Preclinical-clinical transition initiated for Angelman syndrome gene therapy

In a significant development for the treatment of Angelman syndrome, an investigational ASO therapy named GTX-102 is being evaluated in the Phase 1/2 KIK-AS clinical trial (NCT04259281). This therapy, developed by Scott Dindot, PhD, at Texas A&M University's School of Veterinary Medicine and Biomedical Sciences, is specifically designed to be effective in patients and relevant animal models.

GTX-102 targets a genetic region associated with Angelman that is similar between humans and nonhuman primates. The UBE3A gene, which encodes for ubiquitin protein ligase E3A (UBE3A), an enzyme crucial for cellular recycling, is only active in specific regions of the brain in the mother, while the father's gene is silenced by the UBE3A antisense (UBE3A-AS) transcript. Defects in the maternal UBE3A gene impair UBE3A enzyme activity and cellular recycling, leading to Angelman symptoms.

Last year, interim data for 11 treated patients showed GTX-102 was well tolerated and improved behavior, motor function, communication, and sleep. However, higher doses were associated with leg weakness in five children. The study was paused to amend the dosing and administration protocols, and it resumed in 2021. An amendment was made to allow higher monthly doses based on the promising results from the 11 patients in the Phase 1/2 study.

Scott Dindot, who is also an executive director at Ultragenyx Pharmaceutical, the sponsor of the clinical trial for GTX-102, and affiliated with the University of Texas Rio Grande Valley (UTRGV), discovered a previously unknown regulatory region at the start of human UBE3A-AS that is conserved across mammals. ASOs designed to target this conserved region were successfully used to repress UBE3A-AS and activate the paternal UBE3A gene in nerve cells from a person with Angelman.

Infusing the ASO into the spinal canal in macaque monkeys reduced UBE3A-AS and increased paternal gene activity in several regions of the brain and spinal cord. The Phase 1/2 KIK-AS 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.

The research and findings offer promise for Angelman syndrome and provide a path forward for developing ASO therapies for other genetic disorders. The advancement of this investigational molecular therapy into clinical development supports the hope for a potential treatment for this debilitating condition.