While most researchers plumb the depths of the cell to find drug targets for modern day ailments, Billy Hudson, Ph.D, advances into the great expanse beyond the cells’ margins to uncover drug targets hidden in this extracellular netherworld. All cells exist in a sea of amorphous protein called the extracellular matrix. Composed
primarily of insoluble collagens and proteoglycans, the matrix is more than just filler. It shapes tissues and supports and influences a multitude of cellular processes.

“Matrix components are specifically involved in the etiology and pathogenesis of
disease, making the matrix a valuable drug target,” says Hudson, director of the
Vanderbilt Center for Matrix Biology. Changes within the matrix underlie several of the complications of diabetes, particularly those involving the kidney. When glucose concentrations remain high for long periods, matrix proteins can be altered
by glucose reacting with the amino groups of the proteins.

This process, called glycation, results in large, cross-linked molecules that inhibit normal cell function. In the kidney, glycation can limit the organ’s filtering function and lead to kidney failure. After several years of studying matrix changes involved in diseases of the kidney, Hudson was challenged to “do something” to stop the process by a former postdoctoral fellow at the University of Kansas, J. Wesley Fox, Ph.D.

“We were making strides in understanding the process, when Wes Fox says, ‘Why
don’t you develop a drug to prevent that?’” Hudson recalls. “I said, ‘That sounds good, but I don’t really have the money to do that.’” Fox replied that he would find the money if Hudson worked on the drug. With a unique combination of scientific expertise and a sharp business sense, Fox found investors to support Hudson’s new line of inquiry. In 1994, Fox, Hudson and colleagues at the Karolinska Institute in Sweden founded BioStratum, a biotech company dedicated to pursuing the matrix as a drug target.

Billy Hudson, Ph.D., (left) discusses a research project with graduate student Roberto Vanacore. Photograph by Anne Rayner

Efforts to pharmacologically arrest glycation-related pathology had shown some progress, but the most promising drug candidate, aminoguanidine, hadproven too toxic in clinical studies. Drawing on his studies of the extracellular matrix, where diabetes-induced glycation is very active, Hudson foundan effective compound that inhibited multiple pathways of glycation-related pathology, but was entirely
natural in the body. Hudson answered Fox’s challenge with the compound pyridoxamine (brand name Pyridorin), a vitamin B6 derivative. Both in vitrostudies and animal models showed that pyridoxamine prevented the glycation-related pathology that contributes to diabetic kidney disease. Phase II clinical trials, completed last year, showed that Pyridorin was safe and effectively slowed the progression to kidney failure. Phase III trials are set to begin this year. From this unconventional thinking, a new approach to drug development was born, bringing together academic researchers and the biotech industry to chase down the next
generation of pharmaceutics.

The role of government
The onerously high cost of making new drugs has not escaped the attention of federal health officials. Last year in a report entitled “Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products,” the U.S. Food and Drug Administration called for increased public-private collaboration to boost drug development through the application of new technologies.

“We must modernize the critical development path that leads from scientific discovery to the patient,” the report urged.
Developing new tools to aid drug discovery also is the goal of the Molecular Libraries Screening Center Network, established last year by the National Institutes of help translate new scientific knowledge into “tangible benefits for people.”

The aim is to harvest the fruits of the genomic revolution, make them available to scientists in universities and industry
alike, and encourage them to work together as never before, explains Christopher P. Austin, M.D., senior advisor for translational research at the National Human Genome Research Institute. “What we hope to do ... is the high-capital investment ... take the assay, do the robotic screening on a big library, do some initial chemistry, and give (scientists)
back a small molecule compound which allows them to query the function of that gene or pathway – to test a hypothesis,” Austin says.

The federal efforts have their share of skeptics, including Steven M. Paul, M.D., president of Lilly Research Laboratories. “I am worried that obtaining the kind of molecular probes required for even in vivo testing may prove to be too time-consuming and expensive,” Paul says, “and may divert precious NIH funds away from basic or
clinical biomedical research.”

The federal initiatives in no way are meant to diminish government’s role in supporting fundamental discovery, Austin
responds. Tools developed by the public sector, however, can help establish the therapeutic potential of new compounds, and encourage industry to push them through the pipeline.

“As long as ... we’re all aware of what we can do and can’t do, I think we’ll be fine,” he says.

Pictured left: Three-dimensional crystal structure of a G protein coupled receptor (GPCR) embedded in a cell membrane, with its loosely attached heterotrimeric G protein, con- sisting of alpha, beta and gamma subunits, inside the cell. When a ligand, such as a neurotransmitter or hormone, binds to its GPCR, the receptor changes shape in a way that catalyzes the release of guanosine diphosphate (GDP) from the alpha subunit. GDP, an organic molecule involved in intracellular energy exchange, is replaced by the higher- energy guanosine triphosphate (GTP). That, in turn, causes the alpha subunit to break apart from the beta and gamma subunits. The subunits then interact with other intracel- lular proteins to transmit signals down two independent pathways. Within a few seconds, GTP is converted back to GDP, the subunits recombine, and the signals are "turned off."

In contrast with pharmacetical companies taking over drug development, this approach allows universities to continue to participate in the drug discovery and development process and to reap some of the financial benefits: the university and
researcher can maintain the patent on a therapy and license its use.

Fox has gone on to become president and CEO of another biotechnology company,
NephroGenex, Inc., which was co-founded by Hudson. In Hudson’s case, the foray into biotech has had a beneficial impact on his more basic research interests as well.
“I now have two additional grants based on that drug (Pyridorin) to explore basic
mechanisms – not to develop a drug – and others have been awarded NIH grants to explore the actions of Pyridorin,” Hudson says. “So there is a positive feedback into basic science that can come from this approach.”

This article appeared in Lens, Summer 2005. Lens magazine is a publication of the Vanderbilt University Medical Center.