Huntington's Disease Society of America

Research

The Coalition for the Cure

The Coalition for the Cure is HDSA's flagship research program. Coalition researchers in sixteen laboratories are involved in basic and preclinical research designed to answer questions that will bring us closer to treating the disease. Much has been learned about the normal function of the huntingtin's protein and how the HD version causes dysfunction and cell death and several therapeutic targets have been identified. Key questions remain, however.

In 2005 HDSA Coalition for the Cure investigators identified five questions as the most promising for HD Drug Discovery and Treatment and organized themselves into teams to answer them.

What is different about energy metabolism and mitochondrial function in HD?
How does huntingtin aggregation impact Huntington's Disease development and pathogenesis?
What are the post-translational modifications that huntingtin undergoes and how can interruptions of this alter pathogenesis?
What are the primary signaling pathways through which huntingtin acts and what is its impact on transcription regulation?
What is the role and behavior of normal huntingtin protein?

This focus has been paying off in insights about the disease process and new targets for drug discovery and development. In a study published in the summer of 2007, Coalition member Dr. Marcy MacDonald and colleagues showed that the mitochondria, the energy factories of the cell, are not defective in HD, but rather are not being managed properly. Team One members are now redirecting effort to research in the other categories.

Also during the summer of 2007, Coalition member Dr. Elena Cattaneo and her colleagues published a study that shows how the HD protein interferes with gene transcription. In HD, a repressor protein known as REST enters the cell's nucleus and suppresses key genes such as the one for brain derived neurotrophic factor (BDNF) which protects striatal neurons and encourages neurogenesis. A cell based assay has found a compound which upregulates the suppressed genes and increases the viability of the cell.

In the spring of 2008, Coalition researcher Dr. Jang-Ho Cha added to our knowledge of how transcriptional dysregulation occurs. He and his colleagues have shown that alteration in histone monoubiquitylation is a key mechanism. Histone monoubiquitylation is a part of the process by which specific genes are turned off and on as part of normal gene expression. The research suggests a new target for therapy.

Work continues on developing a safe and effective caspase six inhibitor. In the summer of 2006, Coalition member Dr. Michael Hayden and his colleagues identified caspase six as a potential target. Caspace six is an enzyme which is implicated in the cutting up of the HD protein into toxic fragments. HD mice which were also engineered to be resistant to caspase six never developed the disease.

The above studies represent only some of the exciting work produced by Coalition for the Cure researchers. You can follow their progress through our Research News and Research Archive sections [links] which cover significant studies by Coalition and other researchers and through updates to our Therapies in the Research Pipeline chart [link].

The HDSA Coalition for the Cure meets annually to exchange ideas, report progress and determine the most promising new avenues for research.

Since the Coalition's inception in 1997, HDSA has continued to increase its commitment to the Coalition to $2,400,000 in 2007. This represents an average annual investment of $150,000 per investigator.

Your donations can keep the HDSA Coalition for the Cure investigators working on answers to key questions and identifying targets for drug discovery and development. Donate now to the HDSA and see your dollars continue the progress already made. Donate here.

Members of the Coalition

Gillian Bates, PhD
KINGS COLLEGE (LONDON)