Reducing heart attack tissue damage

Pharmaceutical companies have shifted their focus for cardioprotective drug development based on research conducted at the University of Bristol.

The treatment following a heart attack or stroke is to clear or bypass the block in the circulatory system and restore blood flow to the tissues of the heart and brain, respectively.

However, these tissues, which have been deprived of nutrients and oxygen as a result of the blockage, can become further damaged when the blood supply returns due to inflammation and oxidative stress.

This damage - known as reperfusion injury – is estimated to cause around half of the total tissue damage associated with a heart attack.

In 1995, Professor Andrew Halestrap, in Bristol’s School of Biochemistry, demonstrated that a pore in the membrane of mitochondria – the cell’s power producing organelle – opened during reperfusion injury in the heart.

Since then, Professor Halestrap has been unravelling the molecular mechanism behind this pore, which is known as the mitochondrial permeability transition pore (MPTP). His findings have helped inform the development of novel therapies that inhibit the opening of the pore, thereby protecting tissues from reperfusion injury.

“Since the early 1990s, our research has been developing a better understanding of the pore,” said Professor Halestrap. “We had published a lot on its role in reperfusion injury and how myocardial protection can be improved by influencing the pore opening. However, it wasn’t until the early 2000s that other research groups, which are more clinically related, saw the significance and took it into a much wider clinical setting.”

Interest in the MPTP was not only among clinical researchers.

Pharmaceutical companies began to consult with Professor Halestrap and shift their R&D efforts toward developing drugs that targeted the pore. The University of Bristol entered into a number of formal contracts with pharmaceutical companies, including Novartis, DebioPharm and Trophos. Halestrap’s research was influencing where industry was investing its money.

“[Halestrap’s research] has been a major influence in our decision to focus on inhibition of MPTP opening as the most promising target for protecting the heart from reperfusion injury,” said Dr Rebecca Pruss, Chief Scientific Officer for Trophos.

In 2011, Trophos was awarded a US Patent for their novel cardioprotective compound TRO40303, which has successfully completed Phase I clinical trials and is now in Phase II trials with 180 patients.

Other drugs targeting the MPTP that are undergoing clinical trials include Neurovive Pharmaceutical’s CicloMulsion® and NeuroSTAT® and Antipodean Pharmaceutical’s MitoQ.

At least seven clinical trials involving over 2,000 patients in nine European countries have been initiated to investigate drugs that target the MPTP either directly or indirectly.

Though the details of investment costs for each drug and each company are commercially sensitive, recent estimates have suggested that the out-of-pocket costs for industry to take a single drug from Phase I to Phase III clinical trials is around US $215-220 million (in 2011 USD; approximately £128- 132 million).

These new drug therapies are improving patient outcomes in preliminary clinical trials, with the potential to significantly reduce the amount of tissue damaged after a heart attack or stroke if approved as part of regular treatment protocols.

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