AS Drug Screening, Mechanisms Regulating Imprinting of UBE3A, and New Animal Models of AS

Quick Overview

The speaker discussed their work on developing a therapeutic for Angelman syndrome (AS). They focused on understanding the mechanisms that regulate imprinting of the UBE3A gene in neurons, as well as identifying new treatments for AS through high-throughput screening assays. They also mentioned their efforts to develop a large animal model of AS using pigs. The goal is to use these models to test the efficacy and safety of potential therapies before they are tested in humans. The speaker expressed gratitude to their team and the FAST organization for the opportunity to be involved in this research.

Introduction

In this talk, we will discuss the research being conducted as part of the FIRE project, with a focus on developing a therapeutic for Angelman syndrome (AS). The research aims to understand the mechanisms that regulate imprinting of UBE3A in neurons, identify new treatments for AS through high-throughput screening assays, and develop new animal models of AS.

Understanding Imprinting of UBE3A

UBE3A is a gene that is regulated in a unique way in the brain. The research team is interested in understanding how and why UBE3A is imprinted in neurons. By understanding this process, they hope to develop strategies to circumvent it and reactivate the paternal allele of UBE3A. This could potentially replace the lost function caused by a mutation or deletion on the maternal chromosome.

The team has focused on studying the expression of a long non-coding transcript that is involved in turning off the paternal allele of UBE3A. They have found that this transcript is highly expressed in neurons and inhibits transcription of the paternal allele. The team is working to understand the precise mechanism by which this transcript turns off the expression of the paternal allele.

High-Throughput Screening Assays for New Treatments

The research team is actively involved in identifying new treatments for AS. They have developed high-throughput screening assays to quickly test a large number of drugs and compounds. This approach allows them to screen thousands of potential candidates and expedite the drug discovery process.

The team has used target-based and symptom-based approaches in their screening assays. In the target-based approach, they are looking for therapies that target UBE3A and reactivate the expression of the paternal allele. In the symptom-based approach, they are looking for compounds or drugs that mitigate the symptoms associated with AS. This approach is unbiased and focuses on finding treatments that improve the symptoms, regardless of the underlying mechanism.

The team has already screened thousands of drugs and identified several potential candidates for further validation. They are currently in the process of validating these hits to determine their effectiveness in treating AS.

Development of New Animal Models

In addition to drug screening, the research team is also working on developing new animal models of AS. While there is already a mouse model of AS, the team believes that a large animal model, specifically a pig model, would be more physiologically similar to humans and provide a better platform for testing potential treatments.

The team is collaborating with experts in large animal genetics and characterization to develop the pig model. They plan to use the pig model to test the most promising candidates identified through their drug screening assays. This will provide a crucial step between mouse models and human trials, ensuring that the treatments are effective and safe before being tested in patients.

Conclusion

The research being conducted as part of the FIRE project aims to develop a therapeutic for AS. The team is studying the mechanisms that regulate imprinting of UBE3A, identifying new treatments through high-throughput screening assays, and developing a pig model for preclinical testing. These efforts will contribute to the development of effective treatments for AS and improve the lives of individuals with this condition.