New drug molecules could lead to treatment for rare disease

A new treatment for the rare childhood illness Duchenne Muscular Dystrophy (DMD) could be possible due to the work scientists have done to “rescue” muscle cells that have genetically mutated.

A study led by the Universities of Exeter and Nottingham details how novel drugs being developed at the University of Exeter can “metabolically reprogram” the cellular energy production centres in muscle cells, by providing them with a fuel source to generate metabolic energy.

DMD is caused by a mutation in the dystrophin gene, resulting in progressive muscular degermation and weakening. With no known cure, the condition is treated with steroids such as prednisone, but they can stop working and side-effects are common.

The latest research focused on identifying alternative ways to improve muscle performance when the dystrophin gene is missing or is defective.

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.

The research team 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 defects in the animals’, gait, movement, and muscle strength, and had marked defects in the structure their muscle mitochondria, the tiny organelle responsible for cellular energy regulation.

They also found lower levels of metabolic enzymes used for the generation of the gasotransmitter hydrogen sulfide in their muscles, as well as lower levels of the gas itself. The animals were treated with a compound called NaGYY, which replaced the lost hydrogen sulfide, and 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”.

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.”