We Fund Rett Syndrome Research

Dr. Bajikar has found that MeCP2 could be regulating 2 key genes – GDF11 and Smad3. The imbalance MeCP2 causes within these genes may contribute to the development of Rett syndrome. With this project, he will dig deeper into restoring the proper function of these genes in mouse models and tests drugs that can restore this balance.Mentor: Huda Zoghbi, MD | Baylor College of Medicine

Current gene therapy vectors are not able to differentiate MECP2 expression between different cells. This project is designed to advance the efficacy and safety of gene therapy for moving rapidly to its exploitation in the clinical arena. A new AAV capsid and gene therapy vector with novel elements able to reduce MECP2 gene levels exclusively in glial cells will be validated.

Dr. Emeson’s lab has developed a novel RNA-editing strategy to engineer short RNAs that may help efficiently repair specific mutations in the RNA transcripts encoding MECP2. Now, they will begin further study of this repair mechanism, beginning with a test tube-based system, and later followed by the use of human cell lines which have been modified to carry the MECP2 mutations.

Many individuals with Rett syndrome experience extreme sensitivity to sounds and touch, as well as heightened anxiety, which can impact communication and social interactions. This study will test whether vagus nerve stimulation (VNS) paired with rehabilitation therapy can reduce sensory hypersensitivity and anxiety in a Rett syndrome rat model. VNS is already FDA-approved for epilepsy and depression and has been successfully used in PTSD treatment. If effective, this approach could offer a new therapy to improve sensory processing, social engagement, and quality of life for individuals with Rett syndrome.

The choroid plexus is easily accessible from the circulatory system and has been exploited as an easy target for gene therapy of pediatric neurological diseases. This project explores if the choroid plexus can be a therapeutic target to treat RTT, paving the way to clinical trials.Co-PI: Takao Hensch, PhD – Harvard Medical School

Heat Shock (HS) proteins are a critical mechanism by which all cells respond to stress, and increased HS-signaling is seen in RTT. This project will determine whether increases in HS signaling is driving symptom presentation or serving as a compensatory response to slow disease progression. Targeting HS-signaling would be predicted to impact many of the diverse cell types known to be affected by MeCP2 deficiency.Co-PI: Colleen Niswender, PhD – Vanderbilt University

Dr. Guil’s lab will design a new gene therapy strategy that improves several features of the current approaches. They will explore moderating MeCP2 levels to avoid toxicity due to excessive expression of the gene (which can be as bad as its deficiency) and discriminating between cells that express the normal gene and cells that express the mutant gene.

This project employs a CRISPR-based strategy for restoring MeCP2 through X-chromosome reactivation. An improved CRISPR cassette will be designed that is dramatically reduced in size, thereby allowing it to fit well inside AAV shell for delivery into cells.Kyle Fink, PhD | University of California, Davis

Around 30% of Rett syndrome cases are caused by nonsense mutations, which create premature stop signals that prevent the MECP2 gene from producing a full-length, functional protein. This study will test a novel approach using engineered transfer RNAs (ACE-tRNAs) to override these faulty stop signals and restore MeCP2 production. Unlike traditional gene therapy, this method works at the RNA level, potentially offering a safer and more controlled way to restore MeCP2 function. Researchers will evaluate its effectiveness in patient-derived cells and a specialized mouse model, assessing its potential as a targeted therapy for individuals with nonsense mutations in MECP2.

This study focuses on restoring MECP2 in patients by reactivating its dormant, normal copy carried on the inactive X chromosome via an ASO-based strategy. This will be achieved by performing proof-of-concept studies in a mouse model and optimizing preclinical candidates in patient cells.

Biomarkers are things that can be measured in a person and might relate to how affected a person is. Unfortunately, there are currently no good biomarkers of improvement in RTT which could help with the development of new treatments and clinical trials. This group has found changes in brain waves in patients and in mouse models that they think could be such biomarkers. In this project, they will test if chemicals that have shown functional improvement in mice also improve brain waves. If successful, these brain wave measurements could be used to shorten the length of clinical trial process, getting drugs and other treatments to patients faster.
Co-PI: Hong-Wei Dong, MD, PhD – Vanderbilt University