Drug Discovery Approaches for Rare Neuromuscular Diseases

Abstract

Rare neuromuscular diseases encompass many diverse and debilitating musculoskeletal disorders, ranging from ultra-orphan conditions that affect only a few families, to the so-called ‘common’ orphan diseases like Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), which affect several thousand individuals worldwide. Increasingly, pharmaceutical and biotechnology companies, in an effort to improve productivity and rebuild dwindling pipelines, are shifting their business models away from the formerly popular ‘blockbuster’ strategy, with rare diseases being an area of increased focus in recent years. As a consequence of this paradigm shift, coupled with high-profile campaigns by not-for-profit organisations and patient advocacy groups, rare neuromuscular diseases are attracting considerable attention as new therapeutic areas for improved drug therapy. Much pioneering work has taken place to elucidate the underlying pathological mechanisms of many rare neuromuscular diseases. This, in conjunction with the availability of new screening technologies, has inspired the development of several truly innovative therapeutic strategies aimed at correcting the underlying pathology. A survey of medicinal chemistry approaches and the resulting clinical progress for new therapeutic agents targeting this devastating class of degenerative diseases is presented, using DMD and SMA as examples. Complementary strategies using small-molecule drugs and biological agents are included.

From diagnosis to therapy in Duchenne muscular dystrophy

“…The data from utrophin transgenic mice supported the initiation of drug discovery programmes from a number of companies and academic groups [27]. Strategies that increase utrophin protein include increasing the stability of the utrophin mRNA, promoting an oxidative phenotype or using drugs that feed into regulation of transcription of utrophin (for reviews see [10,28]).…”

Isolation, Structural Identification, Synthesis, and Pharmacological Profiling of 1,2-trans-Dihydro-1,2-diol Metabolites of the Utrophin Modulator Ezutromid

“…6 Initial proof of principle studies in mdx mice 7,8 and DMD dog 9 were encouraging and this data supported the initiation of drug discovery programs from a number of companies. 10 The most advanced small molecule utrophin modulator to date is ezutromid (formerly SMT C1100, Summit Therapeutics plc), 11 a first in class utrophin modulator that progressed further, to a Phase 2 clinical trial in DMD boys (PhaseOut DMD). Encouraging interim 24-week data, demonstrated reduced muscle fibre damage and increased levels of utrophin following ezutromid treatment, providing the first evidence of target engagement and proof of mechanism.…”

Decreasing HepG2 Cytotoxicity by Lowering the Lipophilicity of Benzo[d]oxazolephosphinate Ester Utrophin Modulators

“…Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder caused by loss of function mutations on the dystrophin gene . Though classified as a rare disease, it is one of the most common fatal genetic diseases affecting children .…”

“…D uchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder caused by loss of function mutations on the dystrophin gene. 1 Though classified as a rare disease, it is one of the most common fatal genetic diseases affecting children. 1 Dystrophin is a critical component of the dystrophin-associated protein complex (DAPC) connecting the internal cytoskeleton to the surrounding extracellular matrix.…”

“…1 Though classified as a rare disease, it is one of the most common fatal genetic diseases affecting children. 1 Dystrophin is a critical component of the dystrophin-associated protein complex (DAPC) connecting the internal cytoskeleton to the surrounding extracellular matrix. In the absence of functional dystrophin, the muscles gradually degenerate, leading to inflammation, fibrosis, and failed cycles of regeneration.…”