It is not unfair to say that almost the entire field of therapeutic development for the treatment of HD is founded on the learnings that stem from the cloning of the gene causative of HD, the huntingtin gene. As a monogenic disorder with 100% penetrance, the genetics of the disease told us that a single gene is the sole responsible agent for the disease. All of the work that we do has to bring us back to huntingtin, and to what it does to the brains of those affected by HD. When the gene was identified, everyone thought the ‘cure’ would be near. As things go in life, nothing is quite as easy as one would hope, and Huntingtin itself remains a bit of a mystery protein. Unlike other classes of proteins, we cannot develop traditional ‘drugs’ to attack huntingtin itself, so we are forced to develop novel approaches – these ones molecular, as opposed to ‘traditional chemical approaches’ to treat the disease. There are many other approaches we and others are taking to treat HD using traditional means (a ‘pill’), and those are developed using animal models of HD, which were possible to make because we cloned the gene in the first place. Without understanding the cause of HD, my work would be far far harder.
There is another aspect of HD (and of many other degenerative diseases that belong to the same ‘molecular class’ as HD – the trinucleotide repeat disorders) which has remained unexplained thus far. This is the fact that the age of onset of motor symptoms is highly variable across individuals, and this ‘age at diagnosis’ is inversely proportional to the length of the CAG repeat in HD. See the figure below:
As the repeat length is longer, the typical average age at diagnosis is earlier, and the variability decreases. However, 95% of all people suffering from HD have a repeat length in the low to mid-40s. If you look at the vertical line of the graph, you will notice that some people with a 40 repeat get sick at age 20, and some at age 60. This variability is extraordinarily large and it tells us that something, something can influence the progression of HD prior to diagnosis.This is an extraordinarily hopeful fact. Nature has indeed found a way to affect how huntingtin affects the body. If we could mimic this, we could push the disease back and allow people to have a much longer healthy life, or in some cases, to never develop HD. We also know that there is genetic evidence that this variability is inherited, suggesting that there is at least another gene which, when inherited, can either advance or slow the progression. So what is this gene or genes?
At the CHDI therapeutics conference in Palm Springs, one of the Harvard scientists who discovered that huntingtin causes HD back in 1993 (James Gusella), presented on the progress his group and others are making towards identifying the causes of the variable age of onset. His seminar focused on an approach called ‘genome wide association study’ (GWAS). They accessed over 4000 blood and DNA samples from patients, mostly of European descent, and for the first time presented strong evidence that they had found modifier regions in DNA for the age of onset. This is a true milestone, and after 20 years of searching for this ‘missing link’, they appear to have converged on something real. There are several regions in different chromosomes which statistically show that they are closely inherited with the disease in those who progress at different rates in terms of age of onset. This study would not have been possible were it not for the many, many doctors who have described the progression of the disease and symptoms over all these years. Without detailed records and the participation of patients (in the Registry, Cohort, and other studies), we would never be able to identify those whose rate of progression is different from the average (eg the ‘extreme progressors’). The GWAS studies are ‘association studies’: they do not reveal where the change in the DNA is that makes people develop HD at a different rate. They merely shed light on the regions of the chromosomes which are strongly correlated with the phenotypes. Now the adventure picks up and the researchers have honed into the areas where the mutation or mutations must reside.
The next step is to sequence the DNA in the regions that seem to be associated with the age of onset variation, and to identify what’s different in people who progress slowly or fast. This will take a few months, but there are some candidate genes whose biology we yunderstand somewhat, and certainly they will look into those genes first. regardless of what it is, this will be another milestone for human genetics, and for all of us working on HD. If we can harness that biology, i think we can make rapid progress in delaying the disease. But even if the gene(s) proves to be like huntingtin (eg difficult!), having a ‘second entry point’ into the disease will surely help us understand what we can do to treat it effectively- after all, nature found a way of doing it. And we biologist love to study nature, and to solve its mysteries… we are on our way to solve this one, and in the process change the course of this disease forever. Stay tuned!