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Therapeutics for Rare and Neglected Diseases

PAK Inhibitor for Fragile X Syndrome

Fragile X syndrome (FXS) is the most common inherited cause of mental impairment and the most common known single-gene cause of autism. The disease is caused by mutations in a gene on the X chromosome and affects about one in 3,000 to 4,000 males. Current therapies include anti-psychotics, anti-depressants or other stimulants to manage disease symptoms, but there are no FDA-approved treatments for FXS itself. A specific protein, p21-activated kinase (PAK), has been shown to play a role in the nerve cell defects seen in FXS patients. The purpose of this project is to develop the first therapy directly targeting this FXS-related biological pathway.

Scientific Synopsis

FXS is an X-linked genetic disorder. Clinical manifestations of FXS include developmental delays, cognitive defects, hyperactivity and autistic behaviors in affected males. In collaboration with Afraxis, Inc., a San Diego-based biotechnology company, TRND researchers aim to develop the first disease-modifying FXS treatment by directly addressing the defects in synaptic function that are thought to be the cause of cognitive and behavioral deficits associated with FXS.

Analysis of brain samples from FXS patients show characteristic defects in dendritic spines, which are the post-synaptic structure in most glutamatergic synapses. Specifically, brain samples from FXS patients show an increased number of "immature" dendritic spines and decreased number of functional, or "mature," dendritic spines. It is hypothesized that the defects in synaptic function and plasticity observed in rodent models of FXS are a direct consequence of the defects in dendritic spines. Afraxis, Inc. proposes that reversing the defects in dendritic spine morphology in humans will reverse synaptic function defects associated with FXS and positively affect cognition and behavior in patients. By targeting p21-activated kinase (PAK), a protein kinase that is a critical regulator of dendritic spine morphology, the researchers on this project aim to develop a disease-modifying therapy for FXS. 

Lead Collaborator

Afraxis, Inc., La Jolla, California

David Campbell, Ph.D.

Public Health Impact

There are no treatments for FXS approved by the Food and Drug Administration (FDA), and off-label medications, such as antipsychotics, antidepressants and stimulants, are used to manage disease symptoms rather than address the underlying pathology of the disease. There is a clear unmet medical need for new therapies for FXS.

Outcomes

The project team has developed a series of novel and selective compounds that target the desired molecular pathway underlying the disease. Structure-activity relationship (SAR) studies have been conducted to aid the selection of lead compounds that have the properties required for development as a drug.  Due to Afraxis’ business priority changes, this TRND project was terminated in January 2013.

Last updated: 09-06-2017
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