Program Update on Hematopoietic Stem Cell Gene Therapy for Angelman Syndrome

Quick Overview

In this update presented at the 2020 FAST Science Summit, Joe Anderson from UC Davis discusses their progress in developing a stem cell gene therapy for Angelman Syndrome. The approach involves inserting a modified form of the UBE3A gene into blood stem cells, which can then deliver the gene to affected cells throughout the body, including the brain. The team has completed proof of concept and preclinical studies, submitted a pre-IND package to the FDA, and is currently working on IND enabling studies. They anticipate submitting an IND within the next year for a Phase 1 clinical trial in adult Angelman syndrome patients. The trial will use the patient’s own stem cells to avoid rejection and will monitor safety and efficacy. Once safety is established in adults, pediatric patients may be enrolled. The project is supported by funding from the Foundation for Angelman Syndrome, UC Davis Stem Cell Program, and the MIND Institute.

Introduction

In this talk, we will provide an update on the stem cell gene therapy approach for Angelman Syndrome. This update was presented at the 2020 FAST Science Summit by Joe Anderson, an associate professor at UC Davis.

Therapeutic Approach

The therapeutic approach involves an insertional gene therapy where a modified form of UBE3A, a functional gene, is inserted into hematopoietic stem cells, also known as blood stem cells. Once the gene is inserted, the blood stem cells and the immune system cells derived from them will be able to express and deliver UBE3A to affected cells. A lentiviral vector system is used to permanently insert and integrate the gene into the cells and their daughter cells. The blood system is chosen as the delivery system because it can reach almost any part of the body, including the brain.

Current Progress

Collaborating with Jill Silverman’s lab and Dave Segal’s lab, the research team has completed all proof of concept and preclinical studies. They have assembled a pre-IND (Investigational New Drug) package and submitted it to the FDA. The team has received responses from the FDA and is currently working on the IND enabling studies.

Clinical Trial

The team plans to submit the IND for a Phase 1 clinical trial in Angelman syndrome patients within the next year. The trial will be an autologous transplant, meaning the patient’s own stem cells will be used to prevent rejection. Sufficient stem cells will be obtained from the patient, gene modified, and then infused back into the patient to create an immune system that delivers the UBE3A gene throughout the body.

Initially, the clinical trial will enroll adult patients as the FDA considers it more than minimal risk for pediatric patients. Mobilized peripheral blood stem cells will be taken from the adult patients and gene modified with the UBE3A expressing lentiviral vector. The gene modification will be done outside the body in a GMP (Good Manufacturing Practice) facility. Once the patient is ready, the modified stem cells will be infused back into the patient. The patients will be monitored for safety and efficacy of the therapy. Once the safety profile is established in adult patients, pediatric patients may be enrolled.

Acknowledgments

Joe Anderson acknowledges the contributions of his lab members, Julie Haley, the vivarium staff, Dr. Segal’s lab, Dr. Silverman’s lab, the clinical team led by Dr. Abedi, and Dr. Nolta, Geralyn, and Bill. The research is funded by the Foundation for Angelman Syndrome, UC Davis Stem Cell Program, and the MIND Institute.

Conclusion

The stem cell gene therapy approach for Angelman Syndrome shows promising progress. With ongoing IND enabling studies, the team aims to submit the IND for a Phase 1 clinical trial within the next year. This therapy has the potential to provide a safe and effective treatment for Angelman Syndrome patients.