Researchers receive grant to improve quality of donor limb, tissue for transplant

A Case Western Reserve University School of Medicine faculty member has received $998,500 from the U.S. Department of Defense to develop a new approach to improve the quality and quantity of limbs and tissues obtained from brain dead organ donors. Benefits also could be extended to the more standard transplanted organs (e.g. kidneys, hearts, and lungs).

James D. Reynolds, PhD, associate professor of anesthesiology and perioperative medicine and a member of the Case Institute for Transformative Molecular Medicine, is leading a multi-disciplinary team examining a new class of drug aimed at stabilizing donor limb and tissue biology after brain death. If found to be safe and effective in animals, the process could be used in humans.

Reynolds and colleagues earlier found that brain death disrupted the levels of important molecules in the body called S-nitrosothiols, or SNOs. SNOs control many crucial functions including oxygen delivery, blood flow, and cell activity. SNO deficiency can result in tissue injury and oxygen deprivation in the donor, reducing the likelihood of successful function of the transplant in the recipient.

"Transplantation saves lives," said Reynolds, "but a successful outcome is highly dependent upon the physiologic status of the donor. Brain death can disturb SNO functioning, which we believe is a major contributor to procurement rates of suitable organs as low as twenty percent from consented donors. This is a disheartening figure when one considers how much demand outstrips availability. Clearly, better methods are needed to support the donor after brain death, and we will be exploring one such option under this grant."

Using a drug that grew out of the pioneering work of Reynolds' colleague Jonathan Stamler, MD (director of the Case Institute for Transformative Molecular Medicine), the Reynolds team had previously found that SNO deficiency in animals could be reversed, improving oxygen delivery and reducing tissue injury. With the new funding, they will use additional animal models to examine if treating donors with their proprietary compound improves tissue function in subsequent transplant recipients.

Specifically, they will be focusing on vascular composite allotransplantation, or VCA, the removal of a block of tissue from a donor and its attachment to a recipient. The tissue block is made up of skin, muscle, and bone, hence use of the term "composite." VCA is becoming an accepted method for correcting composite tissue loss (e.g. limb amputation) or catastrophic injury such as abdominal trauma and severe facial damage.

There are about 1,700 US amputee service members and 600 with severe facial disfigurement as a result of the Afghanistan and Iraq conflicts. "While some individuals will opt for prosthesis and grafts of their own tissue, our goal is to present VCA as a safe, viable option for replacing limbs and aiding in correcting devastating facial and trunk damage," said Reynolds.

In addition to assessing the benefits of their SNO medication in animal transplantation, the researchers will search for signs of SNO deficiency in human donors. Building on earlier work, they will do this by conducting blood and muscle biopsies along with non-invasive assessments of blood flow and oxygen utilization.

"If our supposition holds true, we will find that muscle and tissue in human donors, not just animals, are also harmed by deficiencies in SNOs," said Reynolds. "If this is confirmed, in combination with positive results from our drug study in animals, support will be in place for a follow-on clinical trial with human VCA transplants. Then we could enact trials of the medication in standard organ transplantation as well. But for this to truly work, we need more organ donors along with these methods to increase the number of viable organs that can be obtained from currently consented donors."

In the US, over 120,000 individuals are on wait-lists for lifesaving organ transplant, with someone added every 10 minutes, figures that significantly exceed the approximately 14,200 individuals who become deceased organ donors each year. As a result, on average 22 people die each day because their transplant needs were not met.