Progress in designing epigenetic regulators for persistent UBE3A activation

Quick Overview

David Segal from UC Davis presented progress in designing epigenetic regulators for persistent UBE3A activation in Angelman Syndrome. He discussed the use of transcription factors to activate the silenced paternal allele of UBE3A, which is responsible for the syndrome. Segal’s team has developed a protein that can be injected into UBE3A-deficient mice, crossing the blood-brain barrier and activating UBE3A expression in the brain. However, the protein has a relatively short duration of action, requiring frequent injections. To address this, Segal is exploring the use of epigenetic modifying enzymes to achieve more persistent gene activation. He is also investigating cell-based delivery methods and has successfully engineered mesenchymal stem cells to produce the therapeutic protein. Additionally, Segal announced the development of an Angelman Syndrome rat model, which will allow for further study of the syndrome’s behavioral and neurological phenotypes.

Introduction

In this talk, we will discuss the progress made in designing epigenetic regulators for persistent UBE3A activation. This research was presented by David Segal at the 2015 FAST Science Summit.

Background

The research team at UC Davis has been working on developing a transcription factor therapy for Angelman Syndrome. The therapy is based on the understanding that in Angelman Syndrome, there is a silenced paternal allele that is intact but silenced. The team aims to use transcription factors, which are proteins that can bind to DNA near a gene and either activate or turn off the gene, to address this issue.

Transcription Factor Therapy

The team has successfully built a protein that can activate UBE3A, a gene associated with Angelman Syndrome, in UBE3A-deficient mice. By injecting this artificial transcription factor into the mice, the team observed an increase in UBE3A expression in the brain. They also found that the protein was able to cross the blood-brain barrier and distribute widely in the brain.

However, the team discovered that the protein had a relatively short duration of action. After 24 hours, most of the protein was no longer present in the brain. This posed a challenge for the research, as a more persistent effect was desired.

Epigenetic Regulation

To address the challenge of persistence, the team turned to epigenetics. Epigenetics refers to the chemical modifications of proteins that wrap around DNA, which can regulate gene expression. The team designed artificial transcription factors that contained epigenetic modifying enzymes. These enzymes could potentially shut down the antisense transcript associated with UBE3A in a more persistent way.

Initial experiments in mouse cells showed promising results, with a decrease in gene expression when the epigenetic repressors were used. Further studies are needed to determine if this effect is persistent.

In-Situ Production

Another approach the team is exploring is in-situ production, which involves engineering the body to produce the therapeutic protein where it is needed. The team has been investigating cell-based delivery, where cells are introduced into the brain and secrete the protein. Mesenchymal stem cells have been used for this purpose, and initial experiments showed that these cells could produce the therapeutic protein and distribute it throughout the brain.

Animal Models

To further study the effects of UBE3A activation, the team has created animal models of Angelman Syndrome. They have successfully developed a rat model by using targetable nucleases to remove the UBE3A gene from rat embryos. The first generation of rats with the deletion has been born, and further studies will be conducted to characterize their phenotypes and compare them to existing mouse models.

Conclusion

The research team at UC Davis has made significant progress in designing epigenetic regulators for persistent UBE3A activation. Their work with transcription factor therapy, epigenetic regulation, in-situ production, and animal models has provided valuable insights into potential treatments for Angelman Syndrome. Further research is needed to fully understand the effects and potential of these approaches.