Blood Stem Cells: New Gene Therapy Approach for Angelman Syndrome

Quick Overview

Dr. Joe Anderson, an associate professor at the University of California at Davis stem cell program, presented a new gene therapy approach for Angelman Syndrome at the 2018 FAST Science Summit. The approach, called cross-correction, involves genetically modifying blood stem cells to overexpress the UBE3A protein, which is deficient in individuals with Angelman Syndrome. These modified cells are then transplanted back into the patient, allowing the functional protein to be transferred to affected neurons and restore their function. Initial studies in a mouse model have shown promising results, with one transplanted mouse showing significant improvement in motor and behavioral skills. Further studies are ongoing to evaluate the efficacy and safety of this approach.

Introduction

Dr. Joe Anderson, an associate professor at the University of California at Davis stem cell program, presented a new gene therapy approach for Angelman Syndrome at the 2018 FAST Science Summit. Dr. Anderson’s research focuses on developing cell and gene therapies for various diseases, including Angelman Syndrome, lysosomal storage diseases, and HIV. In his presentation, he discussed the use of blood stem cells and a cross-correction strategy to restore the function of the UBE3A gene, which is deleted in individuals with Angelman Syndrome.

Cross-Correction Strategy

Dr. Anderson’s research is based on a cross-correction strategy, which involves genetically modifying cells to overexpress the wild type form of the UBE3A protein. These modified cells then transfer the functional protein to the affected neurons, restoring their function. While this strategy is currently being used for lysosomal storage diseases and leukodystrophies, Dr. Anderson proposed applying it to Angelman Syndrome as well.

Gene Therapy Approach

The gene therapy approach used by Dr. Anderson’s team is an insertional gene therapy, where the functional copy of the UBE3A gene is inserted into donor cells using a lentiviral vector gene transfer system. This modified UBE3A gene is then permanently integrated into the DNA of the cells. The lentiviral vector is a modified human virus that delivers the gene into the cells of interest. The advantage of this approach is that it allows for the long-term expression of the functional UBE3A gene.

Targeting Blood-Forming Stem Cells

To deliver the modified UBE3A gene throughout the body, Dr. Anderson’s team targets blood-forming stem cells, also known as hematopoietic stem cells. These stem cells are isolated from the patient and genetically modified ex vivo using the lentiviral vector. The modified cells are then transplanted back into the patient, where they home back to the bone marrow and start producing new blood cells that express functional UBE3A.

Preclinical Studies and Results

Dr. Anderson’s team conducted preclinical studies using an immunodeficient UBE3A mouse model. They demonstrated the functionality of the modified UBE3A protein and observed phenotypic recovery in motor and behavioral skills in one transplanted mouse. The team is currently evaluating more mice and plans to conduct safety and toxicity studies in the future. They aim to submit a pre-IND package to the FDA and eventually move towards human clinical trials.

Conclusion

Dr. Anderson’s research presents a promising gene therapy approach for Angelman Syndrome using blood stem cells and a cross-correction strategy. The use of genetically modified cells to restore the function of the UBE3A gene shows potential for long-term treatment. While further studies are needed, the initial results are encouraging and pave the way for future advancements in the treatment of Angelman Syndrome.