Using Human Neuronal Models to Validate a Novel Antisense Oligonucleotide Therapeutic for Fragile X Syndrome
James Fink, PhD
Principal Investigator
Noelle Germain, PhD
Co-Principal Investigator
Graham Dempsey
Co-Principal Investigator
Quiver Bioscience
Cambridge, MA
2025 Grant Funding: $100,000
Supported through FRAXA’s Curative Therapies Fund
Summary
This project explores important questions related to a cutting-edge treatment approach for Fragile X syndrome that aims to restore production of the missing FMRP protein — an approach that goes beyond treatments targeted at individual symptoms.
Most individuals with FXS produce faulty RNA from the FMR1 gene due to a splicing error. The team will test whether antisense oligonucleotides (ASOs) that correct this mistake and restore FMRP, reverses neuronal dysfunction. If successful, this could lead to a disease-modifying therapy that targets the root cause of Fragile X using personalized, human-based models.
UMass Chan Medical School has licensed a groundbreaking RNA-based treatment to QurAlis, a Cambridge, MA based biotechnology company that is expert in developing ASOs for rare diseases. Quiver, also based in Cambridge, is collaborating with QurAlis to determine the optimal ASO to tackle Fragile X syndrome.
The goal is to bring ASO treatment for Fragile X to clinical trials.
The Science
Fragile X syndrome (FXS) is caused by inherited disruptive changes in a single gene called FMR1. FMR1 normally produces the Fragile X Messenger Ribonucleoprotein (FMRP), which has many functions in the human brain. Loss of FMRP results in functional deficits in the neurons of Fragile X individuals that lead to some of the symptoms of the disorder.
Because animal research models, such as mice, do not completely share FXS genetic mechanisms with humans, we have developed human neuronal models of FXS using stem cell technology. We convert Fragile X syndrome patient blood samples into stem cells and then direct them to become neurons, which function similarly to those in the Fragile X brain. We use these human neuronal models to understand the underlying cellular dysfunction resulting from Fragile X. Specifically, we use our proprietary optical technology to measure defects in the electrical communication between neurons. Importantly, we also use these models to study potential therapies for normalizing FXS-associated cellular dysfunction.
A recent scientific study reported that, in some Fragile X syndrome patients, rather than having no product from their FMR1 gene, they produced a non-functional gene product due to a fault in a process called RNA splicing. Using a drug known as an antisense oligonucleotide (ASO), the researchers showed preliminary evidence that they could correct this faulty splicing and produce a healthy, functional gene product from FMR1, resulting in restored FMRP in FXS blood samples. Because Fragile X is mainly a disease of the nervous system, it is imperative to determine if this same mechanism occurs in brain cells such as neurons and if this FMRP rescue approach can be applied in the Fragile X brain.
The overall goal of this proposal is to use human neuronal models of FXS to further investigate a novel treatment for these patients which involves restoring FMRP production through the correction of a flawed genetic mechanism. We will study the impact of the previously reported alternative FMR1 splicing event on neuronal function using FXS patient stem cell-derived neurons. We will then test the ability of ASOs that correct the spicing defect and restore FMRP to improve neuronal functional deficits.
If successful, the findings from this proposal will further improve our understanding of the biological basis of FXS in human neurons and lead to the advancement of a potentially disease-modifying therapy for FXS. Therapies that address the root cause of neurological disease, rather than just treating the symptoms, can potentially have a transformative impact on the quality of life for individuals with FXS.
