Looking to advance the discovery and development of therapeutics, Structural GenomiX Inc. and the Hereditary Disease Foundation entered a collaboration to use SGX's structure-directed drug discovery technologies to investigate the structure of the protein responsible for Huntington's disease.
The parties labeled their endeavor the first large-scale effort aimed at determining the structure of the huntingtin protein since the 1993 discovery of its gene. The cause of Huntington's disease, an inherited, fatal brain disorder that destroys motor control and impairs thinking and feeling, results from a genetic mutation on the fourth chromosome.
"We are enthusiastic about using structure to learn enough about huntingtin, the gene product of the Huntington's disease gene, to understand the molecular basis of the pathology that develops when you have expanded glutamine repeats," SGX Chief Scientific Officer Stephen Burley told BioWorld Today.
The agreement includes undisclosed payments to San Diego-based SGX for research funding, as well as success payments upon achievement of certain research milestones.
"The milestones are initially based on obtaining protein," Burley said. "Huntingtin has been notoriously difficult to express and purify. Thereafter, the milestones are based on obtaining X-ray crystal structures of fragments and ultimately the full-length huntingtin protein."
Specific financial terms were not disclosed, though Burley said SGX retains downstream royalties on resultant compounds developed by the foundation. SGX said its ability to generate structural data could assist the foundation in identifying potential drug leads that interact with the huntingtin protein. No cure or treatment for the disease exists, but genetic testing can identify carriers of the faulty gene. All carriers eventually become sufferers of the disease, which causes cognitive difficulty, memory problems, severe depression and, ultimately, death 15 to 20 years down the road.
Using its high-throughput structure determination technologies, privately held SGX will work with the Santa Monica, Calif.-based foundation to focus on a dual-track research effort. The first segment, over two years, will use structural information to discover how modifications in the 3-dimensional structure of the huntingtin protein are involved in the transition from normal to pathological function. The second area of research will use further structural analysis of the huntingtin protein to determine how the 3-dimensional structure of the protein domains can help elucidate the normal cellular function of the protein.
"Our gene-to-structure platform allows us to tackle multidomain, eukaryotic proteins," Burley said. "Specifically, we have a lot of expertise working with other human disease gene products. We can mount the kind of systematic effort required to overcome problems with expression and solubility and then move on to purification."
SGX plans to use its high-throughput crystallography platform to perform co-crystallization experiments in parallel fashion with the truncated forms of huntingtin protein it generates. Such products would then be analyzed for the collection of macromolecular X-ray diffraction data at the Advanced Photon Source at the U.S. Department of Energy's Argonne National Laboratory in Argonne, Ill., where SGX houses a dedicated facility.
SGX has undertaken similar endeavors before this deal. The company also is involved in a $13 million deal with the Cystic Fibrosis Foundation to decipher the 3-dimensional structure of the cystic fibrosis transmembrane conductance regulator protein that, when defective, can cause cystic fibrosis. SGX in April received a payment based on the achievement of its first milestone in the collaboration - progress in solving the protein's 3-D structure.
"We are working on the cystic fibrosis project to understand the pathologic basis of a mutation in the nucleotype-binding domain that is the leading cause of cystic fibrosis," Burley said. "It's very similar, exploiting the same platform strength."
SGX is at the center of a recent initiative entered into by the Bethesda, Md.-based National Institutes of Health, which last month awarded SGX the authority to manage $18.1 million over three years in a public-private venture focused on protein structure research. SGX will share the funding with other New York Structural Genomics Research Consortium participants, including scientists at the Albert Einstein College of Medicine, the Brookhaven National Laboratory, Columbia University, The Rockefeller University and the Weill Medical College of Cornell University. (See BioWorld Today, Nov. 18, 2002.)
SGX is involved in several other deals, including an agreement signed earlier this year to develop antibacterial drugs with Anadys Pharmaceuticals Inc., of San Diego. Also in the past year, it has entered drug discovery deals with Cambridge, Mass.-based Millennium Pharmaceuticals Inc. and Bridgewater, N.J.-based Aventis Pharmaceuticals Inc.
Internally, Burley said, SGX is developing a human kinase program, which features two oncology targets already advanced to the lead-optimization stage. Behind that tier, SGX is examining a dozen protein kinases, most of which are oncology targets, with a goal of advancing them to lead discovery.
"In our kinase pipeline program, we are working on all of the human kinases that are implicated in disease," Burley said.