Progress Toward ATF and CRISPR Therapies for Angelman Syndrome
Dr. Dave Segal discussed the progress towards artificial transcription factors (ATF) and CRISPR therapies for Angelman Syndrome. He explained the role of DNA, RNA, and proteins in gene expression and the importance of UBE3A protein in Angelman Syndrome. Dr. Segal mentioned the use of antisense oligonucleotides (ASOs) to activate UBE3A and the potential of CRISPR-Cas13 as a gene therapy. He shared the challenges faced in their experiments and the potential of zinc finger proteins as an alternative approach. Preliminary results showed promising restoration of motor functions in mice. Dr. Segal emphasized the need for further research and funding to develop effective treatments for Angelman Syndrome.
Dr. Dave Segal, a prominent figure in the Angelman community, presented his research on the progress toward artificial transcription factors (ATF) and CRISPR therapies for Angelman Syndrome at the 2023 FAST Science Summit. Dr. Segal discussed the work funded by FAST and other organizations, highlighting the potential of gene-targeted therapies for treating Angelman Syndrome.
Understanding the Genetics
Dr. Segal began by explaining the basic genetics of Angelman Syndrome. He described how genes are encoded in DNA, which then produces RNA, and ultimately leads to the production of proteins. In the case of Angelman Syndrome, a specific gene called UBE3A is silenced on the paternal allele, resulting in the absence of the UBE3A protein. This is the underlying cause of the syndrome.
Dr. Segal acknowledged the groundbreaking work done by Scott Dindot’s group and others in developing antisense oligonucleotide (ASO) therapy for Angelman Syndrome. ASOs are designed to target and remove the portion of RNA that is inhibiting the expression of UBE3A. This therapy has shown promising results in clinical trials, allowing UBE3A to be expressed at its normal level.
Exploring Gene Therapy with CRISPR
Building on the success of ASO therapy, Dr. Segal and his team at UC Davis explored the possibility of using CRISPR technology for gene therapy. They focused on a specific CRISPR protein called Cas13, which has the ability to target and cut RNA. The goal was to deliver Cas13 using adeno-associated virus (AAV) vectors, allowing it to remove the inhibitory RNA and activate UBE3A.
Challenges and New Approaches
Dr. Segal shared the challenges they encountered in their initial experiments with Cas13. They discovered that Cas13 had increased toxicity, making it unsuitable for therapy. However, they also explored a high-fidelity version of Cas13 and an alternative approach using zinc finger proteins to target the inhibitory RNA. These experiments showed promising results in restoring UBE3A expression and improving motor function in mouse models of Angelman Syndrome.
In conclusion, Dr. Segal highlighted the ongoing research and development of ATF and CRISPR therapies for Angelman Syndrome. While there are still challenges to overcome, such as optimizing the dosage and delivery methods, the progress made so far is promising. Dr. Segal expressed gratitude for the funding received from FAST and emphasized the importance of continued research to find effective treatments for Angelman Syndrome.
During the Q&A session, Dr. Segal addressed questions about the potential complications of reactivating the paternal gene in individuals with uniparental disomy (UPD) and the possibility of using injectable proteins for therapy. He acknowledged the need for further research and monitoring to ensure that UBE3A expression remains within a safe range.
Dr. Dave Segal’s presentation at the 2023 FAST Science Summit highlighted the progress and challenges in developing ATF and CRISPR therapies for Angelman Syndrome. His research, funded by FAST and other organizations, offers hope for future treatments that could restore UBE3A expression and improve the lives of individuals with Angelman Syndrome.
- Title: Progress Toward ATF and CRISPR Therapies for Angelman Syndrome
- Author(s): David Segal
- Author(s)’ affiliation: University of California, Davis
- Publication date: 2023-11-12
- Collection: 2023 FAST Science Summit