Hematopoietic Stem Cell Gene Therapy: What is ube-cel?
Hematopoietic stem cell gene therapy, specifically ex vivo gene therapy, is a promising approach for treating Angelman syndrome. This involves taking a patient’s own stem cells, transducing them with a modified UBE3A gene using a lentiviral vector, and then transplanting these cells back into the patient’s body. This approach has shown positive results in animal studies, improving motor function and brain structure. However, there have been concerns about the safety of lentiviral gene therapies, particularly related to insertional oncogenesis. A specific promoter used in some lentiviral gene therapies has been associated with cancer events. As a result, the ube-cel program, which aims to develop a gene therapy for Angelman syndrome, is currently in the preclinical stage and working to redesign the vector with a new promoter. Despite setbacks, the promising results from early studies have motivated researchers to continue exploring this approach.
In this talk, we will discuss a new investigational program called ube-cel, which focuses on hematopoietic stem cell gene therapy. This therapy involves the use of ex vivo gene therapy, where a patient’s own cells are taken outside of the body, modified with gene therapy, and then reintroduced into the body. We will explore the process of ube-cel therapy and its potential benefits for treating Angelman syndrome.
Ex Vivo Gene Therapy
Ex vivo gene therapy is a method of administering gene therapy outside of the body. It involves taking a patient’s own cells, such as stem cells, and introducing the gene therapy into these cells. The modified cells are then transplanted back into the patient’s body, where they can differentiate into blood cells and express the desired gene. This process, known as cross-correction, allows the modified cells to provide functional copies of the gene throughout the body, including the brain.
The Process of Ube-cel Therapy
The ube-cel therapy for Angelman syndrome begins with mobilizing the patient’s blood cells. This is done by administering a drug that helps the stem cells come out of the bone marrow and circulate into the blood. The blood cells are then harvested through a process called apheresis, where the stem cells are separated and collected. These CD34 stem cells are sent to a manufacturing facility, where the gene therapy is introduced into them.
Before reintroducing the modified cells back into the patient’s body, a conditioning process is performed. This involves administering chemotherapy, such as busulfan, to lower the levels of blood cells in the body and create space for the new cells to engraft and grow. After conditioning, the blood cells with the gene therapy are transfused back into the patient’s body.
Promising Research and Redesigning the Construct
The idea of using ex vivo gene therapy for treating CNS diseases, such as Angelman syndrome, was initially explored by researcher Alessandra Biffi. Her work on a degenerative brain disease called metachromatic leukodystrophy showed promising results, with treated patients experiencing improvements in motor function and brain structure.
Inspired by this transformative research, the Foundation for Angelman Syndrome Therapeutics (FAST) sponsored a program at UC Davis to develop a modified UBE3A lentiviral gene therapy for Angelman syndrome. The initial studies in mice showed significant improvements in motor function and gait analysis.
However, further investigation into a similar lentiviral gene therapy called Skysona revealed concerns about the safety of the MNDU3 promoter used in the construct. The European Regulatory Agency raised concerns about insertional oncogenesis, where the therapy integrates into the genome in unintended ways, potentially leading to cancer events.
As a result, the ube-cel program decided to redesign the construct and explore alternative promoters to ensure the safety and efficacy of the therapy. The program has enlisted the expertise of renowned researchers in HSC gene therapy, including Dr. Biffi and Dr. Donald Kohn at UCLA, to move forward with the development of ube-cel.
Hematopoietic stem cell gene therapy, specifically the ube-cel program, holds great promise for the treatment of Angelman syndrome. By utilizing ex vivo gene therapy and modifying a patient’s own stem cells, this therapy aims to provide functional copies of the UBE3A gene throughout the body, including the brain. Although the program has faced setbacks due to safety concerns with the original construct, the research and development of ube-cel continue with the goal of bringing transformative therapies to patients with Angelman syndrome.
- Title: Hematopoeitic Stem Cell Gene Therapy: What is ube-cel?
- Author(s): Jennifer Panagoulias
- Author(s)’ affiliation: FAST
- Publication date: 2022-12-03
- Collection: 2022 FAST Science Summit