatment risks.
N of 1 … and another, and another
Unlike in Europe, in the United States “N of
1” can mean “N of 1 at a time.” Jacifusen is an
ASO designed against the FUS gene (RNA
binding protein fused in sarcoma), which,
when mutated, causes an aggressive form of
amyotrophic lateral sclerosis (ALS). It’s named
for Jaci Hermstad, who in 2019 became the
first patient to receive the drug, but it wasn’t
designed specifically for her. The drug was
already being developed by Ionis and collabo-
rators at Columbia University and had shown
efficacy in a Fus-mutant mouse model5 when
Hermstad received her diagnosis at age 25.
Her twin sister, Alex, had died of the disease
when she was 17, and, terrified of losing their
remaining daughter, Jaci’s parents launched
a campaign to get permission from the FDA
for Jaci to try the drug, even though it hadn’t
yet been tested in humans. At the time Jaci’s
disease was diagnosed, the FDA had not yet
released their draft guidance around the use
of individualized ASOs in patients.
“The FDA were extremely responsive,
thoughtful, reasonable partners in this,” says
Neil Shneider of Columbia, who developed
jacifusen. “Their goal was clearly to protect
my patient but at the same time recognize
the desperate nature of the disease and the
risks the disease presented to her.” Although
Shneider had limited toxicity data on
jacifusen, the drug was chemically similar to
News feature

Cryptic splicing mutation identified resulting in progressive eye or brain disease in

The unexpected adverse event under-
patient who might benefit from treatment scores the importance of data sharing, which
Yu emphasizes as key to advancing the field.
“The moment we encountered hydrocephalus
Assess whether patient is willing to undergo experimental treatment
in our patients, we contacted everybody in the
field we knew that worked with ASO drugs,” Yu
says. “People have been studying ASOs, includ-
Patient responds positively
ing extensive animal testing, for 30 years.
ASO design and testing Everyone said, ‘No, we've never seen this.’
• ASO design So it’s something that we have to work on.”
• Select optimal cell model
• Assess whether ASOs induce exon skipping
Although it hadn’t been seen in animal studies,
however, hydrocephalus had occurred previ-
ously in people treated with an ASO. In March
2021, a phase 3 trial for the drug tominersen,
Functional studies developed by Ionis for patients with Hunting-
• Assess whether ASO restores protein in cell model
• Assess whether ASO improves pathology in cell model
ton’s disease, was prematurely halted due to
“ventricular expansion” — essentially, hydro-
Lead compounds selected cephalus — which was observed in a dose-
dependent fashion. Testing of tominersen has
Preparing for treatment resumed under the auspices of Roche, which
• Interact with patient to set clear expectations and stop criteria is partnering with Ionis.
• Generate GMP batch of ASOs
• Conduct toxicity studies (with GMP ASOs) in vitro and in vivo (rats) Yu says the most likely hypothesis is that
the fluid buildup is a class effect, but the
No toxicity concerns mechanism responsible for it remains unclear.
Treatment
“It would be really nice if we could simply just
• Conduct first in human treatment (with GMP ASOs) get some tominersen and get some valeriasen
• Collect safety data and do the appropriate experiments to try to
•
identify mechanistic commonalities between
the two sequences,” he says. “That isn’t exactly
how the world always works. But the sooner
Deposit sequence we can get to a point where we’re doing those
• Continue treating and monitoring patient
• Deposit sequence and related data in DCRT database (public)
sorts of things in a collaborative way, the
better for everybody.”
Fig. 1 | Workflow for N-of-1 therapeutic ASO development. ASOs are under development for patients with Together with Julia Vitarello, the mother of
an ultra-rare (fewer than 100 worldwide) serious, life-threatening diseases who have no therapy available, Mila, Yu launched the N=1 Collaborative, or
and where there is no commercial incentive to develop therapies. Source: Dutch Center for RNA Therapeutics N1C, an organization dedicated to connecting
(DCRT). ASO, antisense oligonucleotide; GMP, good manufacturing practices; IND, Investigational New Drug. ASO investigators around the world and pro-
viding a hub for communication and data shar-
ing. Yu points out that, often, barriers to data
two other Ionis ASOs for ALS that had already Data sharing sharing arise as unintended consequences of
been introduced into the clinic. Jaci started After milasen, Yu began hearing from families the way medical data are handled and patients’
treatment under an expanded-access Inves- hoping that antisense drugs could help their privacy is protected. “One of the critical things
tigational New Drug (IND) application, and children. Mindful of the ethical considerations that I’m hoping the N=1 Collaborative can do
after that, more patients with FUS-related involved, Yu decided to take on a devastating is nip some of that in the bud,” Yu says, “and
ALS wanted to try it. “The program grew, but genetic disease, ataxia–telangiectasia, creating set sharing standards that make it easy for
it was incremental, one by one,” Shneider says. a drug called atipeksen for a 3-year-old patient investigators and the families they work with
“We ultimately submitted 12 INDs in total for named Ipek in October 2019. Ipek is doing well to volunteer for their data to be shared and
the same therapeutic.” After the first few 3 years into treatment, Yu says, but the results aggregated in a way that informs the field.”
patients, the FDA set limits on the serial IND have not yet been published. In 2020, he “The platform technologies are continu-
approach, urging Shneider to conduct a clini- treated two toddlers with a severe form of epi- ing to improve, and I would say right now, the
cal trial. “The program might have ended, but lepsy with an ASO called valeriasen. Although therapeutic index is reasonably narrow,” says
it was saved by Ionis,” he says. “They agreed to the drug reduced the frequency of the seizures Watts. “We can find sequences that are well
sponsor a proper clinical trial and they did it in one patient and eliminated them in the other, tolerated and that save lives. But there are
very quickly.” both children developed hydrocephalus and also definitely examples that are quite toxic
Shneider expects to publish the data on the subsequently stopped treatment. One even- of these ASOs of different sequences with
12 IND patients in 2023; although Jaci passed tually died (of causes unrelated to the treat- the same chemistry. There are examples that
away about a year after starting the drug, ment); the other has seen her seizures increase are a little bit borderline — they have some
“she showed encouraging signs that she was in frequency since stopping treatment, and her beneficial effect, but it’s not clear whether
responding to the ASO,” Shneider says parents are considering restarting it. they’re safe enough yet. I think if we could get

nature biotechnology
News feature
Tim Yu of Boston Children’s Hospital is
helping to create a centralized resource
to help streamline ASO development for
N-of-1 diseases.
the platform to have a therapeutic index that
was ten times greater, it would be so much
easier to do single-patient drugs.” The way to
get there, Watts says, is through collaboration
and sharing of data.
N1C also sponsors workshops to help the
field develop consensus on certain best
practices, including guidelines for mutation
selection, preclinical testing, safety tests, reg-
ulatory issues, and metrics to define how well
a treatment is working. The organization also
serves as a resource for doctors who might not
have experience in genetic therapies. Last year
the group published consensus guidelines6
for designing and testing ASOs, and they are
putting together an online database of con-
trol ASOs confirmed to work well in various
cell types.
“A lot of clinicians might have a patient with
a rare disease and want to help, but don’t have
any idea how to approach the FDA. Where do
you find a source of oligonucleotide for under
$500,000? For a single patient?” Watts says.
“Sharing information and help, guidance and
resources and protocols around all of those
kinds of questions is another thing that the
more clinically minded people in the collabo-
rative do for each other.”
One major player in ASOs has so far declined
to share data in the collaborative: n-Lorem.
nature biotechnology
Giving away ASOs for free
Stanley Crooke, founder of Ionis, recognizing
that the traditional for-profit pharma com-
pany model couldn’t support developing
N-of-1 ASOs, founded the n-Lorem Founda-
tion in 2020. n-Lorem’s mission is to provide
experimental ASO treatments to people
with genetic diseases that affect fewer than
30 patients worldwide. The foundation was
launched with personal funding from Crooke
and Rosanne Crooke, his wife, plus $3.4 mil-
lion from Ionis and $1.75 million from Biogen.
Crooke says that other companies are stepping
up to contribute as well. “We’ve had wonderful
response,” Crooke says. “Really every vendor
in the oligonucleotide industry is giving either
free or deeply discounted work, and often cash
donations as well.” They’ve also received dona-
tions from disease advocacy organizations.
Crooke also has kind words for the FDA in
terms of how they’ve handled the personalized
therapies. “Being fast is important. Being high
quality is even more important. And it’s the
combination of the efficiency and versatility
of antisense technology with the special guid-
ance that the FDA has issued for the treatment
of nano-rare patients with ASOs that allow us
to move as fast as we are,” he says.
At the same time, he resists the idea that
n-Lorem should contribute their data to the
N1C efforts. Pointing out that Ionis has been
“perfecting” ASO technology since 1989, he
says it wouldn’t make sense to compare their
data with that of others just starting out.
“We offer to collaborate with basically every
investigator who approaches us,” he says.
“Our collaborations are that we design and
make the ASOs, and then we bring an optimal
ASO forward, and then the investigator treats
the patient.”
Crooke expressed support for the idea of
establishing databases, as long as minimum
standards for preclinical testing processes and
performance are defined and rigorous clinical
evaluation protocols with well-defined clinical
endpoints are agreed on. “As such, n-Lorem
is open to contributing data to the N=1 Col-
laborative or other data platforms as appro-
priate,” he says. But, because N1C pools data
from different investigators all using different
methods to make ASOs, Crooke says, “one of
the worries that I have is that this is being taken
on by people who don’t really understand
this technology.”
Mining for hidden gems
ASOs are not the only route to N-of-1 therapies.
CRISPR can help people with ultra-rare dis-
eases. Rather than changing a patient’s DNA,
the technology enables researchers to create
yeast or worm models with genetic errors that
match those in the patients, thus creating a
personalized resource for high-throughput
screening of small-molecule drug candidates.
“You don’t program the medicine, like in the
ASO model; you program the yeast model,”
explains Ethan Perlstein, CEO and founder of
Perlara, a public benefit corporation (Box 1).
“What has a faster path to the clinic than even
a customized ASO? A repurposed drug that
already has a safety record.”
Perlstein says the idea behind Perlara is to
“productize” drug repurposing by using exist-
ing yeast, worm and fly models. The company
is actually on its second iteration, having been
founded originally in 2014 before shutting
its doors in 2019 because of lack of funding.
Yet some important unfinished business lin-
gered. For two years, Perlara had been work-
ing with Maggie’s Cure, an LLC formed by the
family of Maggie Carmichael. Maggie has a
congenital disorder of glycosylation (CDG),
PMM2-CDG, that affects multiple organ sys-
tems. Researchers working with Perlara were
already screening yeast and worm models of
Maggie’s disease, looking for a drug that might
be effective. The project continued after the
company officially closed, and in January
2020, Maggie began a drug called epalrestat
under the supervision of doctors at the Mayo
Clinic in Rochester, Minnesota. The drug is
not FDA-approved for any indication, but it is
approved in Japan as a treatment for diabetic
neuropathy. Since she began taking epalrestat,
Maggie’s motor skills have improved and her
vocabulary has grown dramatically.
Around the time that Maggie was starting on
epalrestat, another family was searching for
answers for their son’s CDG. Jake Carroll was
diagnosed with Man1b1-CDG in early 2020,
and his parents, Claire Fast and Matt Carroll,
soon discovered how little was known about
the disease. “It was quite a helpless feeling,”
Fast says. “Very few people in the world know
about this disorder.” The Carrolls met the
Carmichaels in a Facebook group for families
affected by CDG, and that’s when they learned
Credit: Michael Goderre, Boston Children’s Hospital
about Perlara. In 2022, Perlstein connected the
family with Clement Chow at the University
of Utah. Chow works on CDGs in fruit flies,
and he agreed to conduct a screen for Man1b1
drugs in flies.
“We were so desperate at that point,”
Fast recalls. “Learning about what Perlara
was doing was very exciting for us, just to
find somebody who knew how to navigate
the research. It’s really hard to know where
to start.”
News feature
Box 1
What is a public benefit corporation?
A public benefit corporation (PBC) is a
for-profit corporation that balances its
duties to stockholders with an explicitly
defined mission to benefit the public in some
way. What constitutes a “public benefit”
is broadly defined and can be as general
or specific as the company chooses, and
ideally will dovetail with the ability to make
a profit. However, the PBC designation can
protect the director in making decisions that
advance the mission even if they may not be
profitable in the short term.
“The public benefit statute says you have
to do what is called a tripartite balancing,”
says Pamela Marcogliese, head of US
corporate advisory and governance at
Freshfields. “When you make a decision
on behalf of the corporation, you have to
balance three things in making that decision.”
First, the director must consider the best
Chow’s fly models did not carry an exact
replica of Jake’s mutation, but rather a general
Man1b1 knockdown made using RNA inter-
ference (RNAi). “In the future, we may want
to move toward making more personalized
models, using CRISPR to put in real patient
mutations, but that takes so much more time,”
he says. “We can order up all the reagents to do
this RNAi knockdown experiment right after
the call with the patients, get the reagents
within a week, have a few tests done in about
three weeks, and then it’s off to the races. If we
do CRISPR, it’s months before we even have a
fly we can test.”
As of January 2023, the screen has identified
several drugs, and the next step will be to sit
down as a team and discuss how to proceed.
“About 20% of the hits we found in our screen
all fell into the same category, so that was
really encouraging,” Chow says. “A number of
them either have a pretty good history in pedi-
atric administration or they’re actually OTC
[over the counter].” Once a drug is selected,
theoretically, Jake could begin treatment
right away. Indeed, another Perlara patient
named Lucy, who suffers from a different CDG,
PGAP3, received her first dose 48 hours after
her yeast screen was completed. In that case,
the family was working with two labs in paral-
lel: while one performed the yeast screen, the
other was studying Lucy’s own cultured cells,
nature biotechnology
interest of the shareholders, just as in a
traditional for-profit corporation, Marcogliese
explains. Second, the director must also
consider the company’s mission, and third,
the best interest of the stakeholders, who are
the people most affected by the company’s
conduct. “A PBC model works best when
the mission is aligned with the interests of
shareholders,” Marcogliese says, but points
out that, in the short term, “it allows you
to do things that are good for the mission
without having to worry about whether, in the
short term, on any specific day, it maximizes
shareholder value.”
Whether the PBC is adequately fulfilling
its mission is up to the shareholders,
Marcogliese says. The company is required
to provide stockholders with a statement
detailing the ways it has served the best
interests of public and the stakeholders,
and both teams identified the same biochemi-
cal pathway. Within a week of starting her drug
regimen, Lucy took her first unassisted step.
The vast collection of small-molecule drugs
that have already been safety-tested repre-
sents an underutilized resource that can be
mined for cures. “We’re banking on being
able to find all these hidden gems amongst
the things we’ve already approved as safe,”
says Chow. “I think that it will work for a large
number of diseases. There’s just so much biol-
ogy hidden in these drugs. Most of them, we
don’t really have a good sense of the exact
mechanism of action.”
Perlstein says he has around 30 clients
looking for treatments. “Drug repurposing is
going to go exponential soon,” Perlstein pre-
dicts. “What were these few N-of-1s is going to
become a tide of N-of-1s. And, of course, that’s
what they talk about with ASOs, that’s what
n-Lorem is meant to accommodate, and the
N=1 Collaborative. They’re trying to get ahead
of this tsunami. And it’s coming.”
Can rare disease drugs be profitable?
One year ago, the US National Institutes
of Health (NIH) launched its Ultra-rare
Gene-based Therapy (URGenT) program
to accelerate the clinical development of
therapies for neurological diseases7. “It’s still
under construction,” says program director
but there’s no third-party oversight holding
PBCs accountable. They also can’t be
sued by outside organizations for failing
to provide their promised benefit. For
instance, a PBC that claims to protect the
environment can’t be sued by Greenpeace,
Marcogliese says. She also pointed out
that people often use “PBC” and “B-corp”
interchangeably, but they are not the
same thing. Like a PBC, a B corporation
is generally focused on a public benefit
mission, but B corporations are certified by
the nonprofit B Lab and must meet certain
standards of sustainability, accountability
and transparency to retain their certification.
Unlike a PBC, a B-corporation’s fiduciary
duties do not extend to the public and the
stakeholders. A company can be both a
PBC and a B corporation, or just one and
not the other.
Chris Boshoff. “At the moment, it only con-
sists of a preclinical component. There are
two funding opportunity announcements
for projects up to and including an IND filing.”
A clinical network is in development and pro-
jected to be up and running sometime in 2023,
he says. “That will really change the dynamics
of this program. We hope it will provide almost
a seamless transition from preclinical to clini-
cal, and a streamlined access process. If appli-
cants already have an IND, they don’t have to
go through the same lengthy application pro-
cess for funding.” The clinical network data-
base will also serve as a data sharing resource,
which can help other researchers. “Even if it’s
as small as just sharing a clinical trial protocol,
or sharing assays during development, it’s a
start,” Boshoff says.
No projects have been funded so far, but
Boshoff says the scope of the program encom-
passes any gene-based or transcript-directed
technology, including ASOs, gene editing, or
classical AAV-based gene therapy, provided
they address ultra-rare neurological diseases.
In a recent New York Times editorial,
Fyodor Urnov, scientific director at the Innova-
tive Genomics Institute and professor at the
University of California Berkeley, suggested
that for rare diseases, public funding makes
more sense than for-profit businesses, point-
ing to the financial struggles of two flagship
News feature
Six-year-old Jake Carroll has an ultra-rare
metabolic disorder called Man1b1-CDG.
Perlara helped his parents find a researcher
who could make a fruit fly model of his
disease for drug screening.
gene therapy companies, bluebird bio and
Editas Medicine, as evidence8. By contrast,
he says, “the California Institute for Regen-
erative Medicine has consistently and vig-
orously supported a path to the clinic for
experimental therapies including CRISPR”
and is the only such state-funded program
to do so. At the federal level, he says, the NIH
offers funding for academic researchers to
develop CRISPR-based medicines. “I think
this is exactly the right approach,” he says.
“The federal government’s investment in
establishing the feasibility of CRISPR cures,
I think, ultimately will benefit the taxpayers.
Why? Because as we learn more and more
nature biotechnology
about gene editing for rare disease, we will
learn more and more how to safely gene edit
for common disease.”
Meanwhile, taking lessons from his prior
attempt at industrial biotech, Perlstein
revived Perlara in late 2021, but this time
creating a leaner and stronger company. “It’s
decentralized biotech,” he says. “We offer
a fundamentally different business model,
which is a virtual consultancy.” Perlstein sees
Perlara’s role as accelerating the research
to find treatments for patients who would
otherwise remain under the radar of big
pharma. “The whole purpose of the company
now is to become the Y Combinator for rare
diseases,” Perlstein said. “What Y Combinator
did for overlooked founders, I’m doing the
same thing with overlooked families.”
In its new format, Perlara no longer has a
permanent, physical lab space or full-time
employees; it has dispensed with them in
favor of geographically distributed pop-up
labs and “cure guides” who work as independ-
ent contractors with the company. “It’s kind
of like Uber,” quips Perlstein, “except that
instead of drivers, I have cure guides.” The
cure guides get matched with families and
form research teams to develop a personal-
ized treatment, much as Chow’s lab took on
Jake Carroll’s case.
For now, Perlstein acknowledges, families
working with Perlara are largely self-financed.
He calls them “the tip of the spear” in the quest
for rare disease treatments, which could ulti-
mately become available to other patients.
“I’m not trying to make something that only
benefits the 1%,” he said. “But I’m not going
to ignore the fact that they exist.” Indeed,
Maggie’s success with epalrestat led to the
launch in December 2022 of a 40-person
phase 3 clinical trial. Without the Carmichaels’
efforts, epalrestat’s benefits for CDGs may
have remained unknown, even though the
genetic and biochemical technology required
to find it is accessible in most modern labs.
It remains to be seen whether rare disease
drug discovery will be financially sustain-
able, whether using the Perlara model, which
so far relies on funding from families; the
n-Lorem model, which draws on corporate
donations and advocacy organizations; or
the public-funding scenario proposed by
Urnov. Other for-profit ventures are spring-
ing up to try to accelerate N-of-1 therapies;
for instance, Julia Vitarello, Mila’s mother,
recently co-founded EveryONE Medicines
with investment support from GV and Khosla.
“This is the time for rare diseases,” says
Chow. “In the next ten years, I think you’ll see
therapies rolling out left and right because
it’s just been waiting for the technology to
be there.” He points out that rare genetic dis-
eases are far simpler to model in the lab than
complex multifactorial conditions like heart
disease or cancer. “I think we have all the tools,”
he says. “What’s lacking is the funding.”
Caroline Seydel
Los Angeles, CA, USA.
Published online: xx xx xxxx
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Credit: Carroll family