Action Medical Research is a leading UK-wide charity saving and changing children’s lives through medical research. For 70 years we’ve helped pioneer ways to prevent disease and develop treatments benefiting millions of people. Our research has helped to beat polio in the UK, develop ultrasound in pregnancy, fight meningitis and prevent stillbirths.

LifeArc is a self-funded medical research charity. Our mission is to advance translation of early science into health care treatments or diagnostics that can be taken through to full development and made available to patients. We have been doing this for more than 25 years and our work has resulted in a diagnostic for antibiotic resistance and four licensed medicines.

LifeArc is proud to be renewing joint funding with Action Medical Research, which is the latest in a series of strategic collaborations that leverage LifeArc’ s expertise in translational science – advancing strong discoveries from the lab to a point where rare disease patients can benefit. This includes a recent £8m commitment made by LifeArc to support the delivery of new gene therapy treatment through a unique partnership with the MRC.

Through this partnership, LifeArc is partly funding a network of cutting-edge facilities – also known as Hubs – to enable the progress of novel, academic gene therapy research into early-stage clinical trials and bring a new generation of medicines to healthcare. It is hoped that promising gene therapy approaches, such as those supported by LifeArc’s joint fund with Action Medical Research, may benefit from interaction with the Hubs as they progress towards clinical trials.

Title: Small molecule AhR antagonists for the treatment of Duchenne Muscular Dystrophy

Project team: Professor Angela Russell, Professor Dame Kay Davies

Location: University of Oxford, Departments of Chemistry and Pharmacology and Department of Physiology, Anatomy and Genetics

Duchenne muscular dystrophy (DMD) is an inherited disease that mainly affects boys, causing muscle weakness and wasting. Symptoms are often first noticed in early childhood and deterioration over time means most of those with the condition develop heart and breathing problems. These symptoms often have life-threatening complications and there is currently no cure. Around 100 boys are born with DMD in the UK each year.

Children with the condition have a faulty gene which means they don’t produce enough dystrophin, a protein that is vital in protecting muscles.

The project team, led by Professor Angela Russell and Professor Dame Kay Davies, hope to develop a new treatment based on molecules that increase levels of utrophin, a protein related to dystrophin. They are building on earlier work in developing a drug, ezutromid, which was shown to increase the amount of utrophin in muscle cells. A clinical trial of ezutromid in boys with DMD showed promising results after 24 weeks of treatment. However, sadly it was not effective over a longer period and the pharmaceutical company involved ceased development.

The team are now testing alternative molecules that could lead to higher levels of utrophin production, potentially leading to a utrophin replacement therapy that could slow the disease’s progress.

Find out more on the Action Medical Research website.

Title: Using proteomic approaches to investigate the role of plasma and urine biomarkers for disease stratification in childhood hypertrophic cardiomyopathy

Project team: Dr Juan Kaski, Dr Kevin Mills, Dr Wendy Heywood

Location: University College London, Institute of Cardiovascular Science

Other locations: UCL Great Ormond Street Institute of Child Health, UCL Centre for Inborn Errors of Metabolism; Great Ormond Street Hospital for Children, Centre for Inherited Cardiovascular Diseases

Hypertrophic cardiomyopathy (HCM) causes thickening of the heart muscle and is associated with sudden death in young people. Current treatments aim to manage  symptoms, screen relatives and prevent complications – including sudden death, heart failure and stroke.

However, we currently do not have any treatments targeting the underlying molecular processes or preventing the development of the disease in at-risk individuals.

To develop such therapies, we have to understand the early features of the condition and how it progresses over time. We need simple, non-invasive tests to achieve that.

Using a simple blood test, the team had developed a set of biomarkers that identifies adults with HCM and identifies the severity of their disease.

Dr Juan Kaski and his team are using a similar approach in this study to:

• validate the new adult biomarkers in children with HCM and in pre-symptomatic gene carriers
• identify new markers specific to children with HCM and gene carriers without evidence of disease
• match the findings from the biomarker tests with clinical features of disease severity and progression.

This study takes advantage of the only paediatric HCM bioresource in the UK at GOSH and UCL and state of the art laboratory techniques at the UCL Institute of Child Health. If successful, this project may result in faster and cheaper diagnostic tests and the development of new tools to monitor disease progression and treatments, with the potential to improve clinical outcomes and potentially significant cost benefits to the NHS.

Find out more at: Epilepsy: developing a new drug treatment for a rare and debilitating form of the condition | Action Medical Research

Title: Developing small molecule inhibitors for a rare childhood seizure disorder (Pyridoxine dependent epilepsy)

Project team: Professor Wyatt Yue, Professor Paul Brennan, Dr Cassandra Adams

Locations: Newcastle University Biosciences Institute Centre for Medicines Discovery; University of Oxford

Pyridoxine dependent epilepsy (PDE) causes frequent seizures that begin soon after birth or during infancy.

A faulty enzyme, ALDH7A1, is unable to play its usual role of breaking down an amino acid called lysine. As a result, toxic chemicals build up in the child’s body. These chemical imbalances lead to seizures and – in some children – delayed development and learning disabilities.

Current treatment focusses on seizure control but does not address the long-term neurological and cognitive causes. Led by Professor Wyatt Yue, the team aims to develop a therapy that reduces the build-up of the toxic chemicals in the body.

Professor Yue and his colleagues hope to achieve that by reducing the activity of another enzyme also involved in lysine break-down, an approach known as substrate reduction therapy. The approach has been successfully applied to other rare diseases. The team are making tiny changes to the chemical structures of several potential drug compounds they have already identified.

They will then test the effects of the most promising drug candidates in cell studies, selecting the best ones for potential future development into treatments for patients.

Find out more on the Action Medical Research website.

Title: Synergistic ablation of MLL-Fusion onco-proteins as a novel acute leukaemia therapy.

Project team: Dr Owen Williams, Dr Jasper de Boer, Professor Ajay Vora, Professor Adele Fielding

Location: UCL Great Ormond Street Institute of Child Health, Developmental Biology and Cancer Programme

Other locations: Great Ormond Street Hospital, Haematology and Oncology Department; University College London, UCL Cancer Institute, Research Department of Haematology

Some sub-types of childhood leukaemia have much poorer outcomes than others. One such subtype seen in infants is caused by a genetic mutation which occurs when two or more genes fuse together, causing the affected blood cells to make a ‘fusion protein’ that drives the disease. New treatments are urgently needed as there are no effective treatments available.

The research team recently discovered a potential new treatment using two drugs which combine to destroy the fusion protein. Laboratory studies have shown that this combination of drugs halts the cancer’s progress. Led by Dr Owen Williams, this project is investigating the potential impact of this targeted treatment in pre-clinical models and the team ultimately hopes to take the potential treatment to a clinical trial.

Find out more on the Action Medical Research website.

Title: Improving blood brain barrier crossing peptides in lentiviral-mediated stem cell gene therapy for Hunter disease.

Project team: Professor Brian Bigger, Dr Shaun Wood

Location: The University of Manchester, Division of Cell Matrix Biology and Regenerative Medicine

Hunter syndrome, also called mucopolysaccharidosis type II, is a rare genetic disease that almost always affects boys. Children born with the condition can experience a wide range of symptoms affecting many tissues and organs, including their brain, liver, lungs, bones, eyes, skin and heart. Sadly, their lives will often be cut tragically short.

The condition is caused by a faulty gene – called ID2 – that leads to the lack of an enzyme that breaks down complex sugars in the body. As a result, these molecules start to build up in the child’s body, causing a range of problems. Children with the most severe forms of the illness will have progressive learning difficulties and behavioural challenges.

There is an urgent need to develop new treatments for boys with this devastating condition – especially those that can reduce brain symptoms.

Professor Brian Bigger’s team has previously developed a stem cell gene therapy approach that aims to deliver the missing enzyme into the child’s body. This involves taking stem cells from the bone marrow, inserting a correct copy of the IDS gene, and transplanting them into the body. These cells can then make the IDS enzyme, treating the symptoms of the disease.

But unfortunately, the researchers have so far struggled to get high enough levels of the enzyme into the brain, as it is protected by the blood-brain barrier. They have had an impact on brain symptoms by adding a small protein tag that helps the enzyme to cross the blood-brain barrier. Building on these encouraging results, the team is now testing several other tags to find out if they can further boost the levels of the enzyme in the brain and other organs.

If this laboratory research shows this innovative stem gene therapy is safe and effective, it could pave the way for a future clinical trial in boys with Hunter syndrome.

Find out more on the Action Medical Research website.