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New Compounds and Methods for the Treatment of Spinal Muscular Atrophy and Other Diseases

Posted Apr 30 2007 5:00pm

Description of Invention:
Spinal muscular atrophy (SMA) is caused by mutations in the SMN1 gene that result in reduced expression of the survival motor neuron (SMN) protein and a loss of spinal motor neurons. An SMN2 gene paralog that differs from SMN by a single base pair has inadequate expression of SMN to support motor neuron survival. Alternative splicing caused by the single base substitution in the SMN2 gene results in a slightly truncated and highly unstable SMN protein. Drugs that allow translational read through of the stop codons introduced by the alternative splice event have been shown to stabilize the mutant protein, resulting in increased levels of SMN.

A chemical library screen identified indoprofen, a nonsteroidal anti-inflammatory drug, as an inducer of SMN expression in cultured cells. However, indoprofen cannot enter the brain in satisfactory amounts, has a relatively low level of activity and can cause substantial side-effects in part due to its cyclooxygenase inhibitory activity. NIH inventors designed indoprofen derivatives without cyclooxygenase activity that can enter the CNS and increase expression of a SMN protein from the SMN2 gene with increased potency and efficacy. The mechanism of action of these indoprofen analogs appears to be translational readthrough of stop codons introduced by the alternative SMN2 splicing event. In addition to treating SMA, novel drugs that allow read through of stop codons could potentially treat many other diseases caused by such mutations such as cystic fibrosis and muscular dystrophy.

Available for licensing are compounds and methods useful for the treatment of spinal muscular atrophy by increasing SMN expression and increasing the expression from any nucleic acid that encodes a translational stop codon.

  • Efficacious treatment for SMA, utilizing indoprofen analogs that increase SMN protein expression
  • Treatment of any genetic disease caused by premature termination of protein translation

Development Status:
Clinical candidate selection scheduled for June 2007.

Jill E Heemskerk (NINDS)

Patent Status:
HHS, Reference No. E-133-2006/1
US, Application No. 12/293,268 filed 16 Sep 2008

Relevant Publication:
  1. MR Lunn, DE Root, AM Martino, SP Flaherty, BP Kelley, DD Coovert, AH Burghes, NT Man, GE Morris, J Zhou, EJ Androphy, CJ Sumner, BR Stockwell. Indoprofen upregulates the survival motor neuron protein through a cyclooxygenase-independent mechanism. Chem. Biol. 2004 Nov;11(11):1489-1493. [ PubMed abs ]

Licensing Status:
Available for exclusive and non-exclusive licensing.

Central Nervous System
Central Nervous System - Therapeutics
Rare Diseases

For Additional Information Please Contact:
Norbert Pontzer Ph.D., J.D.
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325 Room 23,
Rockville, MD 20852
United States
Phone: 301-435-5502
Fax: 301-402-0220

Ref No: 1546

Updated: 05/2007

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