Drug Screening and Drug Repositioning as Promising Therapeutic Approaches for Spinal Muscular Atrophy Treatment

Abstract

Spinal muscular atrophy (SMA) is the most common genetic disease affecting infants and young adults. Due to mutation/deletion of the survival motor neuron (SMN) gene, SMA is characterized by the SMN protein lack, resulting in motor neuron impairment, skeletal muscle atrophy and premature death. Even if the genetic causes of SMA are well known, many aspects of its pathogenesis remain unclear and only three drugs have been recently approved by the Food and Drug Administration (Nusinersen-Spinraza; Onasemnogene abeparvovec or AVXS-101-Zolgensma; Risdiplam-Evrysdi): although assuring remarkable results, the therapies show some important limits including high costs, still unknown long-term effects, side effects and disregarding of SMN-independent targets. Therefore, the research of new therapeutic strategies is still a hot topic in the SMA field and many efforts are spent in drug discovery. In this review, we describe two promising strategies to select effective molecules: drug screening (DS) and drug repositioning (DR). By using compounds libraries of chemical/natural compounds and/or Food and Drug Administration-approved substances, DS aims at identifying new potentially effective compounds, whereas DR at testing drugs originally designed for the treatment of other pathologies. The drastic reduction in risks, costs and time expenditure assured by these strategies make them particularly interesting, especially for those diseases for which the canonical drug discovery process would be long and expensive. Interestingly, among the identified molecules by DS/DR in the context of SMA, besides the modulators of SMN2 transcription, we highlighted a convergence of some targeted molecular cascades contributing to SMA pathology, including cell death related-pathways, mitochondria and cytoskeleton dynamics, neurotransmitter and hormone modulation.

Keywords: cell death and degradation; cytoskeleton dynamics; mitochondria; motor neuron disease; neuromuscular junction stabilization; neurotransmitter modulation; survival motor neuron; therapy.

FIGURE 1

DS and DR methods as powerful approaches in SMA therapeutic research. The two approaches, eventually in combination, can pave the way for rapid identification of drugs for novel SMA treatments. The compounds (present in large screening libraries) can be tested for primary outcomes (continuous arrow, in the middle) firstly on “simplified” SMA models (cell cultures and/or invertebrates models), and then on SMA mice and/or patient-derived iPSCs (differentiated in neurons, MNs and muscle cells, eventually cocultured) to achieve secondary outcomes. In some cases (dotted arrow, in the middle) the hit compounds can be directly tested on murine models and iPSCs. Created with BioRender software. DR, drug repositioning; DS, drug screening; MN, motor neuron; SMA, spinal muscular atrophy.

FIGURE 2

Involved and converging pathways targeted by DS and DR. The drugs identified by DS and DR influence and converge on a limited number of cellular and molecular pathways, that in turn act on specific districts, in particular involving MNs, NMJs and skeletal muscles. Created with BioRender software. DR, drug repositioning; DS, drug screening; MN, motor neuron; NMJ, neuromuscular junction; SMN, survival motor neuron.