Late stage HD mice recover motor functions after gene silencing

HD Lighthouse Contributing Editor's Comment: Six years ago, research by Ai Yamamoto and colleagues gave new hope to those already symptomatic with Huntington's Disease. The researchers used a mouse model in which the Huntington's Disease gene could be turned off by the administration of doxycycline, an antibiotic. This was not a treatment but an artificially created mouse model in which the expression of the gene was regulated by the presence or absence of doxycycline. When the production of the HD protein was turned off, the mice experienced a reversal of symptoms.

With the success of RNAi in silencing the HD gene in mice, Miguel Diaz-Hernandez and colleagues wondered if gene silencing could be a viable therapy for later stage patients. They decided to conduct a similar experiment to one conducted by Yamamoto and her colleagues, but this time with mice in the later stages of the disease. They found that despite significant neuronal loss, once the production of the mutant protein was shut off, the mice were able to recover their motor function.

Reference
A. Yamamoto, J. Lucas, R. Hen, "Reversal of Neuropathology and Motor Dysfunction in a Conditional Model of Huntington's Disease." Cell, Volume 101, Issue 1, Pages 57-66

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 23 Apr 2006

The primary mechanism responsible for Huntington's disease remains unknown. Postulated early pathogenic events include the following:

• impaired protein folding
• altered protein degradation
• mitochondrial dysfunction
• transcriptional dysregulation.

Although related therapies can delay disease progression in mouse models, they target downstream and probably indirect effects of mutant-huntingtin expression. Accordingly, in case they prove beneficial in humans, they might only palliate some aspects of disease.

Our previous studies in the Tet/HD94 conditional model and the recently reported efficacy of RNA interference against mutant huntingtin in another mouse model support silencing mutant-huntingtin expression as a valid therapeutic approach that has the advantage of targeting toxicity at its root. Here, we address whether gene silencing can still be beneficial in the late stages of disease with detectable striatal neuron loss. Stereological analysis was applied to determine an age at which Tet/HD94 mice show a decrease in the number of striatal neurons. Then, progression of neuropathology and motor phenotype were analyzed in mice that were allowed to continue expressing mutant huntingtin and in mice that no longer expressed it.

Neuronal loss did not revert in gene-off mice, but the additional loss that takes place in gene-on mice was prevented. The total number of huntingtin-containing inclusions dramatically reverted, but a small fraction of inclusions positive for the amyloid dye thioflavin-S remained. Interestingly, despite a 20% decrease in striatal neurons and the presence of amyloid-like irreversible inclusions, gene-off mice fully recover from their motor deficit, thus ruling out amyloid-like huntingtin inclusions as the main toxic species and suggesting that gene-silencing therapies might work in late stages of disease.

Source: Journal of Neuroscience October 19, 2005, 25(42):9773-9781

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