MAIL trial opens to recruitment

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Acute Liver Failure

Paracetamol (acetaminophen) overdose is the leading cause of acute liver failure (ALF) in the Western World. ALF is characterised as rapid onset of liver damage and loss of liver function. Every year, in the UK, there are >100,000 people who attend hospital following a paracetamol overdose, with around half requiring emergency treatment with the antidote n-acetylcysteine (NAC). Currently NAC is the only treatment for paracetamol overdose and to be optimally effective must be administered within 8 hours of overdose. Unfortunately, due to late presentation of paracetamol overdose, many patients miss this critical time period, after which NAC efficacy becomes substantially reduced. Despite treatment with NAC, around three people die from liver failure due to paracetamol every week. ALF has no effective treatment other than liver transplantation, which is of limited use because of its associated complications, and shortage of donors. Therefore, new treatments are urgently required. Using cell therapy, researchers at the Centre for Precision Cell Therapy for the Liver (PRaCTicAL) are investigating the therapeutic use of macrophages in liver repair.

Macrophage Cell Therapy

Macrophages are cells of the immune system, capable of eliminating damaged cells and fighting pathogens. They have also been shown to have an important role in tissue repair. Previous studies, led by Professor Stuart Forbes, Director of the Centre for Regenerative Medicine at the University of Edinburgh, have shown alternatively activated macrophages (AAMs) can eliminate dead liver cells, reduce inflammation, and promote liver regeneration in pre-clinical models of paracetamol overdose.

The MAIL trial

Building on the success of the Medical Research Council (MRC)-funded Macrophage Therapy for CirrHosis (MATCH) study (PI, Stuart Forbes), the MAIL study, also MRC-funded (PI, Stuart Forbes), is being led by Professor James Dear, Professor of Clinical Pharmacology at the University of Edinburgh. Patients will receive a single infusion of donor AAMs, which are manufactured to good manufacturing practice (GMP) standards within the production facility at the Scottish National Blood Transfusion Service (SNBTS). The AAMs have been cryopreserved before use, enabling flexibility over the timing of cell therapy delivery. Each cohort of patients will receive an increasing dose, with each dose being independently reviewed for safety before progression to the next dose. Researchers will conduct different tests before, during and after the infusion, including routine checks of patients’ general well-being, an electrocardiogram (ECG), a physical exam and blood taking. Following ethical approval, the trial has now opened for recruitment to patients with ALI due to paracetamol overdose. AAM cell therapy has the potential to reduce inflammation and increase liver regeneration in late-presenting paracetamol induced ALI.

There is no treatment that is effective at reversing the liver damage which can occur after a paracetamol overdose. To prevent death, patients with severe liver injury require a liver transplantation but donor livers are scarce, only suitable for certain patients and receiving a transplant carries significant risks. Treatment with macrophage cell therapy is highly effective in mice. If these cells are also effective in humans, then macrophage therapy could offer a new treatment for a condition with no current therapy.

Professor James Dear

Macrophages are important cells that help the body to repair organs after damage, which is why we have developed them as a cell therapy to enhance this process. If we found them to have clinical benefit for this important indication it could increase our range of tools to combat this important cause of liver failure.

Professor Stuart Forbes

Links

MAIL Trial on Edinburgh Clinical Trials Unit website