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7 Sep 16

Issue 103, December 2008

HD Research Update

By Don Lamont, Huntington Society of Canada CEO and Executive Director

There continues to be a real sense of hope for effective Huntington disease (HD) treatments in the HD research community, accompanied by the knowledge that we still face many challenges before that day arrives. In this article, we present a layman's view of the status of the HD drug discovery campaign, as well as an update about the role the Huntington Society of Canada (HSC) is playing.

To get a sense of when effective HD treatments might arrive, one can focus on specific drugs which are potential candidates for clinical trials, and you can also consider the barriers standing in the way of bringing HD drugs to market, as well as the strength of the drug discovery process itself. In this article, we explore all these avenues.

An Exemplary Discovery Process
The international Huntington movement, which comprises families, scientists and clinicians, is a world class drug discovery process. When the gene was discovered in 1993, there were heavy expectations that treatments would soon be found. With the gene discovery the Huntington movement has the advantage of knowing with certainty who will get HD and roughly when; therefore scientists can detect and understand the disease before symptoms appear. However, even though HD starts with a single gene, the disease processes that are caused by it have proven to be very complicated.

With HD, a variety of things go wrong in various parts of the brain. Looking at the larger picture relative to other brain diseases, fifteen years is not a long time to discover a treatment for a complicated disorder like Huntington's disease. Considerably more effort has been put into Alzheimer's disease over the years, but HD research is considered to be much further ahead.

Ultimately, it is the strength of the HD drug discovery movement that determines how fast treatments will come to people - the expertise and tools scientists have available to them, the way in which they share information, set priorities, coordinate their work and focus their efforts. Most importantly, this is the area where the Huntington movement really excels - the sphere where people living with Huntington's disease can get the greatest sense of comfort that everything possible is being done.

Many knowledgeable observers acknowledge that we have a robust, world class discovery process that will inevitably produce results. The HD research community was small at the beginning, and scientists worked together and shared their findings. Over the years a series of organizations have come on board to fulfil various roles and functions that a complete discovery process requires, such as building tools to measure disease progression and assess the outcome of clinical trials, databases and registries for people participating in trials, animal models to study the disease, and methods to disseminate scientific information.

The HD movement's drug discovery company is the Cure Huntington's Disease Initiative, or CHDI, which is dedicated exclusively to HD. CHDI has taken advantage of the basic science accumulated since the gene was discovered to help develop drugs to treat HD.

In the drug discovery process, a target is a key molecule involved in a process or pathway implicated in a disease. Around 600 targets, at which HD drugs could be aimed, have been found to date along with about 200 different compounds that might form the basis of these drugs. Validating all these targets and compounds is a large, but practical logistical and scientific challenge, but CHDI has been designed in a new, unique drug discovery model to streamline the process of bringing a drug to the patient.

In short, CHDI sets priorities for the HD movement among these targets and engages companies with expertise to design drugs to hit the most promising targets. Less than three years old, CHDI is starting to gain momentum. They are already leaders in an emerging field and releasing the potential of biotech and pharmaceutical companies to work for rare diseases.

A recent, informal survey of Canadian health causes found that, with exceptions, scientists generally tend to collaborate less on a worldwide basis than the HD movement. Often there are no clear set of priorities for their movements internationally nor ways to effectively follow up on discoveries in basic science to design drugs. For example, 33 million people have AIDS and just last year that movement came together to form the Global HIV Vaccine Enterprise to accelerate the development of a preventative vaccine. Compared to other disease groups, the international Huntington movement is doing extremely well.

Real Barriers Still Exist
Certain barriers still stand in the way of effective treatments, but the HD movement is fully capable of surmounting them. Simply put, two basic components must be in place to yield a treatment. First, we must have a viable target that has the potential to favourably influence the disease. Second, a compound or drug must be found to successfully hit that target and either block or enhance a process in the body.

As mentioned, the HD movement has a number of viable targets, but to actually produce small molecule drugs which could be tested in clinical trials, scientists must build a number of complicated chemical structures. Getting these molecules through the blood brain barrier to hit the target is a major focus of attention today.

Even though the HD movement has made tremendous progress developing scientific tools, like mouse models, to study the disease, more work must be done to develop sensitive tools equal to the scientific challenge. For example, today our tests are not sufficiently sensitive to pick up changes in patients occurring over short periods of time. Therefore, even if a treatment was slowing the progression of HD, we might not be able to detect it, or tell if the treatment was influencing the underlying disease or simply impacting the symptoms.

The number of drugs that successfully make their way through the regulatory process in the U.S. has dropped dramatically in recent years. As the basic science advances and the focus evolves in designing drugs to hit the most promising targets, the HD movement is giving more attention to trial design and measuring clinical end points to convince regulators of the efficacy and safety of HD drugs. The recent hearings about the drug Tetrabenazine (for chorea) held by the Federal Drug Administration in the U.S., has sensitized the HD movement about the need to shore up this aspect of our program before more HD drugs go to trial.

Clinical trials offer interested families a vital opportunity to contribute to the drug discovery process. One comprehensive cure involving a single compound may not emerge from the drug discovery pipeline; a combination of therapies is more likely. It is possible that a number of compounds specifically targeted to HD might go to clinical trials simultaneously in the next few years. Some foresee that certain treatments might be specifically tailored to the CAG repeat profile of the individual patient. Given the size of the HD population, and the number of compounds in the queue, the HD movement will be challenged to adequately test these therapies and get them approved by regulatory bodies. Clearly, in the near future we will need all family members available to participate in a range of clinical trials.

Acknowledgement: Huntington Society of Canada "Horizon" No 125 Spring 2008

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