RNA interference (RNAi) therapy was an important theme at the 2010 HD Therapeutics Conference. If this type of therapy can be fully mastered by scientists and drug developers it could be very promising because it will treat HD at its source by reducing the amount of defective huntingtin protein that is produced in cells. RNA interference works by introducing into cells short pieces of RNA that recognize and then destroy the means to produce huntingtin protein. While there were many posters detailing research in different types of RNAi, the major presentations centered on small molecule RNAi.

The Major Points:

  • Description of an RNAi therapy now entering Phase I clinical trial for familial amyotrophic lateral sclerosis (FLS), which is a rare type of amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease) that has a single gene inheritance similar to Huntington's (HD).
  • Discussion centering on safety of RNAi drugs that lower not just the mutant protein that causes HD, but the normal protein as well. Lowering the normal protein might cause serious side effects. Specifically there was discussion about how much lowering of each protein will be needed for best treatment effect with the least side effects. And in an effort to help answer these questions, we heard about a mouse model developed by CHDI and partner Psychogenics that may help answer some of these questions.
  • Discussion centering on the best method to deliver RNAi medications to Huntington patients: Is it enough to deliver RNAi medications into the fluid space within the brain, or will direct infusion into brain be necessary?

Dr. Timothy Miller from the University of Washington in St. Louis talked about an antisense oligonucleotide RNA (ASO) that is being tested in a Phase 1 human trial for familial ALS. This trial will test the safety of this RNAi drug developed by ISIS Pharmaceuticals that will be delivered through a catheter into spinal fluid that surrounds the spinal cord. This disease is caused by problems in (motor) neurons located in spinal cord areas, so brain delivery isn't necessary. The ISIS drug lowers both normal and mutant protein, but unlike HD there is animal evidence that lowering the normal ALS protein causes no harm.

ISIS is also working on similar drugs for HD that are not yet ready for human clinical trials. Unlike delivery in ALS, drug delivery for Huntington's would likely be directly into a ventricle, a fluid-filled space on each side of the brain. In Huntington's there are unresolved questions whether this type of delivery will be sufficient to deliver enough drug into brain areas needed for HD. The ISIS type of RNAi therapy would lower levels of both normal and mutant huntingtin protein.

Dr. Don Cleveland from the University of California at San Diego presented data from his laboratory showing that an ISIS-developed RNAi can successfully slow disease progression in rat models of familial ALS. He further showed that in the rat, the ISIS drug was well distributed to all brain areas. However he showed that in the larger brain of a monkey, brainstem penetration (where it is needed in HD) was much lower. This suggests that delivery of ISIS type of compounds at a level to help HD may be problematic in the much larger human brain.

Dr. Dinah Sah from Alnylam Pharmaceutical presented an update on ALN-HTT, a small interfering RNA (siRNA) drug that has shown benefit and is well tolerated in animal models. She presented detailed data showing that the drug can penetrate into the putamen of large animal brains and decrease levels of huntingtin protein by 50%. And by using those results in large animal brains, they can model the dose and pressure needed to deliver drug into the putamen of the much larger human brain.

At present Alnylam is working with Medtronic to bring forward a drug-device combination product for HD patients. In this situation the drug would be delivered continuously by a pressure-controlled catheter device directly into brain, and would require placement of catheters on both sides of the brain.

Work to be done and decisions to be made before human clinical trials:

  • Which stage of Huntington's is most promising for first clinical trials?
  • What is optimal dose or range of dosing for people?
  • What are best endpoints that can show whether the drug is effective?
  • What biomarker or brain imaging tests can be used to confirm drug presence and activity?

The Alnylam type of RNAi drug lowers levels of both normal and mutant huntingtin protein.

Dr. Neil Aronin from the University of Massachusetts presented the case for selective allele targeting by designing a type of RNAi drug that lowers only the mutant while not changing the level of the normal huntingtin protein. In the lab this can be done by finding differences (called SNPS) that are common in Huntington gene pairs, and then designing a drug that targets the SNP differences on the corresponding mutant huntingtin RNA. By using this type of RNAi in animal models, scientists in his laboratory, can lower mutant huntingtin protein without affecting the normal one.

In HD patients this would mean analyzing each Huntington's patient for SNP patterns, then matching the pattern to the specific RNAi drug that best fits. Dr. Aronin has found that only 4 such drugs would be enough to cover at least 75% -- but not all -- of the HD patient population.

Dr. Andrea Kudwas from Psychogenics Inc. and CHDI presented work being done with a new mouse model that has been developed to study the effects of lowering the levels of normal huntingtin protein. Using this animal model, scientists can learn more about how much normal huntingtin protein can be lowered without causing harm. This may help predict whether there is a "safe" level the normal protein may be lowered in people.

This animal model will also help develop tests to monitor levels of the mutant and normal protein in HD patients when RNAi drugs are given to HD patients. Such tests would help determine doses that can be used in human clinical trials before toxic side effects occur.