The full article detailing results of Repligen Corporation's HDAC 4 inhibitor drug candidate was published in the jounal Proceedings of the National Academy of Sciences (PNAS). Scientists from Repligen and the Scripps Institute in California detail exciting results from study of their drug candidate in the R6-2 mouse model. So far, it is looking good . .

Why this study is important: Based on critical work that identified HDAC 4 as an important enzyme that promotes Huntington's disease activity, Repligen designed a molecule that selectively decreases activity of this enzyme while not affecting other types of important HDAC enzymes. They showed it was both 1) very effective and 2) less toxic than previously available HDAC inhibitors [Thomas EA 2008].

The Experiment: The experimental drug, or placebo was started at the time the Huntington mice developed motor symptoms. There were two control (wild type) groups: one receiving drug, the other placebo, and two Huntington (R6/2) groups, one receiving drug, the other placebo. The scientists followed motor tests, body and brain weight, brain morphology (how it looks under a microscope). They also profiled gene function differences in varying parts of the brains of treated and untreated animals.

There were other experiments using cell models to test for drug safety.

The Results: In the drug treated mice there was greatly improved motor function as measured by standard testing that included rotor-rod, gait analysis, and clasping. In fact, the clasping behavior of the treated R6-2 mouse was nearly identical to the control (non-HD mouse) even late in the disease course. Though weight loss occurred, it was much milder than that observed in other HDAC drugs (SAHA and Phenylbutyrate).

Also very exciting, the drug treated mice had significant neuroprotective benefit shown by brain weight, ventricular size, and striatal volumes. Brain weights were significantly higher in the treated mice (407 mg) than the untreated (356 mg). Compared to the brain size of normal mice (462 mg) this represents very significant neuroprotection. There were similar results in the other parameters tested.

The mutant Huntington protein impairs transcription and function of many important genes. The authors performed gene profiling experiments showing that the drug improved impaired gene function, in some cases returning gene function to a normal range.

Comments: These results are very exciting. This HDAC-4 inhibitor drug candidate has shown both greater benefit and lesser toxicity than any other HDAC inhibitor that has been tested in mice. Note also that the drug was given only after symptom development, and if (as in some other drugs) it is given earlier it might give even greater benefit.

But for sure, this advance toward treatment for Huntington's (including the identification of the importance of HDAC-4 as a target) was made possible by years of collaborative work from many basic research scientists backed by major funding from National Institutes of Health, Repligen and CHDI. Hats off to you all!

Now -- for the next very big and exciting step -- getting ready to test it (or a similar drug) in people in clinical trials.


Thomas EA, Coppola G, Desplats PA, Tang B, Soragni E, Burnett R, Gao F, Fitzgerald KM, Borok JF, Herman D, Geschwind DH, Gottesfeld JM. The HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington's disease transgenic mice. Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15564-9. doi: 10.1073/pnas.0804249105. Epub 2008 Sep 30. PubMed abstract