Seaside Therapeutics today announced the publication of a review paper detailing the evolving scientific and drug development landscape for fragile X syndrome, the most common inherited form of intellectual disability and the most common known cause of autism. The cognitive impairment associated with fragile X syndrome and other intellectual disabilities has long been considered permanent and untreatable, and drug development efforts have largely focused on relieving the symptoms of these disorders rather than correcting the underlying cause(s). This review article draws upon more than 100 studies to propose a paradigm shift in the approach to drug development for intellectual disabilities based on a new-found understanding of the core pathophysiology of fragile X syndrome. This paper highlights a number of recent scientific advances in understanding the genetic and biologic causes of fragile X syndrome, which are informing the development of novel therapeutic candidates to address the root cognitive deficits of fragile X. This work may have application to the treatment of other neurodevelopmental disorders.

The paper, "Fragile X Syndrome (FXS) - an update on developing treatment modalities," was published online in the journal ACS Chemical Neuroscience and includes a discussion of the mGluR theory of fragile X syndrome. This theory is based on research suggesting that inhibition of group I mGluR signaling reduces protein synthesis and, in turn, may correct the cognitive and behavioral phenotypes associated with fragile X syndrome. Multiple genetic and pharmacologic studies support mGluR5 inhibition as a promising therapeutic opportunity, providing compelling evidence that altering mGluR5-dependent protein synthesis may directly affect the synaptic alterations underlying the fragile X phenotypes. Additionally, the importance of gamma-aminobutyric acid (GABA), the main inhibitory transmitter in the central nervous system, has recently emerged and been show to oppose the action of mGluR5, providing a novel mechanism for therapeutic inhibition. Studies examining induced seizure activity in mice suggest that the opposing actions of mGluRs and GABA-B receptors provide a therapeutic path for fragile X syndrome. This novel insight reinforces the potential for GABA-B agonists like Seaside Therapeutics' drug candidate STX209 to counter the effects of mGluR5 in fragile X syndrome and possibly correct specific deficiencies in GABA neurotransmission. This finding could have broad applications in research to treat intellectual disability.

Dr. Aileen Healy, Vice President of Research at Seaside commented, "We are now beginning to believe that intellectual disability is not, as previously understood, an immutable condition. Translating our understanding of the biological effects of key genetic mutations has revealed a variety of promising mechanistic approaches to treat fragile X syndrome, which I believe represent an exciting opportunity to realize the mission of developing effective therapeutics for patients in need."

About STX209

STX209 is a selective gamma-amino butyric acid type B (GABA-B) receptor agonist. Pathologies observed in certain neurodevelopmental disorders, including fragile X syndrome (FXS) and autism spectrum disorders (ASD), are believed to be caused by excessive activation of glutamate receptors and abnormally high ratios of excitatory to inhibitory neurotransmission in the brain. GABA-B receptors play an important role in modulating the release of glutamate and maintaining the optimal excitatory-inhibitory balance. STX209 has demonstrated efficacy in preclinical models, suggesting that the functional deficits of individuals with FXS and ASD may be ameliorated by modulating glutamate release and optimizing the ratio of excitatory to inhibitory neurotransmission.

STX209 has successfully completed the largest ever randomized, blinded, placebo-controlled trial (Phase 2) in patients with fragile X syndrome and an open-label Phase 2 exploratory trial in patients with autism spectrum disorders. Later stage trials in both indications are expected to begin by summer 2011.

About Fragile X Syndrome

Fragile X syndrome is a neurodevelopmental disorder characterized by impaired social function, cognition and speech, as well as attention deficits and low functional independence. It is the most common inherited form of intellectual disability and affects roughly 100,000 individuals in the U.S. It is also the largest known cause of autism. Fragile X syndrome is caused by a mutation of a single gene, the Fragile X mental retardation 1 (FMR1) gene, on the X chromosome. The FMR1 gene produces a protein needed for normal brain development. Individuals with fragile X syndrome lack this protein and, as a result, the majority of affected individuals will have significant intellectual disabilities, requiring life-time care. To date, there are no approved treatments for this disorder. The FDA has designated fragile X syndrome as an orphan disease.

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