Angelman Updates with Dr. Terry Jo Bichell, featuring Dr. Ralf Schmid

Quick Overview

Dr. Ralf Schmid, a translational research director at the Gene Therapy Program at the University of Pennsylvania, discusses the use of gene therapy for Angelman Syndrome in an interview with Dr. Terry Jo Bichell. Dr. Schmid explains that gene therapy involves delivering the UBE3A gene, which is missing or mutated in Angelman Syndrome patients, into the brain using a modified virus called adeno-associated virus (AAV). The AAV delivers the gene to neurons, where it is expected to produce the UBE3A protein and improve the patient’s condition. Dr. Schmid also discusses the safety and persistence of the gene therapy, as well as the ongoing research and clinical trials in the field. He emphasizes the need for further studies in animal models and clinical trials to determine the effectiveness of gene therapy in patients. Overall, gene therapy shows promise as a potential treatment for Angelman Syndrome, but more research is needed to fully understand its impact.


In this edition of Angelman Updates, we have the pleasure of interviewing Dr. Ralf Schmid, a translational research director at the Gene Therapy Program at the University of Pennsylvania. Dr. Schmid shares his background and how he got involved in the field of neuroscience and gene therapy. He also discusses his work in developing gene therapy for Angelman Syndrome and other neurodevelopmental disorders.

Background and Journey

Dr. Schmid originally trained as a biochemist but developed a keen interest in neuroscience during his PhD studies. He specialized in neuroscience and focused on brain development and diseases associated with it during his postdoctoral training. Dr. Schmid’s work gradually shifted towards more cutting-edge technologies, eventually leading him to gene therapy.

He became involved in the Angelman program while working at UNC Chapel Hill, where he collaborated with Ben Philpott’s lab. Dr. Philpott’s lab had discovered a small molecule that could reactivate UBE3A, the gene associated with Angelman Syndrome, in mice. Dr. Schmid joined the lab and worked on both Angelman Syndrome and Rett Syndrome, another neurodevelopmental disorder. Eventually, he received an opportunity to lead a team at the University of Pennsylvania to develop gene therapy for both diseases.

Gene Therapy for Angelman Syndrome

Dr. Schmid explains that gene therapy for Angelman Syndrome involves delivering the UBE3A gene into the brain using a virus called adeno-associated virus (AAV). AAV is a safe and well-tolerated virus that can be targeted to specific organs. The AAV used for Angelman Syndrome gene therapy, AAV9, is designed to target neurons in the brain.

Once the AAV9 virus delivers the UBE3A gene into the brain, it enters the nucleus of the neuron and activates the production of UBE3A protein. The goal is to replace the missing or mutated UBE3A gene in Angelman Syndrome patients and improve their condition. Dr. Schmid emphasizes that gene therapy does not alter the patient’s genome but introduces a new gene into the cells.

Challenges and Future Directions

Dr. Schmid acknowledges that gene therapy is a complex process that is still being optimized for central nervous system (CNS) applications. The scientific community is working on improving the delivery and effectiveness of gene therapy for neurological disorders. He also addresses concerns about the immune response to the AAV virus used in gene therapy. Researchers are exploring ways to suppress antibodies temporarily to allow repeated administration of the same AAV vector.

Clinical Trials and Expectations

Dr. Schmid highlights the importance of conducting clinical trials to evaluate the safety and therapeutic value of gene therapy in patients. Animal models, such as mice and non-human primates, are used to study the administration and effects of gene therapy. However, the ultimate test is to try gene therapy in human patients.

He explains that the timeline for observing the effects of gene therapy in patients is not yet clear. In animal models, it takes a minimum of two weeks for the UBE3A protein expression to stabilize. It may take several weeks or months to see improvements in patients, but the exact timeline is uncertain.

The Fascination with Neuroscience and Gene Therapy

Dr. Schmid expresses his fascination with neuroscience and gene therapy, describing them as frontiers of the unknown. He finds the brain and its diseases incredibly intriguing, and he believes there is still much to learn. The opportunity to explore and make a difference in the field of gene therapy for neurodevelopmental disorders like Angelman Syndrome motivates him.


Dr. Ralf Schmid’s work in gene therapy for Angelman Syndrome offers hope for patients and their families. His dedication to understanding the brain and developing innovative treatments demonstrates the potential of gene therapy in improving the lives of individuals with neurodevelopmental disorders. As research progresses, the field of gene therapy continues to push the boundaries of what is known, offering new possibilities for treatment and understanding.

Talk details

  • Title: Angelman Updates with Dr. Terry Jo Bichell, featuring Dr. Ralf Schmid
  • Author(s): Ralf Schmid
  • Author(s)’ affiliation: University of Pennsylvania
  • Publication date: 2022-05-23
  • Collection: Angelman Updates with Dr. Terry Jo Bichell