The Foundation for Angelman Syndrome Therapeutics announced today that it has taken license to a lentiviral gene therapy for the treatment of Angelman syndrome, and formed a new company around it called Transformatx Biotherapeutics LLC.
The investigational modified UBE3A lentiviral therapy program, now named ube-cel, first came out of a 2016 sponsored research agreement with the University of California at Davis. The transformative technology resulted in broad phenotype rescue in both newborn and adult mice with Angelman syndrome, similar to their wild-type counterparts.
The formation of Transformatx is an example of the importance of patient advocacy groups engaging in the drug development pipeline in rare diseases—for fiercely advocating for safety on the one hand, but also not losing promising therapies because of surmountable obstacles.
The goal of gene therapy is to begin producing the UBE3A protein—and the on-switch, or promoter, is the mechanism that permits the new gene that codes for the protein to start being expressed. During initial development efforts, it was discovered that the specific promoter being used in the Angelman syndrome program was also used in a different trial, with a different drug, where it was found to have a safety risk in a small subset of the patients called myelodysplastic syndrome. As Sharyl Fyffe-Maricich explained in yesterday’s presentation, all viral vectors have a theoretical risk of insertional oncogenesis, but it is more commonly with lentiviruses with specific promoters. By using safer promoters, this seems to be a much lower risk—based off of 15 years of data in human patients.
When this other program’s finding was disclosed, FAST moved quickly to abandon that promoter and begin identifying a new one with a good safety track record—adding additional expertise by engaging Alessandra Biffi, MD, a pediatric transplant surgeon from the University of Padua and the Harvard Stem Cell Institute, and Donald Kohn, MD of the UCLA Broad Stem Cell Research Center. Dr. Biffi has been involved in the development of multiple lentiviral therapies for rare neurological diseases, including Libmeldy (atidarsagene autotemcel), a gene therapy treatment approved in the E.U. for metachromatic leukodystrophy. Dr. Kohn has worked for over 35 years on the development of therapies to treat genetic diseases, which includes extensive work on hematopoietic stem cell gene therapy.
Watch the videos above again. The efficacy of this approach in the mouse is remarkable. We didn’t want to lose that if we didn’t have to. We look forward to keeping everyone posted on Transformatx as it progresses!