The Rett Syndrome Research Trust (RSRT) continues to spearhead groundbreaking research in its pursuit of a cure for Rett syndrome. RSRT has announced an investment of $10.3 million in 2023 to highly innovative research projects, bringing together leading scientists, institutions, and biotechnology companies dedicated to advancing a cure for the disorder. This is a record for the most funds that RSRT has awarded in a single year. Founded in 2008, RSRT is the largest funder of Rett research globally. The Trust’s total funding to expedite a cure has reached $77 million.

Rett syndrome, stemming from mutations in the MECP2 gene, presents a devastating array of progressive neurological symptoms, robbing individuals of speech, normal movement, and hand use during early childhood. Symptom treatments to date remain palliative though first-generation gene therapies to correct the underlying cause of Rett syndrome have recently entered the clinic with encouraging preliminary results, adding significant momentum to the pursuit of curative therapeutics.

In the new age of genetic medicine, addressing the underlying genetic cause is possible not only via gene therapy but also by correcting mutations in either the gene or the RNA. In 2023, RSRT boldly embraced continued innovation in the field, significantly boosting investments and enlisting top-tier scientists to spearhead new breakthroughs in gene therapy, DNA editing including base and prime editing, and various RNA editing strategies. With significant strides advancing the field almost daily, RSRT is pushing forward all genetic modalities, ensuring a comprehensive exploration of therapeutic possibilities to cure Rett syndrome. Additional clinical development support including biomarker discovery and validation, biosensor development work, as well as accumulation of real-world patient data in the Rett Syndrome Global Registry and CARE (Ciitizen Aggregated health Record Extraction) study were also key areas of investment.

“We are immensely grateful to the Rett families that fundraise for RSRT and to all our donors. Without them, this exciting research simply would not happen. I thank every supporter of RSRT for sharing our sense of urgency to change lives. With the progress we’ve made in recent years coupled with these exciting new awards, I’m more optimistic than ever that we are getting closer to genetic-based medicines that can have a profound impact,” says Monica Coenraads, Chief Executive Officer of RSRT.

Highlights of RSRT's 2023 Research Awards:

Quantitative, dosage-compensated gene therapy for Rett Syndrome

Investigator: Michael Elowitz and Viviana Gradinaru, CalTech
Modality: Gene therapy
Budget: $500,000

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.

Directed RNA Editing for the Repair of MECP2 Mutations Causing Rett Syndrome

Investigator: Peter Beal, UC Davis
Modality: RNA editing
Budget: $390,506

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.

Correction of R270X mutations in MECP2 RNA using Axiomer® Technology

Company: ProQR
Modality: RNA editing
Budget: $1,120,000

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.

Single AAV Deliverable and Transiently Inducible Base Editors for Rett Syndrome

Investigator: Guoping Feng, MIT
Modality: Base editing
Budget: $3,734,738

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.

Correcting Rett syndrome-causing C-terminal Deletions using Adenine Base Editors

Investigator: Adrian Bird and Jacky Guy, University of Edinburgh
Modality: Base editing
Budget: $315,502

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.

Translating Advanced Genome Editing Approaches for Rett Syndrome Therapeutics

Investigators: Erik Sontheimer, Jonathan Watts, Scot Wolfe, UMASS Medical School
Modalities: Base and prime editing
Budget: $2,343,091

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.

Correlating Rett Syndrome Brain CSF Proteomes with Blood Plasma Profile

Investigator: Victor Faundez, Emory University
Category: Clinical Accelerator - Biomarkers
Budget: $1,150,965

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.