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Pharmaceutical Compounds for the Treatment of Spinal Muscular Atrophy and Other Uses

Posted Sep 19 2011 8:00pm

Description of Invention:
The SMA Project ( http://www.smaproject.org/programs.html ) was established by NINDS to identify new compounds with improved effectiveness, safety, and pharmacokinetic characteristics aimed at finding a new therapeutic treatment for Spinal Muscular Atrophy (SMA), a paralyzing and often fatal disease of infants and children. The result of the SMA Project medicinal chemistry optimization effort is a library of ~1400 indoprofren analogues with drug like properties. A lead pre-clinical candidate for SMA has been identified based on several factors, including its ability to increase SMN expression.

The mechanism by which these compounds affect ribosomal fidelity proves to be useful for many genetic CNS diseases. The ability of these compounds to read through nonsense stop codons, coupled with the ability to cross the blood-brain barrier and drug like properties, makes these compounds attractive as therapeutics for diseases such as Muscular Dystrophy and Cystic Fibrosis. Preliminary results in HIV and HPV assays show that these compounds potently inhibit viral replication, presumably via inducing ribosomal frame shift, suggesting potential for antiviral therapy. In addition, these compounds have been shown to be non-toxic and well-tolerated at high doses in rodents.

Applications:
Broad applications based on mechanism of action —
  • Read through = many genetic CNS diseases
    • Spinal Muscular Atrophy (SMA)
    • Muscular Dystrophy, Rett Syndrome, Diabetes Cancer, Niemann Pick disease, Cystic Fibrosis
    • Frame shift = broad anti-viral
      • Efficacy similar to AZT in HIV replication assay
      • Effective suppression of HPV replication
      • Brain penetrant compounds —> neuronal viruses


    Advantages:
    • No treatments available for SMA
    • First-in-class anti-viral with host-directed mechanism of action
    • Optimized activity and pharmaceutical properties:
      • nM potency and efficacy in SMN expression assays
      • Good brain penetrance
      • Metabolic stability in multiple species
      • Demonstrated favorable ADMET characteristics
      • Demonstrated safety in 7-day rat tox studies
      • High yield synthesis process


    Development Status:
    • Early-stage
    • Pre-clinical
    • In vitro data available
    • In vivo data available (animal)


    Inventors:
    Jill E Heemskerk (NINDS)


    Patent Status:
    HHS, Reference No. E-050-2011/0
    US, Application No. 61/475,541 filed 14 Apr 2011


    Related Technologies:
    US, Application No. 12/293,268 filed 16 Sep 2008, Reference No. E-133-2006/1 and foreign patent applications
    US, Application No. 12/680,285 filed 26 Mar 2010, Reference No. E-187-2007/0 and foreign patent applications
    US, Application No. 60/975,675 filed 27 Sep 2007, Reference No. E-187-2007/0


    Collaborative Research Opportunity:
    The National Institute of Neurological Disorders and Stroke is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize treatment for SMA. For collaboration opportunities, please contact Melissa Maderia at maderiam@mail.nih.gov .


    For Licensing Information Please Contact:
    Charlene Sydnor Ph.D.
    NIH Office of Technology Transfer
    6011 Executive Blvd. Suite 325,
    Rockville, MD 20852
    United States
    Email: sydnorc@mail.nih.gov
    Phone: 301-435-4689
    Fax: 301-402-0220


    Ref No: 2317

    Updated: 09/2011

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