Screening Yields a Promising Compound

HD Lighthouse Contributing Editor's Comment: Drug screening and development will be the key to getting highly effective treatments to the HD patient community. The Massachusetts General Institute for Neurodegenerative Disease (MIND) is a leader in this effort. MIND is researching Huntington's Disease as well as Parkinson's, Alzheimer's and ALS.

MIND utilizes high throughput screening to identify promising compounds which might treat the disease. First an assay or test is developed. This involves a cell model of the disease or some aspect of its pathology. Then robotics are used to test any or all of the 30,000 compounds in MIND's laboratory to look for an effect. 'Hits' are tested again manually.

In this article, Dr. Aleksey G. Kazantsev, director of the screening lab, and his team report on the discovery of a novel compound they call C2-8. This compound enhances the clearance of the HD form of the huntingtin's protein but does not affect the normal huntingtin's protein. Basic research into Huntington's Disease has suggested that problems in clearing away the protein are a major pathology so this compound is a promising one for the research pipeline to treatments.

Once a compound has been identified as promising through the screening procedure, the next step is to test it in animal models. Drosophilia (fruitflies) are used at MIND. Other research centers may use c. elegans (worm) model. Both are cheaper and quicker than the HD mouse model which would be tried next. Since there are several different mouse models of the disease, each mimicking Huntington's Disease in somewhat different ways, preclinical testing may involve more than one model.

The Lighthouse will report on the results of testing in drosophilia (Part Two) and in the R6/2 mouse (Part Three).

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 01-01-2008

Aleksey G. Kazantsev, Ph.D.

Discovery of a Novel Small-Molecule Targeting Selective Clearance of Mutant Huntingtin Fragments

Myra Coufal, Michele Maxwell, Deborah Russel, Allison Amore, Stephen Altmann, Zane Hollingsworth, Anne Young, David Housman & Aleksey G. Kazantsev

CAG-triplet repeat extension, translated into polyglutamines within the coding frame of otherwise unrelated gene products, causes 9 incurable neurodegenerative disorders, including Huntington's disease. Although an expansion in the CAG repeat length is the autosomal dominant mutation that causes the fully penetrant neurological phenotypes, the repeat length is inversely correlated with the age of onset. The precise molecular mechanism(s) of neurodegeneration remains elusive, but compelling evidence implicates the protein or its proteolytic fragments as the cause for the gain of novel pathological function(s). The authors sought to identify small molecules that target the selective clearance of polypeptides containing pathological polyglutamine extension. In a high-throughput chemical screen, they identified compounds that facilitate the clearance of a small huntingtin fragment with extended polyglutamines fused to green fluorescent protein reporter. Identified hits were validated in dose-response and toxicity tests. Compounds have been further tested in an assay for clearance of a larger huntingtin fragment, containing either pathological or normal polyglutamine repeats. In this assay, the authors identified compounds selectively targeting the clearance of mutant but not normal huntingtin fragments. These compounds were subjected to a functional assay, which yielded a lead compound that rescues cells from induced mutant polyglutamine toxicity. (Journal of Biomolecular Screening 2007:351-360)

Source: Journal of Biomolecular Screening, Vol. 12, No. 3, 351-360 (2007)