Posted to the HDL: 21 Jun 2007

Research Update from the 2007 HDSA Convention: Part One

by Marsha Miller, Ph.D.

Attendees at the 2007 HDSA convention received some encouraging reports on progress on the research front. Dr. James Gusella (R) discussed the strategic plan for basic research, which is still needed since Huntington's Disease has yet to yield all of its secrets. Dr. Robert Pacifici (L) discussed progress on the strategic plan for developing treatments for the HD community. We also learned from Neurosearch that ACR 16 will be going into Phase III clinical trials at the end of the year, and from Avicena that creatine will be going into Phase III trials at the beginning of 2008.

Dr. Gusella gave a talk on "Clinical Trial Research: the Culmination of the Drug Development Pipeline" during the Saturday morning research forum. The goal of the research is to determine whether drugs or other interventions are safe and effective in treating Huntington's Disease. The FDA requires data which shows that a compound is both safe and effective before it will approve it for a specific medical condition.

Treating HD has different meanings depending on the stage of the disease and the purpose of the treatment. Potential treatment goals for the presymptomatic are to either 1) prevent the disease or 2) delay clinical onset. Treatment goals for the symptomatic are to 1) halt the disease process, 2) delay disease progression or 3) alleviate symptoms even if there is no delay in progression.

The shape of the HD protein hasn't been fully delineated yet but it seems to look something like a slinky. The extra CAG repeats cause problems with folding at the upper end. The mutant huntingtin's protein causes the debilitation of the cell and then cell death. At the time of clinical diagnosis, 30 percent of cells in the caudate nucleus are dead.

We can also think of treatments in regard to the cell. Treatments can be designed for the healthy cell, the sick cell, the dying cell, or after the cell has already died.

To begin to determine if a potential treatment is safe, the researchers need to conduct a Phase I trial. Typically this involves a small number of participants to determine whether the drug has obvious adverse effects.

Determining whether the potential treatment is effective in producing the desired clinical outcome requires first a Phase II and then a Phase III clinical trial. They involve increasing numbers of participants. The researchers must compare subjects who receive the potential treatment with subjects who do not (either historical or simultaneous data) for some pre-specified measure.

For the presymptomatic, the hope is to prevent or at least delay clinical onset of the disease. How can effectiveness be measured without waiting years and years? One possibility is to use biomarkers and another is to use brain imaging.

For treatments which do not prevent the disease but rather delay it, age of onset can also be used as a measure of effectiveness.

For treatments during the symptomatic phase which halt or delay disease progression, measures of progression can be used. For treatments that alleviate symptoms, the symptoms themselves need to be measured.

Studies such as Predict-HD and COHORT are very important for the development of treatments for the presymptomatic since they will identify and validate biomarkers which appear before onset and delineate the rate of change in both biomarkers and the brain as onset approaches.

Dr. Gusella urged everyone to sign up for COHORT. This is an observational study being conducted in North America and Australia. Participants include adults and children with clinically diagnosed HD as well as HD family members, including those at risk and spouses of people with the disease. The study requires one visit each year which will involve a clinical assessment, family history, research genotyping, and the collection of biological samples. So far 683 people have enrolled and the goal is unlimited.

A list of the 40 participating sites can be found on the Huntington Study Group website: http://www.huntington-study-group.org/COHORTSites.htm

Dr. Gusella also spoke about the Coalition for the Cure. The fundamental goals of the coalition are to "1) discover the biochemical differences that occur in HD." and "2) to define which ones are critical in the disease process." These will be the targets for CHDI's translational research.

The coalition for the cure involves 16 international labs. There were originally five teams organized around key issues about pathologies but one team has finished its work and disbanded. The mitochondrial dysfunction and energy metabolism team found that the mitochondria, the energy factories of the cell, are not defective in HD, but rather are not being managed properly.

Team two is looking at folding, aggregation, and clearance of the HD protein.

Team three is looking at huntingtin proteolysis and postranslational modification.

Team four is looking at transcription.

Team five is looking at the function of the huntingtin's protein.

Dr. Gusella told the audience that The Coalition for the Cure is "closely aligned with CHDI to order to capitalize quickly on the basic research findings."

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