Allele specific RNAi gets closer

HD Lighthouse Contributing Editor's Comment: 

Lighthouse readers have been following the progress of RNA interference as a potential treatment for Huntington's DIsease for some years now. One issue is whether it is necessary to silence only the HD gene and leave the normal gene to function and if so, is it technically possible to do so.

Over the last few years, I believe it has become increasingly clear that the normal huntingtin's protein is needed and that allele-specific RNA interference is needed.

Neal Aronin's group has been working on ...... (see ).

Researchers from the Netherlands report in the study below that they have been able to .....

This work represents a significant advance towards therapy, but we are still issues of safety to be resolved.

Where does this leave those individuals with two copies of the HD gene? Only a small number of people who have tested in the U.S. and Canada have been found to have two copies. However, this is much more common in areas like Lake Maricaibo in Venezuela. There are other possibilities for treatment. One is to simultaneously knock down the HD genes while introducing a normal copy of the gene which is engineered to be sufficiently different that the RNA interence won't recognize it. This has been done in an animal model of..... (see ).

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 06-16-2008

Identification and Allele-Specific Silencing of the Mutant Huntingtin Allele in Huntington's Disease Patient-Derived Fibroblasts

P.H.J. van Bilsen, L. Jaspers, M.S. Lombardi, J.C.E. Odekerken, E.N. Burright, W.F. Kaemmerer.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by the expression of mutant huntingtin protein (Htt). Suppression of Htt expression, using RNA interference, might be an effective therapy. However, if reduction of wild-type protein is not well tolerated in the brain, it may be necessary to suppress just the product of the mutant allele. We present a small interfering RNA (siRNA) that selectively reduces the endogenous mRNA for a heterozygous HD donor's pathogenic allele by approximately 80% by specifically targeting a single-nucleotide polymorphism (SNP) located several thousand bases downstream from the disease-causing mutation. In addition, we show selective suppression of endogenous mutant Htt protein, using this siRNA. We further present a method, using just a heterozygous patient's own mRNA, to determine which SNP variants correspond to the mutant allele. The method may be useful in any disorder in which a targeted SNP is far downstream from the pathogenic mutation. These results indicate that allele-specific treatment for Huntington's disease may be clinically feasible and practical.

Source: Human Gene Therapy 2008 Jun 12. [Epub ahead of print]