Modality: Gene therapy
Michael Elowitz and Viviana Gradinaru from Caltech aim to tackle the "Goldilocks" challenge in Rett syndrome gene therapy, focusing on precise expression of the MECP2 gene. Previous funding from RSRT enabled the Elowitz lab to develop a family of MECP2 expression cassettes that allows gene expression to be independent of how many copies of a gene are delivered into a cell. This new funding will allow for testing of these regulatory circuits in mice and iPSCs. We expect the outcome will provide a novel way to regulate MECP2 levels in gene therapies and enhance our understanding of how MECP2 levels affect Rett symptoms.
Investigator: Peter Beal, UC Davis
Modality: RNA editing
Peter Beal from UC Davis, with RSRT funding, has been focused on RNA editing, a process that modifies nucleotides in RNA strands, with the potential to correct disease-causing mutations leading to Rett syndrome. This new funding will allow the Beal lab to optimize chemically-modified guide RNAs to recruit ADAR, a naturally occurring enzyme in cells, to repair mutations in the MECP2 gene associated with Rett syndrome. Challenges such as designing effective guide RNAs and ensuring high on-target editing efficiency with minimal off-target effects will be addressed.
Modality: RNA editing
ProQR, in collaboration with RSRT and Peter Beal, is conducting a pilot study to correct R270X mutations in MECP2 RNA using Axiomer® Technology as a proof of concept aimed to broaden to include other mutations. ProQR plans to create a panel of small RNAs for R270X, advancing translational studies in pre-clinical mouse models. This collaboration aims to establish a development partnership for a pipeline of allele-specific therapeutics, marking a significant step toward clinical entry within the next three years.
Investigator: Guoping Feng, MIT
Modality: Base editing
Guoping Feng at MIT is taking a next-generation approach to genome editing for Rett syndrome. Building on previous RSRT funding, Feng's team aims to generate smaller and self-inactivating editors, create new viral vectors, and test editases in cells and animal models. Feng's multi-pronged attack on genome editing showcases the potential for significant advancements in Rett syndrome therapeutics.
Investigator: Adrian Bird and Jacky Guy, University of Edinburgh
Modality: Base editing
Adrian Bird and Jacky Guy at the University of Edinburgh are addressing C-terminal deletions (CTDs) in MECP2, which account for approximately 10% of all Rett cases. By using base editing, Bird and Guy aim to change stop codons into tryptophan codons, stabilizing truncated proteins associated with CTD mutations. This method could potentially treat all Rett patients with CTD mutations using a single therapeutic.
Investigators: Erik Sontheimer, Jonathan Watts, Scot Wolfe, UMASS Medical School
Modalities: Base and prime editing
Erik Sontheimer, Jonathan Watts, and Scot Wolfe at the University of Massachusetts Medical School will focus on base and prime editing approaches for Rett syndrome. Building on previous funding from RSRT, this collaborative trio aims to utilize base editing and prime editing technologies, discovered by David Liu, to fix mutations in MECP2. Base editing, being closer to clinical application, will be aggressively pursued for specific mutations, while prime editing, a newer technology, will be explored for its potential to edit multiple mutations with a single therapeutic. The UMASS collaboration is expected to play a crucial role in advancing editing approaches for Rett syndrome.
Investigator: Victor Faundez, Emory University
Category: Clinical Accelerator - Biomarkers
Victor Faundez at Emory University is working on correlating Rett syndrome brain-cerebrospinal fluid (CSF) proteomes with blood plasma profiles. With considerable expertise in proteomic analysis, Faundez aims to identify proteomic alterations characteristic of Rett syndrome, potentially serving as biomarkers for disease monitoring and therapy. By analyzing post-mortem brains, spinal fluid, and plasma samples from Rett patients, Faundez seeks to answer key questions about differences in brain proteomes, confirm alignment with mouse models, and advance candidates for reliable biomarker potential, addressing the urgent need for prognostic tools in Rett syndrome.
For a complete list of projects please click here.
About Rett Syndrome Research Trust
RSRT is the patient advocacy organization working to cure Rett syndrome. As the largest funder of Rett syndrome research worldwide, RSRT has played a vital role in initiating and evolving the trajectory of progress toward a cure. All genetic therapies in development by biopharmaceutical companies have leveraged discoveries and resources made possible by RSRT.
About Rett Syndrome
Rett syndrome is a genetic childhood neurological disorder caused by random mutations of the MECP2 gene on the X chromosome. The disorder affects predominantly girls but can rarely also affect boys. Symptoms typically become apparent between the ages of 12 to 18 months. Rett syndrome is devastating as it deprives toddlers of speech, hand use, and normal movement often including the ability to walk. As childhood progresses the disorder brings anxiety, seizures, tremors, breathing difficulties, and severe gastrointestinal issues. While their bodies suffer, it is believed that their cognitive abilities remain largely intact. Although most children survive to adulthood, they require total round- the-clock care.