It is beginning to look like RNA therapy might become a reality for Huntington's disease. While there can still be unforeseen problems, a recent announcement from CHDI and ISIS Pharmaceuticals tells us that very important steps demonstrating efficacy and safety have been made. This is very good news because a potent RNA drug will stop Huntington's at its source, and we could let ourselves say the "cure" word.

The Story: CHDI has awarded almost $10 million divided over 3 years to ISIS Pharmaceuticals for further development of an RNA treatment for Huntington's disease. This company has a proven track record with a similar drug (Vitravene) that is already FDA approved for use in an AIDS related disease.

This exciting anouncement comes after successful ISIS experiments on two fronts in normal mice. First, the ISIS drug potently decreased levels of huntingtin RNA and protein; and critically important this decrease in huntingtin protein level was well tolerated. The new grant will pay for similar studies in Huntington mice, and if successful further studies in monkeys before proceeding to people. The announced time frame for these steps is exciting too; CHDI projects that major animal model work could be completed in two years, and that the third year will be devoted to research necessary for FDA approval for human testing.

The Time Frame: Many steps are necessary to accomplish RNA treatment, and each step takes years of time. Why the optimistic time frame for Huntington's? Because CHDI has "lined up the ducks." The 3-year projected time to testing in people is realistic because ISIS already has successful and practical experience, both with this type of drug and its delivery. They have already shown that Vitravene, a similar RNA drug works in people for an eye disease associated with AIDS and have efficiently brought it through the FDA process. And on the other important front, they are familiar with, and using. brain delivery systems HD will need in their ongoing studies with an RNA drug for familial amyotrophic lateral sclerosis (ALS).

The Drug: How does the ISIS drug work? It causes a specific attraction between huntingtin RNA and an enzyme that can destroy it before the huntingtin protein is made. Because it is this protein that causes the disease, if its levels are lowered enough, Huntington's could be cured. This drug can't cross the blood brain barrier, so drug delivery takes special effort. But remember that if RNA treatment works, the extra bother will be well worth the effort.

The Delivery Process: The ISIS drug must be delivered directly. The good news is that devices used for direct drug delivery to brain are FDA approved and have been used safely in thousands of people. For HD, the drug is placed into an area in the brain (lateral ventricle) containing fluid that surrounds and circulates through the brain. Inserting the device requires a one-time neurosurgical procedure with anesthesia: After a small portion of the skull is removed, a soft catheter is inserted into the brain ventricle through a skinny needle that is then removed. The remaining catheter is then attached (via another catheter) to a reservoir pocket that is placed under the skin. After the device is in, medication can be injected at a routine doctor's visit (probably not more than once a month) into the pouch for controlled delivery to the brain. Once the device is in place, it is not visible, and shouldn't hamper a person's usual activities.

Comments: I confess that just a year ago I didn't believe I'd see this much progress on RNA therapy in my lifetime, and I'm glad I was wrong. It is indeed a very good sign that CHDI is investing high level funding in this endeavor, and means they believe it has a reasonably good chance to deliver.

If successful, another thing to remember about this type of therapy is that it might do more than prevent onset or stop progression; it may reverse some of the disease. Several studies in HD mouse models have documented recovery of function after RNA treatment. In a recent study, the authors [Díaz-Hernández M 2005] turned off mutant protein production after 20% of striatal brain cells were destroyed. Though the mouse did not regain lost brain cells, it recovered enough to return to normal motor function. The authors give evidence that remaining brain cells not only regained health, but also compensated for the lost neurons.

My Advice: Do those things now--like exercise, environmental stimulation, serotonin enhancing antidepressants, and supplements like creatine or Co-Q-10-- that may slow nerve damage, so that we'll be around for better therapies. RNA therapy does give hope not only for the cure, but for recovery of lost functions. And the good news is that it may not be so far away.


Díaz-Hernández M, Torres-Peraza J, Salvatori-Abarca A, Morán MA, Gómez-Ramos P, Alberch J, Lucas JJ. Full motor recovery despite striatal neuron loss and formation of irreversible amyloid-like inclusions in a conditional mouse model of Huntington's disease. J Neurosci. 2005 Oct 19;25(42):9773-81. PubMed abstract