Current and emerging targeted therapies for spinal muscular atrophy

ABSTRACT

Introduction

Spinal muscular atrophy (SMA) is a progressive neurodegenerative disorder caused by insufficiency or total absence of the survival motor neuron protein due to a mutation in the SMN1 gene. The copy number of its paralog, SMN2, influences disease onset and phenotype severity. Current therapeutic approaches include viral and non-viral modalities affecting gene expression. Regulatory-approved drugs Spinraza (Nusinersen), Zolgensma (Onasemnogene abeparvovec), and Evrysdi (Risdiplam) are still being investigated during clinical trials and show benefits in the long-term for symptomatic and pre-symptomatic patients. However, some ongoing interventions require repeated drug administration.

Areas covered

In this review, the authors describe the existing therapy based on point of application, focusing on recent clinical trials of antisense oligonucleotides, viral gene therapy, and splice modulators and thepotential routes for correcting the mutation to provide therapeutic levels of SMN protein.

Expert opinion

In the opinion of the authors, multiple treatment options for patients with SMA shifted the treatment paradigm from palliative supportive care to improvedmotor function, increased survival, and greater quality of life for such patients. They further believe that the future in SMA treatment development lies incombining existing treatment options, targeting aspects of the disease refractory to these treatments, and using gene editing technologies.

KEYWORDS:

• Base editors
• nusinersen
• onasmogene abeparvovec
• risdiplam
• spinal muscular atrophy
• SMN1

Article highlights

• Spinal muscular atrophy (SMA) is a group of progressive neurodegenerative disorders predominantly caused by insufficiency or total absence of the survival motor neuron protein due to synonymous mutation in SMN1 (5q13) gene.

• During the last five years gene therapy has achieved incredible success in the clinic, leading to the FDA-approval of treatments for SMA.

• Development and approval of disease-modifying therapies, such as nusinersen (Spinraza), onasemnogene abeparvovec (Zolgensma), and risdiplam (Evrysdi), have revolutionized the management of spinal muscular atrophy.

• None of the drugs approved for the treatment of SMA or currently in clinical testing fully restore the expression of SMN or preserve the natural regulation of this protein, and most will require life-long treatment.

• An attractive alternative approach for SMA treatment would be genome editing as already shown in mice models.

• To improve treatment outcomes, the authors believe that attention should be paid to therapies targeting advanced-stage SMA patients, combining existing treatment options, and further investigation to develop new treatment strategies.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.