Genetic Unsilencing of Mecp2 as Novel Therapeutic Approach for Rett Syndrome
Abstract
The proposed project is aligned with the Fiscal Year 2017 Peer Reviewed Medical Research Program Topic Area “Rett syndrome” and focuses on two Areas of Encouragement for Rett syndrome research. The proposed project will aim to develop and validate a novel and innovative intervention for the treatment of Rett syndrome. Rett syndrome is a severe neurodevelopmental disorder affecting 1 in 10,000 girls. Rett syndrome is caused by mutations in a gene called MeCP2. These mutations occur spontaneously during early embryonic development. After apparently typical development after birth, individuals affected with Rett syndrome exhibit regression of skills around the second year of life, leading to hallmark symptoms such as severe communication deficits (e.g., loss of speech) and motor impairments (e.g., loss of the ability to walk). Affected individuals also exhibit lifelong respiratory problems, gastrointestinal dysfunction, seizures, anxiety, and orthopedic problems that pose a heavy emotional and financial burden on parents and caretakers. There is no cure of Rett syndrome; current treatments are ineffective and do not attempt to overcome the causative loss of MeCP2 function. Most individuals affected by Rett syndrome are girls who have one mutated and one normal copy of the MeCP2 gene in each brain cell, called a neuron. These neurons randomly choose to utilize either the mutated or the normal copy of the MeCP2 gene. If normal MeCP2 is silenced and mutant MeCP2 is active, then neurons become dysfunctional and contribute to neurological disease symptoms. Studies in engineered Rett syndrome mouse models have dramatically shown that restoring the normal MeCP2 gene in neurons can reverse most Rett syndrome symptoms, suggesting incredible therapeutic promise for activating of the normal MeCP2 gene copy in human patients. Researchers have been trying for years without success to activate the silenced copy of the MeCP2 gene with the use of drugs. Our novel approach will use genetic tools that directly interact with the chromosome region that is responsible for switching the MeCP2 gene on and off. Our proposed approach aims to flip a switch to turn on the silenced MeCP2 gene copy without changing the genetic code itself. If successful in cell culture and mouse models, our novel approach to activate MeCP2 could lead to a transformative treatment for Rett syndrome in humans.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810734
Entities
People
- Ralf Schmid
Organizations
- United States Army
- University of North Carolina at Chapel Hill