In a new publication from pharmaceutical giant Medtronics Inc., scientists describe a technique for RNA interference that decreases mutant huntingtin protein by 80% without impairing normal protein production. In theory, if this type of technique could be employed for all Huntington's individuals it might be an improvement on the ISIS Pharmaceuticals Inc. product which also can decrease mutant huntingtin production by 80%; but at least (as so far reported) also has the potentially unwanted side effect of decreasing normal huntingtin production.

Why is this Research Important? Because effective RNA interference therapy can stop Huntington's at its source. And an 80% reduction in the mutant protein can bring us close to a cure. A potential problem with previous RNA therapies has been the unintended effect of lowering

Simply Stated

This RNA interference technique greatly decreases mutant protein levels while not affecting the normal levels of protein.

normal huntingtin protein too. Though ISIS has reported that decreased levels of normal huntingtin does not appear to harm the mouse, it is not known whether long-term decrease in normal huntingtin would be harmful in people. This new Medtronics Inc. research is important because their approach may be a solution to this problem.

The Research Goal: To make interfering RNA molecules that are specific for an individual HD person that can decrease levels of the disease gene without interfering with the normal gene.

The Method: The CAG repeat region of the HD gene is about 3 times too long for an interfering RNA molecule, which must be a small size (about 20 nucleotide length) to be effective. Instead of focusing on the CAG-repeat area of the protein, Medtronic scientists [van Bilsen PH 2008] took advantage of known single nucleotide polymorphism (SNP) differences between the mutant gene and the normal huntingtin gene. SNPs are single nucleotide substitutions that occur in all genes about every 300 molecules in the DNA chain. Because SNPs are often present in only one of the two gene pairs, scientists first identified a SNP present only on the mutant gene, then designed an interfering RNA molecule that matched that SNP. This way, the normal gene remained unaffected.

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ISIS description of RNA Biology


The Results: By using cells from a Huntington's patient, scientists created interfering RNA molecules specific to this person's mutant Huntington's gene, decreasing its level (in cell culture) by 80% without causing any decrease in normal huntingtin levels.

The SNP used in this study is present in about 20% of the HD population, just one of a dozen SNP areas that can occur in the Huntington's gene. So to be effective therapy, it must be extended to SNPs of the other 80%. It should be noted that Medtronics chose the SNP that is technically easiest to work with.

What's Next? Results from single cells is far away from results in people. Tests must be done in other predictive animal models (mice, rats, monkeys) before testing in people. Another huge problem is that this covers only 20% of the patient population. The other 80% have SNP areas that are harder to utilize.

FDA Issues: The Medtronic type of molecule would be slightly different for different Huntington patients to match the appropriate SNP variations. This type of drug has never been brought to the FDA. If the FDA required separate clinical trials for each separate (6 or more such molecules would be needed), the costs might be prohibitive to continue drug development.

But though this type of drug is new, this type of drug approval process isn't; the FDA approved the use of only one influenza vaccine. Flu vaccines developed in subsequent years use the initial prototype, but vary each year to match the specific influenza virus strains predicted each year.

We hope Medtronic and the FDA can find a solution. If there is to be progress in personalized medicine for HD, or any other disease, this problem should be addressed early in the process.

Editor's CHDI Comment: It is terribly hard to know whether the Medtronics method is an advance that makes any sense at the pharmaceutical level, or just an interesting report of no practical value. So it is fortunate indeed for the HD community that CHDI Inc. can expertly evaluate and compare the Medtronic approach to other RNA technologies. CHDI is the biotechnology company working exclusively on drug therapy for Huntington's.

But even better than expert evaluation, CHDI is uniquely positioned to take advantage of new advances as they occur by brokering collaborations not just with their own organization (as they have done with ISIS) but also between pharmaceutical companies.


van Bilsen PH, Jaspers L, Lombardi MS, Odekerken JC, Burright EN, Kaemmerer WF. Identification and allele-specific silencing of the mutant huntingtin allele in Huntington's disease patient-derived fibroblasts. Hum Gene Ther. 2008 Jul;19(7):710-9. doi: 10.1089/hum.2007.116. PubMed abstract