GTX-102 is an experimental gene therapy for Angelman syndrome being developed by GeneTx Biotherapeutics and Ultragenyx.

How does GTX-102 work?

Mutations in the maternal copy of the UBE3A gene found on chromosome 15 cause Angelman syndrome. Children inherit one copy of a chromosome from each parent. In certain parts of the body, however, only the copy from one parent is active. This is called genetic/genomic imprinting.

In many cells of the nervous system, only the maternal copy of the UBE3A gene is active. So, if it has a mutation, it will not work properly and produce dysfunctional copies of ubiquitin-protein ligase E3A (UBE3), a protein for which this gene provides instructions.

Studies in mice have shown that UBE3A is critical to the growth and development of nerve cells as well as their ability to communicate with each other.

GTX-102 is a gene therapy called an antisense oligonucleotide. It is designed to target and inhibit the molecule that keeps the paternal copy of the UBE3A gene from being active in cells. This molecule is called UBE3A antisense transcript (UBE3A-AS).

GTX-102 lowers the levels of UBE3A-AS to reactivate the paternal copy of the gene. Research has shown that this can alleviate neurological symptoms in animal models of Angelman syndrome.

GTX-102 in clinical trials

A Phase 1/2 clinical trial (NCT04259281) is evaluating the safety, tolerability, pharmacokinetics (movement in the body), and potential efficacy of GTX-102. This is an open-label, dose-escalating trial in which participants are assigned to one of five dosing groups.

Patients receive intrathecal injections (injections directly into the spinal column) of the treatment following a dose-escalation scheme at the start of the trial, and then at 30, 58, and 86 days.

Patients are monitored for about six months, during which researchers record any adverse events and assess UBE3A protein levels in the cerebrospinal fluid (the fluid that surrounds the brain and spinal cord) as well as any changes in symptoms.

Interim results, announced in five patients in October 2020, showed improvements in multiple symptom domains including sleep, behavior, communication, and gross and fine motor skills.

Researchers measured the improvements using the Clinical Global Impression of Improvement Scale for Angelman Syndrome (CGI-I-AS). Caregivers of the patients also reported improvements such as patients being more communicative, social, and responsive as well as showing improvements in gait and posture.

However, interim safety data also showed that all five patients experienced leg weakness between one and four weeks after a high-level dose. Four of the five patients experienced this serious adverse event after receiving the highest dose, which was 10 times greater than their initial dose. The fifth patient experienced weakness after receiving the second-highest dose, which was six times greater than the initial dose. Two of the patients were no longer able to walk or bear weight on their legs. The weakness fully resolved in four of the five patients within 19 to 70 days after starting intravenous immunoglobulin injections and corticosteroid treatment. The fifth patient almost fully recovered after three to four weeks.

Due to the serious adverse events, GeneTx and Ultragenyx have paused the trial. They plan to decrease the doses to start at the lowest previous dose that led to improvements. They will then increase the doses more slowly from there depending on how each patient responds. They also plan to modify the intrathecal injections to reduce the time the treatment is in contact with the portion of the spinal cord that controls the legs.

Recruitment and treatment will begin again once the U.S. Food and Drug Administration (FDA) accepts the new protocols. The estimated study completion date is in January 2022, at which time participants will have the option to continue treatment through an open-label extension study.

Other information

GTX-102 has received orphan drug, rare pediatric disease, and fast track designations from the FDA.

The only serious adverse reaction experienced by patients so far has been weakness in the legs. Other adverse events were headache, fatigue, and acute transient ataxia (lack of coordination and muscle control), which cleared up in 24 to 72 hours.


Last updated: Dec. 7, 2020


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