Angelman syndrome is a genetic disorder. It causes delayed development, problems with speech and balance, intellectual disability, and sometimes, seizures. People with Angelman syndrome often smile and laugh frequently, and have happy, excitable personalities.

1. ANGELMAN
SYNDROME
Melvin Alex

2. What is it?
“ A genetic disorder that causes developmental
delay and neurological problems.”

3. Introduction to Angelman syndrome
● Humans= 46 chromosomes (23 pairs: 1 maternal and 1 paternal)
● AS is caused by severe reduction in the expression of a gene.
● UBE3A on CHROMOSOME 15
● Random and rarely inherited
● Each chromosome is made up of various genes that are coded to produce
different proteins which result in our bodily functions.

4. Angelman Syndrome

5. ● UBE3A is an enzyme that ubiquitinates
other proteins within neurons , typically
tagging them for degradation.
● Necessary to maintain neural
homeostasis and normal synaptic
function.
● Deficiency results in the accumulation of
unnecessary materials inside and outside
the cells of the brain ->SYNAPTOPATHY

6. Symptoms of Angelman Syndrome
1. Universal lack of speech
2. Life threatening / debilitating seizures
3. Severe developmental delays
4. Poor motor skills and incoordination
5. Apraxia/ Dyspraxia
6. Sleep disturbances / severe insomnia
7. Unable to live independently
8. Feeding issues
9. Significant clinical unmet needs

7. Diagnosis
1) Blood test
1) Genetic tests
i) DNA methylation test
ii) Chromosomal microarray (CMA)
iii) UBE3A gene sequencing test

8. Roadmap for success
Investigative therapeutic strategies
● Gene / protein replacement therapy
● Paternal gene activation
Identify downstream treatments
● Downstream therapeutics
● Symptomatic relief

9. Gene / protein replacement
therapy
● AAV
1. gene replacement
2. Secretory protein
replacement
● Lentivirus with HSC
Paternal gene activation
● ASO
● ATFs
● CRISPR
● shRNA
Disease modification strategies

10. 1. Gene therapy: UBE3A gene replacement
● Delivery: Viral vectors Spinal fluid ,
direct brain injection, IV infusion via
HSC.
● Increasing the level of Ube3a in the
brain was achieved using viral vectors
delivery.
● This delivery improves cognitive
deficits in the adult mice with AS.

11. UBE3A gene replacement STEM CELL
DELIVERY
● Using bone marrow stem cells ( HSCs)
transfected with a modified UBE3A
gene using a lentivirus
● Can travel from bone marrow
throughout the brain crossing blood
brain barrier
● More neurons impacted through
“cross correction”
● Neuronal uptake throughout life

12. 2. Paternal activation via UBE3A-AS knockdown
CRISPR- Clustered Regularly Interspaced
Short Palindromic Repeats
● Targeting specific sequence to
permanently unsilence using gRNA
with AAV vector
● To release UBE3A from antisense
gene
● CRISPR/Cas9 is a gene editing
technique that allow changes to any
part of genome with precision.

13. 2. Paternal activation via UBE3A-AS knockdown
● UBE3A-AS is a large non
coding antisense
transcript in the UBE3A
locus
● Using a short cas9
variant and guide RNA is
that target about 75snord
115 genes were packed in
adeno associated virus to
unsilence UBE3A allele.

14. Conclusion
● AS has been cured in mice both genetically and pharmacologically. This
lets us know we can find a cure for AS in humans.
● The gene responsible for AS is maternally inherited copy of UBE3A,
when it is not expressed in the child. The paternally inherited copy of
UBE3A is present but in most cases silent.
● If scientists and doctors can safely activate the paternal copy , the
protein of this gene could be restored without the need of gene therapy.
● All of the strategies discussed are still undergoing human clinical trials.

15. References
● Cas9 gene therapy for Angelman syndrome traps Ube3a-ATS long non-coding RNA |
Nature
● Therapeutic Strategies for the Treatment of Angelman syndrome Dr Allyson Berent
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