Title: hUBE3A-AAV9 Gene Replacement Therapy for Angelman Syndrome: Progress Toward the Clinic

Quick Overview

Dr. James M. Wilson, a professor at the University of Pennsylvania, presented progress on the development of gene therapy for Angelman Syndrome at the 2022 FAST Science Summit. He discussed the use of the AAV9 vector for gene transfer and the challenges of delivery to the central nervous system. Dr. Wilson also highlighted the potential for cross-correction in Angelman Syndrome, where the secreted UBE3A protein could be taken up by adjacent cells to achieve a broader effect. He shared preclinical data showing promising results in animal models and discussed plans for future clinical trials. Dr. Wilson emphasized the importance of safety and collaboration with the Angelman Syndrome community in advancing gene therapy for the disease.


In this talk, we will discuss the progress made in developing gene therapy for Angelman Syndrome. The speaker, Dr. James M. Wilson, is a professor at the University of Pennsylvania and a pioneer in the field of gene therapy. He will provide insights into the current state of gene therapy and its potential for treating rare monogenetic disorders like Angelman Syndrome.

The Potential of Gene Therapy

Dr. Wilson emphasizes that the science of gene therapy has never been better. Significant advancements have been made in both the technical and clinical aspects of gene therapy. However, he acknowledges that investors may be hesitant to invest in gene therapy due to the challenge of making profits from one-time treatments. Despite this, organizations like FAST (Foundation for Angelman Syndrome Therapeutics) continue to support gene therapy research.

The Stages of Gene Therapy Development

Dr. Wilson explains that gene therapy development for monogenic diseases follows a staged approach. First, studies are conducted in animal models to determine the potential effectiveness of the therapy. Then, non-human primates are used to evaluate the safety and dosing of the therapy. Finally, human studies are conducted to assess safety and target engagement.

Challenges in Gene Delivery

Dr. Wilson highlights the importance of delivery in gene therapy. He explains that the method of administration plays a crucial role in the success of the therapy. Two common routes of administration for CNS diseases are intravenous delivery and injection into the cerebral spinal fluid. Dr. Wilson’s team has popularized the latter approach, which involves injecting the vector into the cisterna magna. However, he acknowledges that delivering the vector to all cells in the brain remains a challenge.

Safety Considerations

Dr. Wilson’s lab pays close attention to safety in gene therapy. They have identified a potential safety concern related to injecting vectors into the cerebrospinal fluid. In some cases, a few cells in the brain may undergo degeneration, leading to peripheral nerve manifestations such as coordination difficulties and pain. However, extensive studies have shown that this safety concern is rare and manageable.

Clinical Trials and Progress

Dr. Wilson discusses ongoing clinical trials for lysosomal storage diseases, which use a similar vector and approach to the one planned for Angelman Syndrome. These trials have shown promising results, with significant reductions in disease biomarkers and stabilization of disease progression. Dr. Wilson emphasizes the importance of biomarkers in evaluating the effectiveness of gene therapy.

Gene Therapy for Angelman Syndrome

Dr. Wilson’s team has developed a clinical candidate vector for Angelman Syndrome. They have conducted preclinical studies in animal models to evaluate the potential effectiveness of the therapy. They have also explored the possibility of achieving cross-correction in Angelman Syndrome, where the therapy’s effects extend beyond the cells that receive the gene. Initial experiments have shown promising results, suggesting that cross-correction may be possible.

Next Steps

Dr. Wilson’s team is preparing for meetings with health authorities to discuss the clinical trial design. They are also developing assays to support manufacturing and planning to initiate IND-enabling studies. Once these steps are completed, they will begin first-in-human studies. Dr. Wilson emphasizes the importance of stakeholder input in the clinical trial design and the need for biomarkers to assess the therapy’s effectiveness.


Dr. Wilson concludes by expressing his excitement about the potential of gene therapy for rare diseases. He acknowledges that there is still much to learn and that biology is often more complex than anticipated. However, he believes that with the support of the community and the experience gained from previous gene therapy programs, they can move forward with confidence in the safety and potential effectiveness of the therapy for Angelman Syndrome.

Talk details

  • Title: hUBE3A-AAV9 Gene Replacement Therapy for Angelman Syndrome: Progress Toward the Clinic
  • Author(s): James M. Wilson
  • Author(s)’ affiliation: Perelman School of Medicine at the University of Pennsylvania
  • Publication date: 2022-12-03
  • Collection: 2022 FAST Science Summit