Fragile X syndrome (FXS) is one of the most common causes of mental impairment and is the most common single-gene cause of autism. The disease is caused by mutations in a gene on the X chromosome, affecting about one in 4,000 to 5,000 males and one in 6,000 to 8,000 females. Patients display a range of neuropsychiatric symptoms, including intellectual disability, delayed language acquisition, poor social interaction, hyperarousal, hypersensitivity, repetitive behaviors, disrupted sleep and attention deficit hyperactivity disorder. Current therapies include antipsychotics, antidepressants and other stimulants to manage disease symptoms, but there are no Food and Drug Administration (FDA)–approved treatments for FXS itself. The lead collaborators have identified a compound that reverses key deficits in genetic models of FXS. The goal of this project is to complete key preclinical studies to enable clinical evaluation in juvenile FXS patients.
Scientific Synopsis
The lead collaborators have developed a small molecule inhibitor (BPN14770) of phosphodiesterase-4D (PDE4D). In FXS, large expansions of CGG repeats within the FMR1 gene result in its silencing and subsequent loss of the encoded protein. This protein product, FMRP, plays a regulatory role in the brain, suppressing the translation of mRNA important for synaptic function. Loss of FMRP results in decreased production of cAMP, overexpression of otherwise tightly regulated genes, and synaptic dysfunction characteristic of FXS. Modulation of cAMP signaling through PDE4 inhibition had previously been tested in fruit fly models of FXS, showing an ability to rescue behavioral and structural phenotypes. The FRAXA Research Foundation tested BPN14770 in mouse models of FXS, showing increases in behavioral activity and social interaction, as well as restoration of brain cAMP levels.
Lead Collaborator
Tetra Discovery Partners, Inc., Grand Rapids, Michigan
Mark Gurney, Ph.D., M.B.A.
Public Health Impact
Fragile X syndrome is a rare disorder affecting approximately 30,000 patients in the United States. There are no FDA-approved therapies for FXS, and the off-label medications commonly used to manage disease symptoms come with undesirable side effects. There is a clear unmet medical need for new therapies for FXS.
Outcomes
Approved studies are ongoing.
Project Details
- Investigational New Drug (IND)-directed toxicology