The HD Pipeline

Research and Drug Development for Huntington's Disease

Drug Optimization

Once a biological target has been identified and has passed preliminary validation, the next step is to identify candidate drugs that can modify the target's actions in living tissues and cells. One way of finding potential drugs is to screen through the thousands of available drugs and compounds to see if any interact with the target in the desired manner. When screening, it is important to consider if the desired effect of the drug is to inhibit or enhance the normal activity of a biological target. A thorough understanding of the target's biochemistry can sometimes enable scientists to guess what kinds of drugs and chemical compounds will interact with it. This can lead to a narrowed, more efficient screen.

In a full-scale screen, there may be more than 10,000 different molecules to look through. Pharmaceutical companies use combinatorial chemistry and high throughput machines to screen chemical compound libraries, looking for interactions between a potential drug and the biological target. They continuously narrow down the drug candidates, refining the search and the criteria they are using until a likely group of compounds is identified. Scientists also have to verify that any candidate drugs are very specific to the biological target- meaning that they interact with only the target, and not any other important molecules in a cell. If a compound interacts with too many molecules in addition to the specific target, it will often cause problems independently of its work in curing the disease. In this case, the side effects it causes would not make it a suitable drug treatment.

After a high throughput screen, a group of chemical compounds may be identified as potential drugs. These compounds will then undergo further testing; scientists will often use biochemistry to modify one of the compounds- this process is called optimization. These modifications can increase the drug's effectiveness and make sure it doesn't target other proteins. After this process, one or two molecules will be put forth for drug development. The most promising one is called the "lead compound", and another is designated as a "backup".

In the past many drugs were discovered by trial and error, or by chance through a screen. More and more often now, scientists are using a process called "rational drug design" to design and create a lead compound, instead of finding one in a screen. In rational drug design, scientists use knowledge about the three dimensional structure of the chosen biological target's active site to design a drug to specifically interact with it. This requires a good knowledge of chemical biology to synthesize molecules and modify their shape so that they may serve as a drug. While many techniques for rational drug design are still being developed, it seems like it will be a good way for scientists to produce targeted and effective drugs with few unwanted interactions or side effects.

HD and Drug Optimization

The HD research community is helping to pioneer a new approach to drug development, using biotechnology in combination with traditional pharmaceutical approaches. In HD, every case has the same cause (the mutation in the HD gene), unlike diseases like Alzheimer's disease, cancer, heart disease, and diabetes, which can be caused by a variety of different factors in individual patients. This allows HD researchers to use biotechnology to develop new treatments to target early disease time points, before the onset of symptoms, as well as treatments for particular symptoms. To learn more about the progression of HD and the onset of symptoms, click here Traditional pharmaceutical companies often develop treatments by modifying a relatively small number of existing drugs to target symptoms that are common in a number of different diseases. But the advent of new biotechnology approaches like those used by many HD researchers have recently started to force the pharmaceutical industry to look into finding other types of rational biological targets. Currently, pharmaceutical companies and biotechnology companies are forming partnerships to do just that.

There are many institutions and pharmaceutical companies devoted to HD drug discovery research. At Harvard Medical School, the Laboratory for Drug Discovery in Neurodegeneration (LDDN) is set up like a small biotechnology company. They have high-throughput screening robotics, a chemical compound library with nearly 100,000 different drugs, and staff and collaborators from all over Harvard University. Their goal is to find lead compounds and then hand them over to larger pharmaceutical companies for further testing and development. Since it doesn't have investors to pay back like pharmaceutical companies often do, researchers have more freedom to pursue high-risk but high-payoff biological targets. Their projects focusing on HD involve screening their compound library for molecules that interact with and/or affect polyglutamine repeats polymerization, and kinases.

CHDI, Inc is a non-profit drug discovery and research organization based in Los Angeles, California. They are sponsored by the High Q Foundation a private philanthropic foundation that was established to bring together academia, industry, governmental agencies, and other funding organizations in the search for HD treatments. CHDI, Inc is a "dry" lab, meaning that rather than conduct experiments at their own facilities, they contract out projects to established laboratories that have the most relevant equipment, supplies, and scientists for the specific experiments. They collaborate with private and academic labs to do research on all aspects of drug discovery and development, from high throughput screening to preclinical development. One of their most recent projects is to partner with Amphora Discovery, a drug discovery and development company that has developed their own high throughput screening process, to find compounds that inhibit caspase-6 activity. For more on caspase-6, click here.

Medivation is a company dedicated to research and drug development in HD, Alzheimer's disease and Prostate Cancer. They work with drugs from the pre-clinical stage through Phase II trials. One of their newest products is a drug called Dimebon, which is an antihistamine that is thought to alleviate symptoms and prevent progression of neurodegenerative diseases like Alzheimer's and now is being tested for its effects in HD. For more information on Dimebon, please click here).

Last Modified: 07/07/2007

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