The Promise of Prostaglandin Transport
Prostaglandins (PGs) are molecules that trigger signals in major tissues and cells throughout the body, including connective tissue, skin, stomach, blood vessels and the nervous system. When prostaglandins interact with their receptors (in the same cell or in nearby cells), these naturally occurring chemicals activate responses such as pain, inflammation, fever, blood vessel dilation and constriction, antiplatelet clumping and kidney filtration.
From left: Richard Kosman, Victor Schuster, Yuling Chi enlarge photo
In the mid-1990s, it was known that prostaglandins had a mechanism that enabled them to enter cells, but the molecular nature of that carrier was still undefined. Victor Schuster, M.D., a physician-scientist specializing in nephrology, physiology and biophysics, uncovered the molecular basis for the prostaglandin transporter (PGT), a finding that could advance the treatment of a diverse range of conditions including glaucoma, stomach ulcers, wounds, high blood pressure and atherosclerosis.
Identifying the prostaglandin transporter was “a complete accident,” according to Dr. Schuster, who was deeply involved in studies of a different organic anion transporter at the time. He identified a genetic relative of the transporter through the NIH database GenBank®, obtained its clone and began testing for its transport substrates. He then obtained a sample of radioactive prostaglandin E2 from a colleague at Vanderbilt University and gave it to a postdoctoral fellow in his laboratory for testing. “My postdoc rolled his eyes, probably thinking as I was—‘Here we go again, testing another candidate substrate without success’—but then two days later, we knew we had a prostaglandin transporter,” Dr. Schuster recalled. “Louis Pasteur once said, ‘Chance favors the prepared mind,’ and that was certainly true in our case.”
The Invention Disclosure
Dr. Schuster submitted this discovery to Einstein’s office of biotechnology in the form of an invention disclosure. This disclosure was reviewed by Einstein’s Committee on Patents, which then formally recommended to the dean that intellectual property (patent) protection be sought on this exciting scientific breakthrough. Years later, the discovery and its improvements were selected to be the inaugural investment of Einstein’s new Technology Development Program.
On October 12, 2010, the Technology Development Program was publicly introduced to the Einstein community in the second installment of the Science & Business series “Investing in the Development of Einstein’s Technologies,” co-presented by Richard Kosman, director of the office of business development, and Dr. Schuster.
In the presentation, the program was described in detail, including its financial (and other) support of the PGT technology. Mr. Kosman and Dr. Schuster presented the need for the program, the history of the PGT technology, the investment selection process of the program and the exciting commercial and scientific successes that have resulted from the program’s support of the PGT technology.
Advancing the Research
Dr. Schuster, who later became chair of the department of medicine, went on to clone the transporter in humans. Human PGT was the subject of his original invention disclosure, and Einstein obtained patent protection on it. He also manipulated and knocked out the transporter gene in mice, and derived the extent of the PGT’s representation down through the phylogenetic tree using zebrafish.
Prostaglandins are metabolized to inactive forms through two pathways, spontaneous hydrolysis (from water contact) and enzymatic oxidation (from oxygen contact). Enzymatic oxidation happens inside cells. In order for prostaglandins to undergo enzymatic oxidation, they must first pass through cell walls assisted by the prostaglandin transporter. Inhibiting the transporter blocks prostaglandin breakdown, thereby increasing prostaglandin levels in the bloodstream and strengthening their signaling, which may be beneficial in certain conditions. Yuling (Julia) Chi, Ph.D., an assistant professor of medicine (nephrology) who had worked as a postdoctoral fellow in Dr. Schuster’s lab, identified a series of PGT inhibitors in collaboration with medicinal chemists at NYU. Dr. Chi’s potent PGT inhibitors provided proof-of-concept data supporting the feasibility of PGT inhibition’s potential therapeutic benefits, including the correction of high blood pressure in mice and accelerated healing of skin wounds. These inhibitors were the subject of a second invention disclosure submitted to the office of biotechnology, for which intellectual property protection was also sought.
The Funding Challenge
Drs. Schuster and Chi’s work was an example of the “early-stage” technology licensing opportunities frequently discovered and developed on academic campuses. Often the most advanced, potentially significant basic research does not fit the criteria for funding by the National Institutes of Health (NIH) and other grant providers. “In our case, the inhibitors lacked the medicinal chemistry properties necessary for them to be considered ‘drug-like’ molecules,” Dr. Schuster said. “Without further funding, our transition to the commercial side would have been uncertain, delayed at best and blocked at worst.”
The Einstein Technology Development Program was established to advance Einstein’s technology licensing opportunities so that they may become more attractive to potential commercial partners and increase the likelihood that they will be licensed, developed and made available to the public. Every disclosure pursued for patent protection is reviewed for potential inclusion in the Technology Development Program using a methodology common to life sciences investment banking corporate finance teams (which Mr. Kosman discussed in the first installment of Science & Business in February), and extensive third-party commercial participation is involved.
New Medicine and Beyond
The program’s successful results have included the creation of more-potent and optimized inhibitor compounds that were subsequently licensed to a third-party entrepreneur who formed a start-up company around the PGT inhibitor portfolio. “It is critical that researchers disclose new inventions to the office of biotechnology,” said Mr. Kosman. “Without Dr. Schuster’s original disclosure, there would have been no basis for support under the program.”
“We can now find new medicines to increase prostaglandin levels. This is the first time we’ve had that opportunity,” Dr. Schuster said.
“As the program advances this and other Einstein technology licensing opportunities, it has and will continue to catalyze the development of products that could benefit patients in the local community, in the United States and throughout the world,” said Mr. Kosman.