Professor Dame Kay Davies (University of Oxford) and her group have recently published encouraging results of a study to test new second-generation compounds to increase the level of utrophin protein as a treatment for boys and men with Duchenne and Becker muscular dystrophies.
The study is funded by the UtroDMD Alliance – of which the Duchenne Research Fund is part, via its membership of the Duchenne Forum.
Utrophin is a protein that occurs naturally in the body. It is usually only made in large amounts during development in the womb and is only present in small amounts in adults. Utrophin is very similar to dystrophin in its structure and previous research has shown that it can compensate for the lack of dystrophin in animal models of Duchenne muscular dystrophy.
Professor Davies and her group have been working on ways to raise the levels of utrophin protein in adult muscle tissue for many years. In conjunction with Summit Therapeutics, a company co-founded by Professor Davies, they have previously identified a compound, SMT C1100, which is able to modulate utrophin levels in cell culture and in a mouse model of Duchenne muscular dystrophy. The Duchenne Research Fund was involved in funding some of the pre-clinical development of SMT C1100. SMT C1100 has been tested in early stage clinical trials, where it was shown to be safe. A further Phase 1b trial in patients with DMD has recently finished and achieved its primary objective, enabling it to progress to Phase 2 clinical trials later this year.
Professor Davies and her team at Oxford University are working in collaboration with Professor Angela Russell as part of the UtroDMD Alliance to identify second- and future-generation compounds that are better able to increase utrophin levels and have better absorption and distribution profiles in the body, which will make them better candidates for a drug. SMT022357 is one of a number of promising second-generation compounds they have discovered through their screening pipeline.
SMT022357 is similar in structure to SMT C1100 but has physical and chemical properties that make it likely to be more stable in the body than SMT C1100. It was tested in the mdx mouse model and was found to increase utrophin protein to higher levels than SMT C1100.
Importantly, for the first time, utrophin protein was shown in this most recent study to be distributed along the length of muscle fibres, at locations where dystrophin protein is lacking in boys with Duchenne muscular dystrophy.
The increase in utrophin protein levels also seemed to decrease muscle fibre death and improve muscle function by protecting against damage caused by contraction. Additionally, the utrophin protein was found in heart and diaphragm, a key respiratory muscle, as well as in other skeletal muscle. The increase in utrophin in many different types of muscle could be potentially beneficial for boys with Duchenne, for whom heart and respiratory function become severely compromised as the condition progresses.
These results are very encouraging as they show that SMT022357 can be given orally and can increase utrophin protein in important parts of muscle fibres in relevant muscles. As raising the levels of utrophin protein is an approach that is not mutation specific it would be applicable to all boys and young men with Duchenne muscular dystrophy, and those with Becker muscular dystrophy.
Read more on Our Projects page, where you can click on Early Stage Research to learn more about our role in the Duchenne Forum and what we fund.