Angelman Syndrome:

Research & Treatment

Kathy Duong, Kaitlyn Greenwood, Aliyah Jackson, Van Hopkins, Allison Weber
Introduction

● Angelman Syndrome (AS)

○ a complex developmental neurological disorder
○ first described by English physician Harry Angelman in 1965 1,2
● No cure1,2
● Occurs in approximately 1 out of every 12,000 to 20,000 people 1,2
● Symptoms manifest 6 to 12 months after birth 1,2
● Primarily due to a deletion of the maternal chromosome 15q11.2-q132
○ causes loss of function in UBE3A gene
■ leads to dysfunctional cellular ubiquitin activity
○ In humans, two copies of the UBE3A gene
○ expressed maternal and silenced paternal copy
○ Most research has been focused on improving the standard of living for patients
○ New research is promising for a cure in the future
Antisense Oligonucleotides (ASOs)
● Angelman Syndrome
○ Maternal allele mutated
○ Paternal silenced
■ Long noncoding RNA
● Antisense Oligonucleotides (ASOs)
○ single-stranded deoxyribonucleotide
○ Complementary to mRNA.
○ ASOs recruit RNase H
■ to remove RNA primers
■ Prevent formation noncoding RNA

Chamberlain, S. J., and M. Lalande. “Angelman

Chattopadhyaya, Jyoti. “Design, Synthesis & Evaluation
Syndrome, a Genomic Imprinting Disorder of the
of Potential Antisense Oligonucleotides (AONs) and
Brain.” Journal of Neuroscience, vol. 30, no. 30,
SiRNA.” Dep't of Bioorganic Chemistry | Research |
2010, pp. 9958–9963.,
Antisense, UPPSALA University,
doi:10.1523/jneurosci.1728-10.2010.
www.boc.uu.se/boc14www/res_proj/Antisense.html.
CRISPR/Cas9

● CRISPR/Cas9
○ is a gene editing technique
○ to modify the paternal UBE3A gene
■ eliminate expression of noncoding
RNA

UNC Health. “UNC Science Short: CRISPR/Cas9

to treat Angelman Syndrome.” Youtube video,
01:51. July 9, 2018,
https://www.youtube.com/watch?v=0lh96B951pE&t
=32s
Topoisomerase Inhibitors

● Topoisomerase
○ Enzymes during DNA replication
○ Relieve supercoil stress
○ Breaks DNA, unwinds, and rejoins
● Topoisomerase inhibitors
○ Inhibit topoisomerase
■ Cannot remove supercoil stress
■ DNA replication prevented
■ Prevent formation of noncoding RNA

Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology.

4th edition. New York: W. H. Freeman; 2000. Section 12.3,
The Role of Topoisomerases in DNA Replication.
 Study: Testing TOP1 Inhibitors

Graph 1:
Dose/Response
Relationship

Topotecan
Graph 2: ● Regulated UBE3A-YFP fasted
UBE3A ● Increased neuron levels at a higher rate for the same
level/treatment duration
duration relationship ● 20x more potent
● Almost completely restored UBE3A proteins to wild
type levels6
Study: Administration

Intracerebroventricular Infusion
● Injection of substances into
cerebrospinal fluid

Intrathecal Delivery
● Pain medication for spasticity is
introduced directly into the spinal
fluid6
Study: Why this Matters

● Possible Treatment = Chance at a normal life

● However…
○ Methods are not perfect
○ Limited Testing
○ Extended side effects have not been explored
○ Still in the process of being studied
 Prevention/Treatment Options
● No way to prevent AS
○ AS occurs as a result of genetic
abnormalities.
● Although there are clinical trials of potential AS
treatments in progress,
○ there are currently no current treatments
for AS itself.
● Available treatments:
○ focus on symptoms
○ helping the individuals find ways to live
with the disease

Angelman Syndrome Information Page. (n.d.). Retrieved from

https://www.ninds.nih.gov/Disorders/All-Disorders/Angelman-Syndrome-Information-Page
Mode of Action

● GABA
● Role in seizures
● Anti-seizure medication
● GABA role in memory

“Introduction.” Wiki,
wiki.mcmaster.ca/LIFESCI_4M03/group_2_presentation_2_-_epilepsy.
Future Research

● Further understanding the UBE3A gene and protein10

○ Hundreds of uncatalogued UBE3A variants
■ Comprehensive mapping will pinpoint dysfunctional areas
● Specific areas and pathways of the brain tied to AS phenotypes 11
○ Awareness will allow for more effective medications
● Other areas of related neurological research into:
○ similar proteins
○ specific AS symptoms
○ other cellular processes
■ ancillary to the unsolved origins of AS
Best Plan of Action

● Possible cures:
○ unsilence the paternal allele
○ understanding the variants of UBE3A
● AS: the maternal copy mutated
○ Activating paternal allele
○ paternal allele not mutated, just silence.
● Understand the impacts of UBE3A variants
○ to treat the general conditions of AS
○ Identify different symptoms
Summary

● AS is an uncured developmental neurological disorder caused by a loss of function in the UBE3A protein
● Current research includes:
○ ASOs, CRISPR/Cas-9, topoisomerase inhibitors
● By using TOP1 inhibitors, like topotecan, the paternal UBE3A gene can be unsilenced for possible AS
treatment.
● There is no standard treatment for Angelman syndrome. Instead, doctors focus on managing symptoms to
maintain the highest possible quality of life.
● Future research includes cataloguing UBE3A variants and pinpointing specific areas AS is expressed in the
nervous system
Citations

1. “Angelman Syndrome - Genetics Home Reference - NIH.” U.S. National Library of Medicine, National Institutes of Health, 2020,
ghr.nlm.nih.gov/condition/angelman-syndrome.
2. Margolis, Seth S, et al. “Angelman Syndrome.” Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics, Springer
US, July 2015, www.ncbi.nlm.nih.gov/pubmed/26040994.
3. Zylka, Mark. “CRISPR/Cas9-Based Early Intervention for Angelman Syndrome.” SFARI, Simons Foundation, 25 June 2019,
www.sfari.org/funded-project/crispr-cas9-based-early-intervention-for-angelman-syndrome/.
4. Scoles, Daniel R, et al. “Antisense Oligonucleotides.” Neurology Genetics, 5 Apr. 2019, doi:.doi.org/10.1212/NXG.0000000000000323.
5. Champoux, James J. “DNA TOPOISOMERASES: Structure, Function, and Mechanism.” Annual Reviews Biochemistry, vol. 70, July 2001, pp. 369–413.,
doi:https://doi.org/10.1146.
6. Huang, Hsien-Sung et al. “Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons.” Nature vol. 481,7380 185-9. 21 Dec. 2011,
doi:10.1038/nature10726.
7. Angelman Syndrome.” Mayo Clinic, Mayo Foundation for Medical Education and Research, 4 Feb. 2020, www.mayoclinic.org/diseases-
conditions/angelman-syndrome/diagnosis-treatment/drc-20355627.
8. Angelman Syndrome Information Page. (n.d.). Retrieved from
https://www.ninds.nih.gov/Disorders/All-Disorders/Angelman-Syndrome-Information-Page
9. “The Royal Children's Hospital Melbourne.” The Royal Children's Hospital Melbourne,
www.rch.org.au/neurology/patient_information/antiepileptic_medications/.
10. “Structure-Function Studies to Characterize UBE3A Missense Variants.” Angelman Syndrome Foundation, 2020,
www.angelman.org/research/structure-function-studies-to-characterize-ube3a-missense-variants/.
11. “To What Extent Are Striatal Deficits Underlying Clinical Features of Angelman Syndrome?” Angelman Syndrome Foundation, 2020,