Scientists have developed a new transgene control system that shows early promise for treating rare brain disorder Rett syndrome.
Preclinical studies have demonstrated that the microRNA system - called Expression Attenuation via Construct Tuning (EXACT) - can regulate the production of MeCP2 protein, which is deficient in Rett syndrome, to a tolerable level, opening the doorway to a potential gene therapy.
Rett syndrome is a rare genetic disorder that affects brain development, resulting in severe mental and physical disability in around 1 in 10,000 girls born each year. It is caused by a mutation in the MECP2 gene, located on the X chromosome, and is rarely seen in boys.
There is currently no disease-modifying treatment for Rett syndrome.
The EXACT platform has been developed by Stuart Cobb, Professor of Translational Neuroscience at Simons Initiative in the Developing Brain and Centre for Discovery Brain Sciences at the University of Edinburgh, working in partnership with Neurogene, a clinical-stage company founded to bring life-changing genetic medicines to patients and families affected by rare neurological diseases.
The preclinical study data, published in Science Translational Medicine, supported the initiation of Neurogene’s ongoing Phase 1/2 clinical trial with NGN-401 gene therapy for Rett syndrome, developed using the EXACT platform.
Rett syndrome is caused by loss of function variants in the MECP2 gene; however, high levels of MeCP2 can lead to toxicity. Conventional, unregulated gene therapy leads to variable cellular uptake that can result in toxic levels of transgene expression. EXACT enables therapeutic and tolerable transgene expression on a cell-by-cell basis through regulation by microRNA.
Professor Cobb, who is also Chief Scientific Officer at Neurogene, said:
Gene therapy with transgene regulation holds the potential to treat a variety of dosage-sensitive disorders that currently have no disease-modifying options available.
The development of a potential treatment option for Rett syndrome was the impetus for creating EXACT, and its translation to NGN-401 is a major advancement. I would like to thank my colleagues at the University of Edinburgh, Edinburgh Innovations and Neurogene for their support in the development of EXACT. ”
Rachel McMinn, Founder and Chief Executive Officer of Neurogene, said:
NGN-401 gene therapy for Rett syndrome is our first product candidate incorporating EXACT, which was intentionally developed to deliver therapeutic and tolerable MeCP2 levels. The preclinical data published today and the translation of the platform into the clinic support the proposition that EXACT has the potential to overcome the limitations of conventional gene therapy to address Rett syndrome and other devastating disorders. ”
