12 October 2007. Researchers led by Steven Hersch, Massachusetts General Hospital, Boston, report in this week’s PNAS online that a compound that limits polyglutamine (polyQ) aggregates improves symptoms in a mouse model of Huntington disease (HD). The small molecule, dubbed C2-8, looks like a promising lead candidate for drug development.
C2-8 came out of a high-throughput screen in yeast for molecules that prevent aggregation of polyQ-expanded protein. How C2-8 works is not clear, but two years ago, Hersch and colleagues reported that the compound limits aggregates in cell culture, brain slices, and live fruit flies. In the flies, the compound rescued neurodegeneration induced by a pathogenic derivative of mutant human huntingtin (see Zhang et al., 2005). The present paper is the first report of the compound having any effect in live mammals.
First author Vanita Chopra and colleagues tested C2-8 in R6/2 transgenic mice, which express mutant human huntingtin. They found that though the compound is not very water soluble, it can be absorbed from an oral suspension and readily penetrates the blood-brain barrier, reaching concentrations of around 25 micromolar in the cerebral cortex. The compound was well tolerated by the mice and slowed their decline in motor performance. Animals that received the compound twice daily beginning at 24 days old performed significantly better in the rotarod at 8 and 11 weeks, for example. The mice had reduced atrophy in the striatum, which is hit hard in Huntington’s, and the size of protein aggregates there was smaller, as well.
The treated R6/2 mice did not live longer, however. In this strain, polyQ aggregation has already begun at birth, so C2-8 might have failed to prolong survival because the treatment came too late, the authors suggest. Alternatively, the compound might lack potency. The compound’s “benefits and drug-like properties are exciting and support developing more potent or more stable analogs based on the identified structural scaffold,” write the authors.—Tom Fagan.
Chopra V, Fox JH, Lieberman G, Dorsey K, Matson W, Waldmeier P, Housman DE, Kazantsev A, Young AB, Hersch S. A small-molecule therapeutic lead for Huntington’s disease: Preclinical pharmacology and efficacy of C2-8 in the R6/2 transgenic mouse. PNAS Early Edition. 2007 Oct 8. Abstract