What big questions remain in the field of HD research? Gusella said that the question, “How does mutant huntingtin trigger the disease cascade?” is, by far, the most important one because learning about the root cause of the disease will help researchers intervene early in the cascade before the onset of symptoms. Secondary questions include:
What is the normal function of the huntingtin protein?
Is there a point at which the disease pathway becomes independent of its trigger?
What are the phenotypes in tissues other than the brain of a person with HD?
Why are cancer rates lower in people with HD?
What is the overall effect of HD on metabolism (not just in certain fat cells)?
What is the origin of the chromosome that gives rise to new mutations?
What produces the long length of the HD allele?
Why don’t nematodes (a type of worm) have a Huntington gene? (Nematodes are multicellular - made up of many cells - just like humans and mice.)
MacDonald discussed what she believes will be an important future discovery: the development of a biomarker to measure the progression of HD in a patient. She thinks that a rating scale that measures the functional decline (the physical deterioration) of people with the disease may prove to be important. She would also like to see a quantitative test that reflects the state of a person’s disease - not just for HD, but for Parkinson’s and cancer, as well. Unlike MacDonald, Gusella thinks that a biomarker would not be particularly meaningful; rather, he would like to see researchers direct their efforts toward developing a marker that could indicate a reversible disease state.
What level of specificity within the body will be targeted by a breakthrough treatment - the cell, gene, protein, DNA, or RNA? After a drug, which would be their first choice, MacDonald and Gusella said that RNA, but not DNA, is a promising level for a treatment. RNA is promising in terms of delivery to nerve cells (siRNA is delivered to the cells via the RNAi technique). At the protein level, it is possible to deliver normal huntingtin to the nerve cells in a similar way. However, the only drawback is that the technology involved in these processes is relatively unknown and underdeveloped. On the bright side, scientists and doctors can target the mutant huntingtin with small-molecule pharmacological drugs that are already available. At the level of the nerve cell, it seems promising to target treatments to nerve cell-nerve cell interactions at a distance from the trigger of the disease cascade. Unfortunately, this may be difficult due to the fact that the trigger is still unknown. On the other hand, targeting drugs to genetic modifiers would be a faster route than targeting nerve cell-nerve cell interaction - if such a route were available.
Last Modified: 05/22/2009
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