HD Lighthouse Contributing Editor's Comment:

The HDL has been calling for new clinical trials. We're delighted to see that two noted HD researchers have published an important new journal article which discusses compounds which are candidates for human clinical trials based on preclinical research with HD models.

The authors first discuss the five major therapeutic target areas of HD pathology. They are nucelar transcriptional dysregulation, HD protein aggregation, mitochondria dysfunction and oxidative damage, excitotoxicity, and apoptosis (cell death).

Two HD researchers review the data available on several compounds they believe are candidates for human clinical trials based on research results with various models of the disease. Each targets one or more of the major pathologies in HD. They are:

• cystamine and/or cysteamine (inhibits aggregation)
• minocycline (inhibits apoptosis)
• the anti-cancer antibiotics mithramycin and/or chromomycin (which aid transcriptional regulation and inhibit apoptosis)
• HDAC inhibitors sodium butyrate and phenylbutyrate (transcriptional regulation)
• creatine (antioxidant, reduces mitochondrial dysfunction)
• CoQ10 (antioxidant, reduces mitochondrial dysfunction)

The authors predict that treatment for HD will involve a therapeutic combination of drugs.

If you are going to the HDSA convention later this month in Atlanta, please pick up an HD Clinical Trials NOW button. I am making up several hundred of these buttons.
--Marsha L. Miller, Ph.D.
Posted to the HDL: 12 Jun 2005

Emerging chemotherapeutic strategies for Huntington's disease.

Hoon Ryu and Robert J. Ferrante

Huntington's disease (HD) is a progressive and fatal neurological disorder caused by an expanded CAG repeat in the gene coding for the protein, huntingtin. There is no clinically proven treatment for HD. Although the exact cause of neuronal death in HD remains unknown, it has been postulated that the abnormal aggregation of the mutant huntingtin protein may cause toxic effects in neurons, leading to a cascade of pathogenic mechanisms associated with transcriptional dysfunction, oxidative stress, mitochondrial alterations, apoptosis, bioenergetic defects and subsequent excitotoxicity. Understanding how these processes interrelate has become important in identifying a pharmacotherapy in HD and in the design of clinical trials. A number of drug compounds that separately target these mechanisms have significantly improved the clinical and neuropathological phenotype of HD transgenic mice and, as such, are immediate candidates for human clinical trials in HD patients. These compounds are discussed herein.

Tracked on the Lighthouse:
creatine
CoQ10
cystamine
minocycline
mithramycin
HDAC inhibitors

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Source: Expert Opin Emerg Drugs. 2005 May;10(2):345-63

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