Molecular mechanisms and therapeutic strategies for neuromuscular diseases

Abstract

Neuromuscular diseases encompass a heterogeneous array of disorders characterized by varying onset ages, clinical presentations, severity, and progression. While these conditions can stem from acquired or inherited causes, this review specifically focuses on disorders arising from genetic abnormalities, excluding metabolic conditions. The pathogenic defect may primarily affect the anterior horn cells, the axonal or myelin component of peripheral nerves, the neuromuscular junction, or skeletal and/or cardiac muscles. While inherited neuromuscular disorders have been historically deemed not treatable, the advent of gene-based and molecular therapies is reshaping the treatment landscape for this group of condition. With the caveat that many products still fail to translate the positive results obtained in pre-clinical models to humans, both the technological development (e.g., implementation of tissue-specific vectors) as well as advances on the knowledge of pathogenetic mechanisms form a collective foundation for potentially curative approaches to these debilitating conditions. This review delineates the current panorama of therapies targeting the most prevalent forms of inherited neuromuscular diseases, emphasizing approved treatments and those already undergoing human testing, offering insights into the state-of-the-art interventions.

Keywords: Motor neuron disease; Myopathy; Neuromuscular junction; Neuropathy; Therapy.

Fig. 1

Schematic representation of the therapeutic landscape applicable to neuromuscular diseases, with a focus on gene and molecular therapies. Treatment strategies vary according to the underlying genetic defect, namely loss of function (LOF) or gain of function (GOF) mutations (depicted in the centre of the figure). A defective gene may be corrected at DNA level via gene editing/silencing obtained, for instance, using Crispr/Cas9 technology, with still important concerns regarding possible off-target events. Alternatively, coding (c)DNA containing a tissue-specific promoter and a gene cassette encoding for a functional or surrogate protein can be delivered by viral vectors and be subsequently translated by the cell apparatus. The persistence of cDNA in time may vary according to cell type. Molecular therapies can act at RNA level either by modulating splicing or by altering messenger (m)RNA transcription. The former strategy is usually obtained using antisense oligonucleotides (ASO) (A), as the ones developed for exon skipping in Duchenne muscular dystrophy or to counteract the splicing of exon 7 of the SMN2 gene in spinal muscular atrophy. Of note, ASO can be conjugated with cell-penetrating peptides, fatty acids, or specific antibodies to increase their delivery to target organs, in order to augment efficacy while reducing potential side effects. The modulation of RNA transcription can be obtained by single-stranded ASO or by double stranded short interfering (si)RNA. The latter can be either directly delivered to cells or processed from short/small hairpin (sh)RNA (B). Lastly, both gene and molecular therapies can be delivered by different viral and non-viral vectors (including nanoparticles and cells), which are being constantly improved