Gene Therapy for Angelman Syndrome through RNA Interference

Quick Overview

Ryan Butler presented his research on RNA gene therapy for Angelman syndrome at the 2021 FAST Science Summit. He discussed the role of UBE3A in protein degradation and how its absence can lead to the phenotypes associated with Angelman syndrome. Butler proposed a “stop-the-stop” approach using short hairpin RNA (shRNA) to target the UBE3A-ATS region and increase UBE3A expression. He shared preliminary data showing a reduction in UBE3A-ATS levels in neuroblastoma cells and an increase in UBE3A expression in mouse cerebellum. Butler also mentioned the importance of testing the shRNA candidates in human iPSC-derived neurons and conducting safety assays in non-human primates. He acknowledged his team and funding from Taysha Gene Therapies Incorporated.


In this talk, I will be discussing the potential of RNA gene therapy for Angelman syndrome. This approach, if successful, could provide a one-time injection that lasts for the patient’s lifetime. I would like to disclose that this work is funded by Taysha Gene Therapies Incorporated, and I have a personal financial interest in Taysha. UT Southwestern also has a financial interest in Taysha through exclusive licensure.

Understanding Angelman Syndrome and UBE3A

Angelman syndrome is a genetic disorder characterized by developmental delays, intellectual disabilities, and neurological problems. The lack of UBE3A, a protein responsible for protein degradation, can directly or indirectly lead to the phenotypes associated with Angelman syndrome. UBE3A also plays a role in neuronal maturation and the development of connections between neurons.

The Stop-the-Stop Approach

The stop-the-stop approach aims to treat Angelman syndrome by inhibiting the long non-coding antisense transcript UBE3A-ATS, which silences the paternal allele of UBE3A. By targeting this region with short hairpin RNA (shRNA) and vectorizing it using adeno-associated viruses (AAV), it is possible to increase UBE3A expression and potentially alleviate the symptoms of Angelman syndrome.

Challenges and Considerations

There are several challenges and considerations in developing this gene therapy approach. One challenge is ensuring that the shRNA does not lead to the degradation of critical genes near the target region, which could result in another genetic disorder, Prader-Willi syndrome. Another consideration is the potential for off-target effects and cardiotoxicity. Extensive bioinformatics analysis and testing in non-human primates are necessary to address these concerns.

Progress and Future Directions

Preliminary experiments have shown promising results in neuroblastoma cells and mouse models. The next step is to test the shRNA candidates on human induced pluripotent stem cells (iPSCs) derived neurons. These iPSCs were obtained from donors and are being used to study the effects of the gene therapy approach. The ultimate goal is to develop a safe and effective treatment for Angelman syndrome that can be tested in clinical trials.


I would like to acknowledge the contributions of Hye Ri Kang and Violeta Zaric, who have played a crucial role in this research. I would also like to thank Dr. Yong-Hui Jiang for providing the iPSCs and the teams at UT Southwestern and Taysha for their support and funding.

In conclusion, RNA gene therapy shows promise as a potential treatment for Angelman syndrome. Further research and development are needed to refine the approach and ensure its safety and efficacy. With continued progress, we hope to bring this therapy closer to clinical use and improve the lives of individuals with Angelman syndrome.

Talk details

  • Title: Gene Therapy for Angelman Syndrome through RNA Interference
  • Author(s): Ryan Butler
  • Author(s)’ affiliation: University of Texas Southwestern Medical Center
  • Publication date: 2022-01-04
  • Collection: 2021 FAST Science Summit