Gene Therapy

Gene therapy is an experimental method of using genes (the fundamental units of heredity) to prevent or treat a disease. It either inactivates a defective gene or replaces it with a healthy copy to slow or halt the progression of a disease.

Gene therapy is still in the experimental stages. Researchers need to perform many safety and efficacy studies before they can test it in clinical trials.

Gene therapy for Angelman syndrome

In Angelman syndrome, there is a mutation in the maternal copy of the UBE3A gene. This results in symptoms that include communication problems, movement and coordination issues, seizures, and scoliosis (abnormal curvature of the spine).

Gene therapy for Angelman syndrome currently focuses on introducing a healthy copy of the UBE3A gene directly into the nerve cells using a harmless adeno-associated virus (AAV) or ways to reactivate the normal paternal copy of the gene. Researchers are investigating several gene therapy approaches for the treatment of Angelman syndrome.


GT-AS is an investigative gene therapy that PTC Therapeutics is developing. (PTC Therapeutics acquired the therapy’s original developer, Agilis Biotherapeutics, in 2018).

GT-AS uses an AAV-based approach to deliver a working copy of the UBE3A gene to the brain and spinal cord. This way, the body can produce its protein product E3A, which is necessary for proper nervous system function.

Preclinical studies have shown that GT-AS is effective in localizing to nerve cells in the brain, increasing levels of E3A, and improving cognitive deficits associated with Angelman syndrome.

GT-AS received orphan drug designation from the U.S. Food and Drug Administration (FDA) in 2015, followed by a similar designation from the European Commission in 2016.


GTX-102 is a gene therapy being developed by GeneTx Biotherapeutics and Ultragenyx. GTX-102 is an antisense oligonucleotide designed to inhibit the molecule that keeps the paternal copy of the UBE3A gene from being active in cells. By lowering levels of the molecule, called UBE3A antisense transcript (UBE3A-AS), researchers believe they can reactivate the paternal copy of the gene to reduce symptoms of Angelman syndrome in patients.

GTX-102 is currently being investigated in a Phase 1/2 clinical trial where patients are receiving intrathecal (into the spinal column) injections on days 1, 30, 58, and 86. Patients will be monitored for six months for adverse reactions and for changes in the levels of the E3A protein in the cerebrospinal fluid (liquid that surrounds the brain and spinal cord). Interim results in five patients showed improvements in multiple symptoms but all patients also experienced leg weakness after a high-level dose leading to the investigators pausing the trial. The trial will resume after a new protocol with lower dose levels has been approved by the FDA.

More gene therapy research

Researchers at the University of North Carolina (UNC) demonstrated the potential of gene therapy to reduce seizures in mouse models of Angelman syndrome. They found that turning on the UBE3A gene using a chemical switch was effective in preventing seizures in juvenile mice models of Angelman syndrome. However, this approach did not seem to be effective in adult mice.

Recently, UNC researchers also showed that gene therapy delivered directly to the fetal brain could offer a possible one-time treatment for Angelman syndrome. They used CRISPR-Cas9 gene-editing tools directly on mouse brains in utero to switch on the paternal dormant copy of the UBE3A gene in several areas of the brain, including the cerebral cortex (which is associated with cognitive functions), hippocampus (associated with learning and memory), and cerebellum (associated with balance and movement). This approach helped in activating UBE3A gene function in these brain regions.

Follow-up studies in human nerve cells grown in the laboratory also proved to be effective. This approach one day may allow the in utero treatment of Angelman syndrome.

Safety concerns

Gene therapy, although highly promising, comes with uncertainties. It requires thorough safety and efficacy evaluations before it can progress into clinical trials. Some of the associated risks of gene therapy include inflammation, toxicity, and cancer.

There also is the possibility of the gene being delivered to the wrong site in the body and the uncontrollable expression of the newly inserted gene, both of which can cause serious complications.


Last updated: May 21, 2020


Angelman Syndrome News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.