Genetic Approaches for Treating Angelman Syndrome

Quick Overview

Dr. Jim Wilson presented at the 2021 FAST Science Summit on genetic approaches for treating Angelman Syndrome. He discussed the use of gene therapy and gene editing techniques to address the genetic mutations associated with the syndrome. Dr. Wilson highlighted the challenges of delivering genes to the brain and discussed different routes of administration, such as intravenous delivery and injection into the cerebral spinal fluid. He also shared data from animal models, including mice and non-human primates, to demonstrate the distribution and expression of genes. Dr. Wilson emphasized the importance of multiple approaches and ongoing research to find the most effective treatment for Angelman Syndrome.


In this talk, we will discuss the genetic approaches being used to treat Angelman Syndrome (AS). AS is a neurodevelopmental disorder caused by a mutation on the maternal allele and the inactivation of UBE3A on the paternal allele. We will explore different strategies, including gene therapy, genome editing, and RNA interference, that are being developed to address this complex genetic disorder.

Animal Models and Translational Research

The first step in developing a therapeutic approach for AS is to study the therapeutic in animal models. Traditionally, mouse models have been used, but larger animal models like non-human primates are also being considered. These animal models help researchers understand gene correction and transgene toxicity. Once sufficient data is gathered, the research moves to human studies to evaluate safety and biomarker readouts.

Challenges in Gene Distribution

One of the major challenges in treating AS is distributing enough gene throughout the brain to achieve a therapeutic effect. Different routes of administration have been explored, including intravenous delivery and neurosurgical injection into the brain. However, these methods have limitations. An alternative approach being considered is injecting the gene vector into the fluid that surrounds the spinal cord and brain, either through the lumbar area or closer to the brain where the cerebrospinal fluid (CSF) resides.

Gene Therapy Studies in Clinical Trials

Several gene therapy studies using AAV vectors have been conducted in clinical trials. The majority of these studies utilize injection into the cisterna magna, a cavity at the bottom of the neck, or directly into the brain. This emerging experience provides valuable insights into the distribution and safety of gene therapy in the context of AS.

AAV9 Vector for Neurologic Diseases

The AAV9 vector has shown promise in treating neurologic diseases. It has the ability to cross the blood-brain barrier to some extent. Studies in monkeys have demonstrated the distribution of the AAV9 vector to the lungs, spleen, and spinal cord. This vector has been successfully used in the treatment of spinal muscular atrophy type 1, a neurodegenerative disease.

Gene Therapy Approaches for AS

Multiple gene therapy approaches are being pursued for AS. One approach aims to reduce the expression of the antisense RNA that suppresses the paternal allele of UBE3A. Another approach involves gene replacement therapy, where a normal version of UBE3A is introduced to compensate for the inactivated gene. These approaches are being evaluated in animal models to assess their effectiveness in reversing neurobehavioral abnormalities.

Genome Editing and RNA Interference

Genome editing techniques, such as CRISPR-Cas9, are being used to permanently knock down the antisense RNA in AS. This approach aims to reactivate the paternal gene by inactivating the antisense RNA. Preliminary studies in mice have shown promising results in terms of reactivating the gene and improving behavioral abnormalities.

RNA interference, using antisense oligos (ASOs), is another approach being explored. ASOs can be delivered via AAV vectors to continuously suppress the expression of the antisense RNA and reactivate UBE3A. Studies in mice have shown some success in downregulating the target region and reactivating the gene.

Future Directions

The gene therapy approach using AAV gene replacement therapy is the closest to clinical trials. Further studies in non-human primates are needed to confirm safety and assess gene transfer efficiency. Additionally, collaborations with other researchers are being pursued to explore alternative delivery systems, such as LNP-mRNA, for more efficient and stable reduction of UBE3A-ATS.

In conclusion, multiple genetic approaches are being pursued to treat Angelman Syndrome. These approaches aim to address the complex genetics of the disorder and provide potential therapeutic options for patients. Ongoing research and collaborations are crucial in advancing these genetic therapies and improving the lives of individuals with Angelman Syndrome.

Talk details

  • Title: Genetic Approaches for Treating Angelman Syndrome
  • Author(s): Jim Wilson
  • Author(s)’ affiliation: Perelman School of Medicine at the University of Pennsylvania
  • Publication date: 2022-01-04
  • Collection: 2021 FAST Science Summit