Generation of mouse lines expressing human UBE3A antisense

Quick Overview

Dr. Art Beaudet, a leading researcher in Angelman Syndrome, presented his work on generating mouse lines expressing human UBE3A antisense at the 2016 FAST Science Summit. He discussed the use of antisense oligonucleotides (ASOs) to activate the paternal copy of the UBE3A gene in mice, which could potentially be used as a treatment for Angelman Syndrome. Dr. Beaudet also mentioned the challenges in developing a humanized mouse model for testing ASOs and the importance of conducting Phase 1 clinical trials to assess the efficacy of this treatment approach.

Introduction

Dr. Art Beaudet, a renowned expert in the field of Angelman Syndrome, presented his research on the generation of mouse lines expressing human UBE3A antisense at the 2016 FAST Science Summit. Dr. Beaudet is known for his groundbreaking work in identifying the UBE3A gene as the cause of Angelman Syndrome. In his presentation, he discussed the potential of using antisense oligonucleotides (ASOs) to activate the paternal copy of the UBE3A gene in mice, as well as the challenges and future directions of his research.

Background

Angelman Syndrome is a neurodevelopmental disorder characterized by severe intellectual disability, speech impairment, motor abnormalities, and a happy demeanor. Dr. Beaudet highlighted the favorable characteristics of Angelman Syndrome for potential treatment, including the relatively normal development of affected individuals at birth and the absence of structural brain abnormalities. He also emphasized the potential of activating the paternal copy of the UBE3A gene as a therapeutic strategy.

ASOs as a potential treatment

Dr. Beaudet discussed the use of ASOs to activate the paternal copy of the UBE3A gene in mice. ASOs are short strands of DNA that can target specific regions of the genome and interact with RNA molecules. In his studies, Dr. Beaudet and his team demonstrated that ASOs can effectively knock down the antisense RNA that silences the paternal copy of the gene, leading to the activation of the gene in mice. These ASOs were injected into the brain ventricles of mice and were found to distribute widely throughout the brain and persist for up to 16 weeks.

Challenges and future directions

While the activation of the paternal copy of the UBE3A gene in mice showed promising results, Dr. Beaudet acknowledged the challenges in translating this research to human clinical trials. One major challenge is the need for a humanized mouse model that expresses the human UBE3A antisense region. Dr. Beaudet and his team have been working on introducing human DNA fragments into the mouse genome, but this has proven to be more difficult than anticipated. Additionally, Dr. Beaudet discussed the potential of using rats as a model for studying Angelman Syndrome, as their antisense region is more similar to humans compared to mice.

Conclusion

Dr. Beaudet’s research on the activation of the paternal copy of the UBE3A gene using ASOs in mice provides valuable insights into potential therapeutic strategies for Angelman Syndrome. While there are challenges to overcome, such as the need for a humanized mouse model, this research opens up new possibilities for the development of targeted treatments for this neurodevelopmental disorder. The partnership between Dr. Beaudet and FAST (Foundation for Angelman Syndrome Therapeutics) is a significant step towards advancing research in this field and bringing hope to individuals with Angelman Syndrome and their families.