Huntington's Disease: The Most Curable Incurable Brain Disorder?

Many scientists and people from families affected by Huntington's ural means of regulating post-transcriptional gene expression across disease prefer to avoid ‘the C-word’: cure. Acknowledging this, I still feel it is justifiable to describe Huntington's as the most curable incurable brain disorder. Everyone with HD has the same basic problem – a CAG expansion mutation in HTT, encoding a polyglutamine tract in the huntingtin protein (The Huntington's Disease Collaborative Research Group, 1993). Everyone with that problem will develop HD at some point, slowly succumbing to progressive cognitive, motor and psychiatric impairment. It is almost fully penetrant and truly dominant, and the genetic test is bleakly reliable. The more prevalent neurodegenerative diseases like Alzheimer's and Parkinson's lack this certainty: only a tiny minority of cases have a defined genetic cause. Therapeutic targets must be prosecuted on the balance of probability. In HD, we operate ‘beyond reasonable doubt’: mutant huntingtin is a smoking gun. Anything that cannot be connected to the mutation or protein may confidently be discarded. History has shown HD is an easy problem to define, for which it is surprisingly difficult to find solutions. Twenty-two years of research since the gene discovery in 1993 (see Fig. 1) has revealed much about huntingtin protein and its toxic twin, resulting in numerous genetically-accurate cell and animal models and theories of molecular and cellular pathogenesis – yielding multiple therapeutic targets (Ross et al., 2014; Wild and Tabrizi, 2014). Based on our early understanding of its pathogenesis, the HD field tested an array of already-licensed neuroactive drugs (including baclofen, lamotrigine, riluzole and minocycline), plus a whole shelf of ‘nutraceuticals’ held to be generally good for neurons (creatine, coenzyme Q, fish oil and others). Nothing worked (Mestre et al., 2009). A failed drug does not imply a failed trial. Collectively, these experiences improved the field's ability to design and run trials that can give a definitive answer, and to prioritise therapeutic targets and generate comprehensive preclinical data to inform decisions about advancing to clinical trials. We also have at our disposal a new generation of drugs that take aim at the known cause of HD. 2005 saw the first attempt to ‘silence’ the HTT gene in an HD mouse model, using RNA interference. Originally discovered in petunia flowers, and eventually found to be a nat-