This is a good year for HD, and for all working to develop medicines to treat all those affected. For the first time in CHDI’s existence, a clinical trial with a new drug entity will start this month. The collaboration between CHDI and Pfizer began over 3 years ago, where we reached out to them to obtain what we call ‘validating ligands’; that is, we suspected based on previous work inside and outside of the HD field, that a class of enzymes which play important roles in neuronal signaling (the phosphodiesterases, or PDEs for short) might hold some promise in HD. Or at least in understanding whether the synaptic problems known to exist in HD might be ‘modulatable’ via this mechanism. We asked Pfizer, the leading company in this area of investigation, if they would be willing to give us access to some of the advanced molecules they were developing for other indications, for us to try in the HD rodent models. We obtain several of these, after about a year of negotiations about the terms of our agreement. CHDI conducted most of the work which lead Pfizer to become very excited about the utility of their molecules, and particularly one which inhibits the activity of the enzyme PDE10, for a potential treatment for HD. Joint work over the next couple of years kept revealing ever more information about the potential of this mechanism for HD. We also enlisted some of the pre-eminent academic scientists in the field of synaptic plasticity to work with CHDI and to evaluate the molecule in their laboratories, replicating and extending our initial positive findings for this drug. This combination of approaches – industry working side by side with academia in a goal-, and hypothesis-directed manner, points to a future where the barriers between these 2 teams of the scientific research world will be lowered, and where we will promote the synergy across disciplines. Also during this time, the same PDE10 molecule, initially developed by Pfizer to treat schizophrenia, failed in Phase II clinical trials for this indication. This enabled us to move swiftly into planning clinical studies jointly. Meetings took place, and the result of these is the initiation of the first PDE10 inhibitor study in HD patients, set to begin towards the end of this month in France, at the ICM institute in Paris (led by Dr Alessandra Durr, a friend and colleague). I remain very hopeful that this is the beginning of a new phase for HD. The process by which we got here marks a change in the field- hypothesis testing in models of HD, and an understanding of the synaptic deficits in HD, at the level of individual neurons, as well as at the level of the entire neural system affected in HD, points to this mechanism as being potentially efficacious at least in the movement domain. The way this molecule modulates the circuitry affected in HD makes us hopeful that other symptoms of the disease might be improved too. Let’s hope we are right in how we think about the problem from a neural perspective. Nonetheless, even it this molecule fails (due to side effects or lack of efficacy), we will undoubtedly learn a lot in the process. A failure will also teach us what we did wrong – how we need to refine our understanding of disease mechanisms, what models or systems lead us astray, what we missed in our thinking… and it will lead us to exploring other, and hopefully better, ways to treat HD. The initial clinical study is a short study of 28 days, aimed mostly at evaluating whether patients can tolerate the drug, and also to explore the domains that might be modulated by this drug (motor, cognitive, apathy, for instance). I the molecule proves to be safe in HD patients, a longer, larger, efficacy study is being planned between Pfizer and CHDI, to begin early in 2014. These are indeed exciting times for all of us who wake up every morning thinking about HD, or living with the disease in our families. Stay tuned!