Emerging therapies and challenges in spinal muscular atrophy

Abstract

Spinal muscular atrophy (SMA) is a hereditary neurodegenerative disease with severity ranging from progressive infantile paralysis and premature death (type I) to limited motor neuron loss and normal life expectancy (type IV). Without disease-modifying therapies, the impact is profound for patients and their families. Improved understanding of the molecular basis of SMA, disease pathogenesis, natural history, and recognition of the impact of standardized care on outcomes has yielded progress toward the development of novel therapeutic strategies and are summarized. Therapeutic strategies in the pipeline are appraised, ranging from SMN1 gene replacement to modulation of SMN2 encoded transcripts, to neuroprotection, to an expanding repertoire of peripheral targets, including muscle. With the advent of preliminary trial data, it can be reasonably anticipated that the SMA treatment landscape will transform significantly. Advancement in presymptomatic diagnosis and screening programs will be critical, with pilot newborn screening studies underway to facilitate preclinical diagnosis. The development of disease-modifying therapies will necessitate monitoring programs to determine the long-term impact, careful evaluation of combined treatments, and further acceleration of improvements in supportive care. In advance of upcoming clinical trial results, we consider the challenges and controversies related to the implementation of novel therapies for all patients and set the scene as the field prepares to enter an era of novel therapies. Ann Neurol 2017;81:355-368.

Figure 1

Genetics of Spinal Muscular Atrophy. In humans, the SMN protein is encoded by the SMN1 and SMN2 genes. The C to T substitution in exon 7 of SMN2 is translationally silent, but alters splicing such that the majority of SMN2 transcripts lack exon 7 and the truncated protein is unstable. Normally, SMN1 produces abundant SMN protein. In SMA, homozygous mutation of SMN1 results in only a small amount of functional SMN protein contributed by the varying copy numbers of SMN2. mRNA = messenger RNA; SMN = survival motor neuron [Color figure can be viewed at wileyonlinelibrary.com].

Figure 2

Pathophysiological findings in SMA. Multiple functional abnormalities in motor networks have been identified in SMA mice and humans, including defects in astrocytes, Schwann cells, motor neurons, and skeletal muscle. Disease‐associated phenotypes have also been reported across a range of other organs in SMA mice (in some cases supported by data from human patients), including cardiac structural and functional abnormalities, gastrointestinal tract dysfunction, and irregular bone remodeling. One potential unifying factor may be a deficiency in the development of vasculature in SMA, with the resulting hypoxia likely impacting a range of cell types. SMA = spinal muscular atrophy. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3

Therapeutic targets for SMA being investigated in clinical trials. SMN1 gene replacement therapy utilizes a self‐complementary adeno‐associated viral vector (AAV9‐SMN) that crosses the blood–brain barrier following intravenous administration. Compounds that increase the production of fully functional SMN protein by modifying the splicing of SMN2 include the orally available small molecules, RG7916 and LMI070, and the intrathecally administered antisense oligonucleotide, nusinersen, which acts by displacing heterogenous nuclear ribonucleoprotein (hnRP) proteins from the intronic splicing silencer site on the SMN2 pre‐mRNA. The neuroprotective effects of olesoxime, through altered mitochondrial permeability, and exercise, through greater motor neuron survival, maintenance of neuromuscular junctions, and improved neuromuscular excitability properties, are being investigated. Additional strategies focused on improving neuromuscular function and physical performance include CK‐2127107, a fast skeletal troponin activator that sensitizes the sarcomere to calcium and increases the contractile response to nerve signaling, and 4‐aminopyridine and pyridostigmine that may facilitate neurotransmitter release and increase its synaptic duration. mRNA = messenger RNA; SMN = survival motor neuron. [Color figure can be viewed at wileyonlinelibrary.com]