A Therapeutic Approach to Treating Angelman Syndrome Using Hematopoietic Stem Cell (HSC) Gene Replacement Therapy

Quick Overview

Researchers at the 2019 FAST Science Summit presented a therapeutic approach to treating Angelman syndrome using hematopoietic stem cell (HSC) gene replacement therapy. The therapy involves genetically modifying a patient’s own stem cells using a lentiviral vector to insert a modified form of the UBE3A gene, which is associated with Angelman syndrome. The modified stem cells are then transplanted back into the patient, allowing them to produce and deliver the functional UBE3A protein to affected neurons. Preclinical studies in mice have shown promising results, with improved motor activity, cognition, and gait observed in the treated mice. The researchers plan to submit a pre-IND package to the FDA and initiate clinical trials in adults and children with Angelman syndrome.

Introduction

In this talk, we will discuss a promising therapeutic approach to treating Angelman Syndrome using hematopoietic stem cell (HSC) gene replacement therapy. This approach involves genetically modifying a patient’s own stem cells to produce a functional copy of the UBE3A gene, which is responsible for the symptoms of Angelman Syndrome. We will explore the process of gene modification, the potential benefits of this therapy, and the progress made in pre-clinical studies.

Background

Angelman Syndrome is a rare genetic disorder that affects the nervous system, causing developmental delays, intellectual disability, speech impairments, and movement and balance problems. Currently, there is no cure for Angelman Syndrome, and treatment focuses on managing the symptoms.

The Therapeutic Approach

The proposed therapy involves using a patient’s own stem cells for gene modification. The stem cells are genetically modified using a lentiviral vector to insert a modified form of the UBE3A gene. This modified gene will produce a functional UBE3A protein, which can then be delivered to affected neurons in the body, including the brain and central nervous system.

The Potential Benefits

One of the key advantages of this therapy is that it has the potential to be a one-time treatment. By genetically modifying the patient’s own stem cells, the therapy aims to provide a long-term solution for Angelman Syndrome. The modified stem cells will continuously produce the functional UBE3A protein, which can help alleviate the symptoms of the disorder.

Pre-Clinical Studies

Pre-clinical studies have been conducted using an immunodeficient mouse model with the UBE3A knockout. These studies involved transplanting genetically modified human stem cells into the mice to assess the effectiveness of the therapy. The results showed promising improvements in motor activity, motor skills, cognition, and brain wave patterns in the mice treated with the modified stem cells.

Clinical Procedure

The clinical procedure for this therapy involves collecting the patient’s stem cells, genetically modifying them using a lentiviral vector, and then transplanting them back into the patient. The procedure is similar to autologous stem cell transplantation, which is commonly used in the treatment of certain cancers and autoimmune disorders. The patient undergoes a one-time chemotherapy to clear the bone marrow and create space for the modified stem cells to engraft.

Safety and Side Effects

The therapy has shown minimal side effects in pre-clinical studies and other gene therapy trials. The chemotherapy used in the procedure is less intense than traditional chemotherapy for cancer treatment. The most common side effect is a temporary decrease in blood counts, which can be managed with transfusions and antibiotics. Long-term side effects are minimal, with a low risk of organ damage or secondary cancers.

Future Plans

The researchers plan to submit a pre-Investigational New Drug (pre-IND) package to the FDA once they have more mature data from their studies. The initial phase of the clinical trial will involve six adults with Angelman Syndrome to assess the safety and efficacy of the therapy. If successful, the trial will be expanded to include more adults and children.

Conclusion

Hematopoietic stem cell gene replacement therapy shows promise as a therapeutic approach for treating Angelman Syndrome. By genetically modifying a patient’s own stem cells, this therapy aims to provide a long-term solution and potentially cure the disorder. Pre-clinical studies have shown encouraging results, and the researchers are optimistic about the future of this therapy.