Preclinical Research on Gene Therapy for Angelman Syndrome Advances Towards Clinical Trials

The investigational ASO therapy, GTX-102, developed by Scott Dindot at Texas A&M University's School of Veterinary Medicine and Biomedical Sciences, is making strides in the treatment of Angelman syndrome. This therapy is currently being evaluated in the Phase 1/2 KIK-AS clinical trial (NCT04259281).

GTX-102 targets a genetic region associated with Angelman, which is similar between humans and nonhuman primates, making it particularly relevant for testing in macaque monkeys, a common nonhuman primate model. The therapy was designed to be effective in both patients and relevant animal models.

Last year, interim data for 11 treated patients showed GTX-102 to be well tolerated and improved behaviour, motor function, communication, and sleep. Based on these promising results, an amendment was made to allow higher monthly doses in the clinical trial.

In 2020, early KIK-AS results supported GTX-102's effectiveness, but higher doses were associated with leg weakness in five children. The study was paused to amend the dosing and administration protocols, and resumed in 2021.

The researchers discovered a previously unknown regulatory region at the start of human UBE3A-AS that is conserved and potentially represents the ancestral origin of the gene in mammals. They designed ASOs to target this conserved region, with the goal of suppressing UBE3A-AS's activity and reactivating paternal UBE3A in both animal models and humans.

The UBE3A gene encodes for ubiquitin protein ligase E3A (UBE3A), an enzyme that tags unwanted or damaged proteins to be broken down as part of the cell's recycling process. Defects in the maternal UBE3A gene impair UBE3A enzyme activity and cellular recycling, leading to Angelman symptoms.

The study on GTX-102 was published in Science Translational Medicine. The research offers promise for Angelman syndrome and provides a path forward for developing ASO therapies for other genetic disorders.

Notably, Astellas Pharma merged with GeneTx Biotherapeutics for the development of GTX-102 and later acquired the product. Ultragenyx Pharmaceutical, which is sponsoring the clinical trial for GTX-102, acquired GeneTx last year to continue GTX-102's development. Scott Dindot, the developer of GTX-102, is now an executive director at Ultragenyx Pharmaceutical.

The clinical trial is expected to enroll up to 83 children with Angelman, ages 4-17, in the U.K., the U.S., Australia, and Canada. As the trial progresses, we eagerly await further developments in the treatment of Angelman syndrome with GTX-102.

Preclinical Research on Gene Therapy for Angelman Syndrome Advances Towards Clinical Trials