Major Advances in Huntington's Disease Research Expected From Powerful Technology to Study Protein Structure

SAN DIEGO, Calif., December 4, 2002 – The Hereditary Disease Foundation (HDF) and Structural GenomiX, Inc. (SGX) today announced a collaboration agreement to investigate the structure of huntingtin, the protein responsible for Huntington’s disease. Determining huntingtin’s structure should help reveal the protein’s normal function and how it causes disease when it is mutated. It should also provide key insights for the design of new therapies.

Ever since the huntingtin gene was discovered in 1993, investigators have been eager for information on the protein’s shape, predicting it would allow them to make important strides towards understanding Huntington’s disease. Indeed, some of the most prestigious scientists who have tackled Huntington’s disease were frustrated by the lack of this information. The late Nobel laureate Max Perutz, for example, repeatedly stressed how much the field could move forward if only they had more data on huntingtin’s structure and how it is altered in disease. “Max Perutz was always saying, ‘Where’s the structure? We need the structure!’” recalls Nancy Wexler, President of the Hereditary Disease Foundation. She also notes that the Foundation is carrying out this new collaborative partnership in his honor.  Max was a good friend to the Hereditary Disease Foundation family and made critical contributions to HD research.

The structure of huntingtin has remained obscure because it is a difficult protein to work with. Unlike most proteins, huntingtin is extremely large and unwieldy. Researchers have met with many obstacles when trying to obtain large amounts of it in pure form, a key requirement for unambiguously deciphering its three-dimensional shape. “It’s huge,” says Wexler.  “We haven’t been able to get our arms around it.”

A highly efficient, industrial approach used by SGX, however, promises to help overcome these problems. Researchers at SGX have developed techniques to streamline the many steps involved in determining a protein’s structure. First, they use proprietary methods based on genetic engineering to generate large amounts of complete proteins or protein fragments. Then they purify these protein products and place them under conditions that prompt them to form crystals. By blasting the crystals with a high-powered X-ray beam, the researchers obtain diffraction patterns that contain information about the structure of the proteins. Applying sophisticated computational tools allows them to then analyze the diffraction data and predict the proteins’ structures.

Wielding such cutting-edge tools, the HDF and SGX hope to get a first-ever view of three-dimensional huntingtin. The new vista should provide important clues of the functions huntingtin normally performs in cells and the proteins it interacts with. By comparing the shapes of normal and mutated huntingtin, the researchers also hope to better understand what goes wrong in Huntington’s disease. “Working side-by-side with an organization like SGX and tapping into their extensive knowledge of protein crystallography brings us many steps closer to uncovering the molecular pathology of Huntington’s disease,” says Wexler.

The study of normal and mutated huntingtin structures is also expected to help researchers design drugs that uniquely target the diseased form of huntingtin. If a promising structure is identified, SGX’s expertise in analyzing structural interactions between small molecules and proteins could greatly accelerate the development of new drug candidates. “The HDF collaboration exemplifies the importance of SGX’s gene-to-structure technology platform in aiding the fight against debilitating diseases like Huntington’s disease,” says Stephen K. Burley, chief scientific officer of SGX.

About Huntington's Disease

Huntington’s disease (HD) is an inherited, fatal brain disorder that destroys motor control and impairs thinking and feeling.  Victims suffer from uncontrolled body movements, known as “chorea,” which eventually leaves them unable to walk, stand or even speak intelligibly.  The disease also causes cognitive difficulty, memory problems, severe depression and, after 15-20 years, death.  Symptoms usually begin to appear in early- to mid-adulthood, but can strike as young as two years of age or as old as 80 years.  There is no cure or treatment for the disease, but genetic testing can now identify carriers of the faulty gene.

Huntington's disease results from a genetic mutation on the fourth chromosome.  This abnormality causes the death of vital nerve cells in a region of the brain known as the basal ganglia.  HD is an autosomal dominant disorder, which means that each child of a parent with the disease has a 50 percent risk of inheriting the illness. The huntingtin gene is considered virtually 100 percent “penetrant,” meaning that anyone who inherits the faulty gene will inevitably develop the disease.  All “carriers” eventually become “patients.”  The disease currently affects 35,000 to 50,000 Americans, with 175,000 to 250,000 more people at risk.

About the Hereditary Disease Foundation                                                                                

Formed in 1968 by Dr. Milton Wexler, the Hereditary Disease Foundation has played a pioneering role in spearheading innovations in modern molecular genetics.  In 1983, the Hereditary Disease Foundation was the first to localize the gene causing Huntington's disease with novel strategies using DNA markers when its chromosomal assignment was unknown.  This success was a critical first step in helping to launch the Human Genome Project.  HDF then organized and supported the Huntington's Disease Collaborative Research Group, a dedicated team of over 100 international investigators who collaborated for a decade to clone the HD gene.

In 1997, the Hereditary Disease Foundation formed the Cure Huntington's Disease Initiative, directed by the Cure Committee, a prestigious group of scientists including members of the National Academy of Sciences and the Institute of Medicine.  CHDI pursues ways to accelerate progress toward treatments and cures by expediting the route from research to therapy.

The HDF supports the development of animal models, studies of protein-protein interactions, strategies for gene therapy, and intercellular signaling in striatal neurons. Through grants, contracts, post-doctoral fellowships, and its unique interdisciplinary workshop program, the Foundation continues to build a research community committed to the cure of Huntington's disease and related disorders.  Further information can be obtained from the Foundation's website at www.hdfoundation.org.

About Structural GenomiX

Structural GenomiX, Inc. (SGX) is a drug discovery company utilizing a genomics-driven high-throughput structure-based platform to increase the efficiency and effectiveness of the drug discovery process. The SGX approach identifies potent and selective drug candidates that are targeted to individual members of protein families. Proprietary SGX technologies include advanced bioinformatics, automated molecular biology and protein biochemistry, high-throughput crystallization, rapid structure determination, high-throughput compound docking and medicinal chemistry. SGX drives the lead optimization process through iterative determination of co-crystal structures that reveal, in great detail, how small molecules interact with drug targets. SGX has established unparalleled capacity in this area by building a world-class facility for the collection of macromolecular X-ray diffraction data at the Advanced Photon Source (APS), located at the U.S. Department of Energy's Argonne National Laboratory. The Company is based in San Diego, California. For more information, please visit our website at www.stromix.com.

Contact:
Hereditary Disease Foundation 
Nancy Wexler – cures@hdfoundation.org
Phone: (212) 928-2121
Fax: (212) 928-2172
www.hdfoundation.org

Hereditary Disease Foundation
3960 Broadway, 6th Floor
Carl Johnson - carljohnson@hdfoundation.org
New York, NY 10032