A Mixed Modality Approach to Treating Rett Syndrome
Abstract
Our proposal relates to the topic area of Rett syndrome (RTT). RTT is a severe neurodevelopmental disorder with an incidence of 1 in ~10,000 girls throughout the world. It is caused by a single gene mutation of the X-linked methyl-CpG-binding protein 2 (MECP2), a chromatin-associated gene product that is crucial for neuronal development. There is presently no disease-specific treatment or cure. Despite its single-gene nature, finding a treatment for RTT has proven especially challenging. Encouraging results have been achieved in mice, where genetically restoring normal MECP2 expression reversed disease even after the onset of symptoms. This provides significant hope that doing the same would treat or cure RTT in humans as well. Our goal is to advance a novel therapeutic that we have been developing over the past 7 years. RTT girls carry one mutant MECP2 allele and one normal allele. In half of their cells, because of X-chromosome inactivation, the mutant copy is expressed while the normal copy lies dormant on the silent X chromosome. Our approach employs an innovative “X-reactivation” strategy and aims to restore endogenous expression of MECP2 by reactivating the dormant, normal copy of MECP2 carried on the inactive X chromosome. We have secured proof-of-concept that a combinatorial approach achieves partial MECP2 restoration. We have also developed a new female mouse model in which to test candidate X-reactivating drugs. We now propose to optimize the drug prototype for RTT in the disease-relevant animal model and in RTT-specific patient cells, and obtain in vivo proof of concept that X-reactivating drugs can rescue symptoms in a mouse model of RTT syndrome. Our goal is to identify a clinical candidate within 3 years’ time and to establish partnerships with industry to bring candidate drugs to the market in the ensuing years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910022
Entities
People
- Jeannie Lee
Organizations
- Massachusetts General Hospital
- United States Army