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Treatments for Smith-Lemli-Opitz Syndrome and Other Disorders of Cholesterol Biosynthesis

Posted Jul 11 2010 5:00pm

Description of Invention:
This technology provides methods for treating Smith-Lemli-Opitz Syndrome and other disorders of cholesterol biosynthesis.

Smith-Lemli-Opitz Syndrome (SLOS) is an autosomal recessive disorder caused by an inborn error of cholesterol biosynthesis. It affects an estimated one in 20,000 to 60,000 newborns, and is most prevalent in Caucasians of Central European ancestry. It is characterized by distinctive facial features, microcephaly, mental retardation or learning disabilities, and behavioral problems, as well as malformations in many parts of the body, such as the heart, lungs, kidneys, gastrointestinal tract, and genitalia. However, the clinical manifestations of this disease can vary widely, ranging from relatively moderate symptoms to profoundly severe and life-threatening symptoms. At least 95% of SLOS patients present with some degree of mental retardation and learning disability.

Biochemically, SLOS is caused by disruption of the DHCR7 gene, which is responsible for the final step in the production of cholesterol; this results in low cholesterol levels and an accumulation of toxic byproducts of cholesterol biosynthesis in the blood, nervous system, and other tissues. Supplementary dietary cholesterol is provided to SLOS patients, but is often of limited clinical benefit; because levels of byproducts remain high, they may interfere with the uptake of free cholesterol.

Although some of the behavioral and learning problems are due to developmental problems, a portion of these symptoms are likely due to a biochemical disturbance. That biochemical disturbance is potentially treatable.

In their recent work, the inventors have discovered that the accumulation in SLOS cells of the cholesterol precursor 7-DHC causes abnormal sphingolipid storage and transport, resulting in a cellular phenotype similar to that observed in the lysosomal storage disease Niemann-Pick type C (NPC). They have also discovered that treatment with inhibitors of sphingolipid biosynthesis corrects these abnormalities, and thus such inhibitors are of potential therapeutic benefit for the treatment of SLOS, as well as for other diseases exhibiting similar defects in sphingolipid trafficking.

This technology claims compounds that inhibit sphingolipid biosynthesis for use in treating diseases which have a secondary Niemann-Pick type C disease-like cellular phenotype, including SLOS, as well as methods of treatment and pharmaceutical compositions.

Development of therapeutics for Smith-Lemli-Opitz Syndrome and other diseases which have a secondary Niemann-Pick type C disease-like cellular phenotype, which includes inborn errors of cholesterol biosynthesis, Huntington's disease, cystic fibrosis, and autism.

Development Status:
In vitro studies have been performed using a sphingolipid biosynthesis inhibitor.

Forbes D Porter (NICHD)

Patent Status:
HHS, Reference No. E-206-2007/0
US, Application No. 12/666,279 filed 19 Jan 2010 , and related International patent applications

Relevant Publication:
  1. FD Porter. Malformation syndromes due to inborn errors of cholesterol synthesis. J Clin Invest. 2002 Sep 15; 110(6):715-724. [ PubMed: 12235098 ]
  2. XS Jiang et al. Quantitative proteomic analysis of inborn errors of cholesterol synthesis: Identification of altered metabolic pathways in DHCR7 and SC5D deficiency. Mol Cell Proteomics. 2010 Jul;9(7):1461-1475. [ PubMed: 20305089 ]
  3. XS Jiang et al. Activation of Rho GTPases in Smith-Lemli-Opitz syndrome: pathophysiological and clinical implications. Hum Mol Genet. 2010 Apr 1;19(7):1347-1357. [ PubMed: 20067919 ]
  4. Tierney et al. Analysis of short-term behavioral effects of dietary cholesterol supplementation in Smith-Lemli-Opitz syndrome. Am J Med Genet A. 2010 Jan;152A(1):91-95. [ PubMed: 20014133 ]

Licensing Status:
Available for licensing.

Collaborative Research Opportunity:
The National Institute of Child Health and Human Development, Section on Molecular Dysmorphology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Alan Hubbs, Ph.D. at 301-594-4263 or for more information. Click here to view the NCI collaborative opportunity announcement.

Internal Medicine
Internal Medicine - Therapeutics
Central Nervous System
Central Nervous System - Therapeutics

For Additional Information Please Contact:
Tara Kirby Ph.D.
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Phone: 301-435-4426
Fax: 301-402-0220

Ref No: 2134

Updated: 07/2010

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