The Use of GTX 102, an ASO as a Potential Therapeutic for Angelman Syndrome (Dr Berry-Kravis)

Quick Overview

Dr. Elizabeth Berry-Kravis presented findings from a study on the use of GTX 102, an ASO, as a potential therapeutic for Angelman Syndrome at the 2020 FAST Science Summit. The study observed five patients who experienced transient ataxia and imbalance, as well as fatigue, after receiving doses of GTX 102. These symptoms resolved on their own and did not cause any significant problems. However, all five patients also developed mild to moderate weakness, primarily in their legs, which occurred six to 30 days after the last infusion. This weakness lasted for one to three weeks and took about 19 to 86 days to fully resolve. Despite these adverse events, the patients showed clinical improvements in multiple domains, including communication, motor skills, sleep, and behavior. The Clinical Global Impression scale showed significant improvements in various areas, and the Bailey scale detected changes in gross motor skills. The study also found potential positive effects on EEG readings and seizure control. Based on these findings, the study plans to amend the protocol to start at lower doses and modify the administration technique to minimize drug concentration at the injection site. The FDA’s approval is required before resuming dosing and enrollment.


In this talk, we will discuss the clinical observations made during a study on the use of GTX 102, an antisense oligonucleotide (ASO), as a potential therapeutic for Angelman Syndrome. The study was conducted by Dr. Elizabeth Berry-Kravis and her team at the 2020 FAST Science Summit.

Safety Observations

The primary outcome of the study was safety, and two safety problems were observed. The first was transient ataxia or imbalance, along with fatigue or tiredness, occurring after 20 milligram doses and higher. This symptom varied between patients and lasted from one day to three days. However, it did not cause any significant problems and resolved on its own.

The second safety issue was the development of mild to moderate weakness in the legs, which occurred in all five patients. This weakness occurred six to 30 days after the last infusion and may have been related to a buildup of the drug over multiple infusions. Three patients experienced significant weakness, with two being unable to walk. This adverse event occurred after the highest dose of 36 milligrams in four patients and after the second dose in one patient. The weakness lasted for one to three weeks, with full resolution taking 19 to 86 days.

Other Adverse Events

Apart from the safety issues mentioned above, there were no other serious adverse events that required hospitalization. Some mild events like headaches, urinary tract infections, and typical childhood infections were unrelated to the drug or the study. The patients tolerated lumbar punctures and anesthesia well.

Clinical Evaluations

Clinical evaluations were conducted to monitor the patients’ progress during the study. The interim evaluation revealed that all five patients showed improvement in multiple domains as assessed by the Clinical Global Impression-Improvement (CGI-I) scale. The mean global CGI-I score increased by 2.4 points, indicating a substantial improvement. All patients had at least two domains that were much or very much improved, and three domains that were minimally improved or better.

Clinical Improvements

The clinical improvements observed in the patients included acquiring spoken words, using new signs and gestures, improved use of augmentative or alternative communication devices, improved reading and response to name, better ability to follow commands and focus on tasks, increased engagement in e-learning, improved fine and gross motor skills, improved sleep, improved social engagement, and decreased maladaptive behaviors.

EEG and Biomarker Analysis

EEGs were conducted as a biomarker of drug effect. Preliminary results showed a reduction in notched delta waves and epileptiform discharges in three out of four patients. Seizures were well controlled at baseline, and no seizure adverse events were recorded.

Lessons Learned and Future Plans

The study revealed that GTX 102 is clinically active, even at lower doses. However, the serious adverse event of weakness in the legs cannot be allowed to happen. The plan is to amend the protocol by starting at lower doses, individual dose titration based on response and safety findings, capping the dose at 14 milligrams, and avoiding the 20 milligram dose. The administration technique will also be modified to minimize the drug at the injection site. The protocol amendment needs to be reviewed and approved by the FDA before resuming dosing and enrollment.


The study on the use of GTX 102 as a potential therapeutic for Angelman Syndrome showed promising clinical improvements in multiple domains. However, safety issues were observed, and the protocol will be amended to ensure patient safety. Further research is needed to explore the effects of GTX 102 in a way that promotes safety.

Talk details

  • Title: The Use of GTX 102, an ASO as a Potential Therapeutic for Angelman Syndrome (Dr Berry-Kravis)
  • Author(s): Elizabeth Berry-Kravis
  • Author(s)’ affiliation: Rush University Medical Center
  • Publication date: 2021-01-02
  • Collection: 2020 FAST Science Summit