Organ transplants can save lives, but unfortunately organs don’t last long in storage. Now scientists have demonstrated that an existing drug can reprogram donor hearts to last much longer outside the body, and reduce their risk of failure after transplantation.
Currently, donated hearts can only survive for around four hours in cold storage, which doesn’t leave much time to get them from donor to recipient. Much of the problem arises from a molecule called succinate, which builds up in the organ while it’s sitting on ice. Later, when blood is reintroduced to the heart, succinate can trigger oxidative stress that can cause damage and lead to heart failure, one of the main causes of early death for transplant patients.
For the new study, scientists at the University of Michigan investigated how to counter that issue using itaconate, an enzyme that’s known to neutralize succinate. By scanning through a database of metabolic effects, the team identified a drug called valproic acid as a promising source of itaconate.
In tests on human and pig hearts in cold storage, the valproic acid helped the hearts produce antioxidants and anti-inflammatory proteins, which helped clear out the stress caused by succinate.
“Using a metabolomic screen, we found that valproic acid can reprogram the donor heart to produce beneficial itaconate during preservation,” said Paul Tang, senior author of the study. “We showed previously that hearts are in fact biologically very active while stored on ice, which opens up the therapeutic opportunity to help it protect itself from metabolic stress during this time. Not only could this possibly double the time a heart could spend in cold storage, but it could reduce the risk of primary graft dysfunction to make transplant even safer.”
This could greatly improve the outcomes for patients needing heart transplants, by allowing the organs to travel farther and giving patients more time to be prepped for surgery. That should also reduce the number of donor hearts that are wasted and help clear the backlog of patients on waiting lists. And the benefits might not stop at heart transplants.
“The overarching principles here can be expected to apply to preservation of other organs, such as lungs, livers and kidneys,” said Eugene Chen, co-author of the study. “I would also anticipate this treatment strategy to be relevant for other conditions where blood supply is disrupted, such as heart attack or stroke.”
And perhaps best of all, valproic acid is already approved by the FDA and in use to treat seizures. That means it should be faster to get it to clinical trials than other drugs that haven’t been fully tested – although of course, hurdles do still remain.
The research was published in the journal Science Translational Medicine.
Source: University of Michigan
