Dr Theodora Markati on the Angelman Syndrome Therapies in Development

Quick Overview

Dr. Theodora Markati, a researcher at the University of Oxford, discusses the current landscape of Angelman Syndrome therapeutics in a webinar supported by FAST UK. She explains the pathology of Angelman Syndrome, which is caused by a deficiency of the UBE3A protein, and the different levels at which therapeutic interventions can act. Dr. Markati discusses the two main categories of therapies: upstream treatments, which aim to restore UBE3A in the brain cells, and downstream treatments, which aim to improve brain cell function and treat specific symptoms. She provides an overview of the different therapies in development, including gene therapy, antisense oligonucleotides, topoisomerase inhibitors, CRISPR-Cas tools, and zinc fingers. Dr. Markati emphasizes the need for objective and cross-comparable measures in clinical trials and the importance of natural history studies and biomarker studies. She concludes by highlighting the complexity of the therapeutic pipeline for Angelman Syndrome and provides a link to a scientific paper for more information.

Introduction

In this webinar, Dr Theodora Markati, a researcher at the University of Oxford, discusses the current landscape of Angelman Syndrome therapeutics. She provides an overview of the different therapeutic categories and their potential impact on the disorder.

Understanding Angelman Syndrome Pathology

Dr Markati begins by explaining the pathology of Angelman Syndrome. The disorder is caused by a deficiency of the UBE3A protein, which is responsible for recycling other proteins in the nervous system. This deficiency leads to disrupted communication between neurons and impaired synaptic plasticity.

Upstream Treatments

The first therapeutic category, known as upstream treatments, focuses on genetic therapies that aim to restore the UBE3A protein in the brain cells of individuals with Angelman Syndrome. Dr Markati discusses two subcategories of upstream treatments: gene therapy and cell therapy. Gene therapy involves using harmless viruses as vectors to deliver a normal copy of the UBE3A gene to the brain cells. Cell therapy, on the other hand, involves collecting the patient’s own blood cells, infecting them with a normal copy of the gene in the lab, and then infusing them back into the body.

Unsilencing the Paternal Copy

The second therapeutic category aims to unsilence the paternal copy of the UBE3A gene, which is blocked by a naturally occurring molecule called antisense transcript. Dr Markati explains that antisense oligonucleotides, which are complementary to the antisense transcript, have shown efficacy in animal studies. She also mentions other approaches, such as topoisomerase inhibitors, CRISPR-Cas tools, and zinc fingers, which have shown promise in preclinical studies.

Downstream Treatments

Downstream treatments, also known as symptomatic treatments, focus on improving the function of brain cells and treating specific symptoms associated with Angelman Syndrome. Dr Markati highlights that these treatments cannot cure the disorder but can be combined with genetic therapies to enhance overall effectiveness. She mentions ongoing clinical trials for downstream treatments, including the assessment of a compound called Gaboxadol.

The Need for Objective Measures

Dr Markati emphasizes the importance of developing objective and cross-comparable measures for assessing the efficacy of different treatments. She explains that these measures are crucial for designing better and more efficient clinical trials. Additionally, she discusses the need for natural history studies and biomarker studies to gather essential data on the progression of the disease and the effectiveness of treatments.

Conclusion

In conclusion, Dr Markati provides key messages about the current state of Angelman Syndrome therapeutics. She highlights the number of different therapeutic approaches in development and the need for further research to determine their efficacy. She encourages participation in natural history studies and biomarker studies and provides contact information for those interested in getting involved.

For more detailed information, Dr Markati refers to a scientific paper titled “Therapies in Preclinical and Clinical Development for Angelman syndrome,” published in the journal Expert Opinion on Investigational Drugs.

Thank you for attending the webinar.