New drug molecules hold promise for treating fatal child disease

Scientists have identified a way to "rescue" muscle cells that have genetically mutated, paving the way to a possible new treatment for rare childhood illness such as Duchenne Muscular Dystrophy (DMD).

The study, led by the Universities of Exeter and Nottingham, is published in the Proceedings of the National Academies of Sciences, USA. The research used novel drugs being developed at the University of Exeter, which "metabolically reprogram" the cellular energy production centres in muscle cells, by providing them with a fuel source to generate metabolic energy.

DMD is a genetic condition caused by a mutation in a gene called dystrophin which results in progressive irreversible muscular degeneration and weakening. Its symptoms include muscle atrophy leading to a loss of the ability to walk in children for which there is no known cure. Currently, the condition is treated with steroids, such as prednisone, but they can stop working and side-effects are common. The research, funded by the Medical Research Council (UK) and United Mitochondrial Disease Foundation in the USA, was led by Professors Nate Szewczyk in Nottingham and Matt Whiteman in Exeter focussed on future alternative ways to improve muscle performance when the dystrophin gene is missing or is defective.

The research team comprising of scientists from Australia, USA, The Netherlands and Germany as well as the UK first used microscopic worms (C. elegans) and then mice with specific genetic mutations affecting muscle strength, that match mutations that cause DMD in humans. The team found that these animals had defects in gait, movement, and muscle strength, and had marked defects in the structure their muscle mitochondria, the tiny organelle responsible for cellular energy regulation.

The animals also had lower levels metabolic enzymes used for the generation of the gasotransmitter hydrogen sulfide in their muscles, as well as lower levels of the gas itself. Treating these animals with a compound called NaGYY, which replaced the lost hydrogen sulfide, partially reversed some of the muscle and mitochondrial defects in the same way the standard of care drug prednisone did. However, specifically targeting mitochondria with hydrogen sulfide using the compound AP39, exhibited the same effects but at 3.7 million fold lower dose.

Professor Nate Szewczyk of the Ohio Musculoskeletal & Neurological Institute, USA commented "Steroids are very effective and safe drugs but their use over a long period of time causes effects wear off and they can have some very unpleasant and life-changing side effects. The compounds we've used in our study are not steroids and they work in a very similar way to these drugs give the same improvement in muscle function, but at a much, much lower dose and because they are not steroids, they are unlikely to produce steroid-induced side effects such as weaker muscle and decreased ability to fight infection".

PhD student Rebecca Ellwood added "Life first emerged on earth in a sulfide rich environment and thrived for billions of years before it was replaced by the oxygen we have today. Our cells and our mitochondria have maintained the ability to both make and use very small amounts of sulfide to keep healthy. Our study now shows that in DMD models, this metabolic pathway is defective, offering a potential for therapeutic intervention to correct this defect".

Professor Matt Whiteman, of the University of Exeter Medical School, who developed the tool compounds used in this study, and next generation molecules for commercialisation, said,: "We're really excited that our findings show that a deficit in muscle sulfide may contribute to the development of Duchenne Muscular Dystrophy. Rectifying this deficit may lead to new treatment approaches for this and other currently incurable diseases, without relying on potentially harmful steroids. At Exeter we are developing more advanced approaches to target muscle mitochondria, and we aim to spin-out a new biotech company called 'MitoRx Therapeutics' to develop these newer approaches for clinical use during 2021."

Dr Kate Adcock, Director of Research and Innovation at the charity Muscular Dystrophy UK, said: "We welcome research that increases our understanding of molecular pathways that could both contribute to the symptoms of Duchenne muscular dystrophy and offer potential new therapeutic targets. Although a long way from patient studies, this research has shown interesting results in animal models of Duchenne muscular dystrophy and it is encouraging to see these early stage studies for such a complex, rare condition."

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Full name of paper -- Mitochondrial hydrogen sulfide supplementation improves health in the C. elegans Duchenne muscular dystrophy model

Notes to editors: About the University of Exeter Medical School

The University of Exeter Medical School is part of the University of Exeter's College of Medicine and Health. Our mission is to improve the health of the South West and beyond, through the development of high quality graduates and world-leading research that has international impact.

As part of a Russell Group university, we combine this world-class research with very high levels of student satisfaction. Exeter has over 19,000 students and is ranked 12th in The Times and Sunday Times Good University Guide 2020.

The University of Exeter Medical School's Medicine course is in the top 10 in the Complete University Guide 2020.

The College's Medical Imaging programme is ranked in the top 5 in the Guardian Guide 2020 and the Complete University Guide 2020.

The University of Exeter entered the world top 20 for Biomedical and Health Sciences in the CWTS Leiden Ranking 2019, based on the percentage of publications ranked in the top 10 per cent most cited.

https://medicine.exeter.ac.uk/

For further information:

Louise Vennells
Press and Media Manager
University of Exeter Medical School
+44 (0)1392 724927 or 07768 511866
l.vennells@exeter.ac.uk

At MitoRx our mission is to become the leading global developer of medicines alleviating the suffering caused by diseases involving mitochondrial dysfunction. We are a preclinical research stage rare disease platform biotech developing our lead program MTRX-1 as a first-in-class first-in-target mitochondrial protective therapeutic initially targeting rare neuromuscular disorders (NMD) including Duchenne, as well as rare metabolic disease and neurodegenerative disease. MitoRx targets diseases of mitochondrial dysfunction where the trans-sulfuration pathway is disturbed, which generates endogenous hydrogen sulfide. MitoRx restores levels of this endogenous signalling molecule within mitochondria, providing the substrate required to activate a conserved response to resist mitochondrial oxidative stress, in a novel mitochondrial protective strategy.

http://www.mitorxtherapeutics.com

Press Contact (MitoRx)

Jon Rees, CEO
jon.rees@jonreesassociates.com
Tel. +44 7826 556622

Important Note

The compounds described in this press release are experimental and have not yet been tested in clinical trials, nor are they approved for medical treatment.