Photo of an unrecognizable chemist taking a test tube in a laboratory

Case Western Reserve University researchers develop therapeutic to enhance tissue repair and regeneration

Rodeo Therapeutics receives early funding to develop 15-PGDH Inhibitors as human therapeutics

Rodeo Therapeutics, a new drug development company created by two highly regarded Case Western Reserve University School of Medicine researchers, has raised $5.9 million to develop small-molecule drugs that promote the body’s repair of diseased or damaged tissues.

The company is based on discoveries by its three scientific founders, Sanford Markowitz, the Markowitz-Ingalls Professor of Cancer Genetics and Distinguished University Professor at CWRU; Stanton L. Gerson, the Asa and Patricia Shiverick- Jane Shiverick (Tripp) Professor of Hematological Oncology and director of the Case Comprehensive Cancer Center; and Joseph Ready, professor of biochemistry at University of Texas Southwestern. The “Rodeo” moniker is intended to invoke the “western” in Case Western Reserve and University of Texas Southwestern, home universities of the firms’ three co-founders.

The company will build on its founders’ research expertise to develop drugs to help the body heal itself by inhibiting a prostaglandin-degrading enzyme called 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Prostaglandins are hormone-like substances crucial for many important activities within the body.

In a 2015 publication in Science, Markowitz, Gerson, and Ready showed that prostaglandins stimulate the ability of tissue stem cells to repair tissue injury, and that this activity could be potently activated by small molecules they developed to inhibit 15-PGDH. In mice models, the 15-PGDH inhibitors stimulated healing of colitis, stimulated recovery of the liver following liver surgery, and markedly accelerated the recovery of bone marrow after a bone marrow transplant.

“The body has enormous potential to heal itself through actions such as tissue regeneration,” Markowitz said. “Our goal was to develop a drug that could recruit these tissue regeneration capacities to assist in treatment of human diseases where tissue damage is often the principal cause of death or significant illness.”

Accelerator Corporation, a Seattle-based life science investment and management firm, led the effort in obtaining a $5.9 million Series A financing for Rodeo Therapeutics. Investors include AbbVie, Alexandria Venture Investments, Arch Venture Partners, Eli Lilly & Co., Johnson & Johnson Innovation – JJDC Inc., Watson Fund, L.P., WRF Capital, and WuXi AppTec. Accelerator will help manage the new firm along with Rodeo’s three scientific founders.

“Rodeo Therapeutics’ founding scientists have achieved a level of biology and medicinal chemistry for their lead product candidate that is advanced beyond what we would typically see in an academic setting,” said David M. Schubert, chief operating officer of Accelerator. “We believe that this Series A investment will provide the financial resources to rapidly advance the company’s development program toward human trials, opening the door to an exciting new therapeutic approach that has significant clinical and commercial potential.”

“Inflammatory diseases often result in serious tissue damage and impairment,” Gerson said. “We have developed a drug that has stimulated tissue regeneration, repairing damage to the colon, liver, and bone marrow in animal models, paving the way to apply our findings to human diseases.”

Rodeo will focus on increasing tissue levels of prostaglandin E2, or PGE2. Research has shown that PGE2 supports production of many types of tissue stem cells, which are crucial for healing to occur. Markowitz and University of Kentucky Professor Hsin-Hsiung Tai earlier showed that 15-PGDH degrades and reduces the amount of PGE2 in the body and that inhibiting 15-PGDH leads to more PGE2 being produced, resulting in tissue regeneration and healing.

Markowitz‘s laboratory developed a test for identifying drugs that could bind to 15-PGDH. Ready and his UT Southwestern colleague, James Willson (former director of the Case Comprehensive Cancer Center), used the test to examine a repository of over 230,000 chemicals, finding one— W033291—that incapacitated 15-PGDH when added at one part in 10 billion in a test-tube-based mixture, raising the possibility that it could be administered as a drug.

Markowitz, Gerson and their colleagues then studied mice that had received lethal doses of radiation, followed by a partial bone marrow transplant. Without SW033291, all the animals died. With it, they all recovered. Additional studies showed that mice given the drug regained normal blood counts six days faster than mice that were transplanted without receiving the drug.

In addition, the researchers found that SW033291 accelerated tissue recovery in other diseases, for example, healing virtually all ulcers associated with ulcerative colitis. In mice that had two-thirds of their livers surgically removed, SW033291 accelerated re-growth of new liver nearly twice as fast as typically happens without the medication. Crucially, there were no adverse side effects, even at doses much higher than needed for inhibiting 15-PGDH.

The new funding for Rodeo will enable the founders to conduct studies aimed at showing the safety of SW033291-related compounds in larger animals, part of the pathway needed to secure approval from the U.S. Food and Drug Administration for trials in humans. The first focus is on developing 15-PGDH inhibitors for inflammatory bowel disease and promoting the reconstitution of blood cells following bone marrow transplant.

“This team and this program provide a blueprint for what can be accomplished with translational research in Cleveland,” said Michael Haag, Case Western Reserve’s executive director of technology management at CWRU’s Technology Transfer Office. “We are indebted to several advisors who provided world-class guidance and mentorship.”

Translational Research Support for the founder’s research on developing 15-PGDH inhibitor drugs came from Case Western Reserve’s Council to Advance Human Health, University Hospitals Cleveland Medical Center’s Harrington Discovery Institute. Also contributing to the technology development to date was a grant from the NIH Center for Accelerated Innovation – Cleveland Clinic, a multi-institutional NIH-funded technology development program focused on translating promising research to commercial development and eventual use in the diagnosis and treatment of patients.

This article was originally published Aug. 17, 2017.