Disease Modifying Therapies for the Management of Children with Spinal Muscular Atrophy (5q SMA): An Update on the Emerging Evidence

Abstract

SMA (5q SMA) is an autosomal recessive neuromuscular disease with an estimated incidence of approximately 1 in 11,000 live births, characterized by progressive degeneration and loss of α-motor neurons in the spinal cord and brain stem, resulting in progressive muscle weakness. The disease spectrum is wide, from a serious congenital to a mild adult-onset disease. SMA is caused by biallelic mutations in the SMN1 gene and disease severity is modified primarily by SMN2 copy number. Before the advent of specific disease altering treatments, SMA was the second most common fatal autosomal recessive disorder after cystic fibrosis and the most common genetic cause of infant mortality. Nusinersen, risdiplam, and onasemnogene abeparvovec are presently the only approved disease modifying therapies for SMA, and the aim of this review is to discuss their mode of action, effects, safety concerns, and results from real-world experience. All exert their action by increasing the level of SMN protein in lower motor neuron. Nusinersen and risdiplam by modifying the SMN2 gene product, and onasemnogene abeparvovec by delivering SMN1 gene copies into cells. All have an established clinical efficacy. An important feature shared by all three is that early intervention is associated with a better treatment outcome, such that in cases where treatment is initiated in an early pre-symptomatic period, it may result in normal – or almost normal – motor development. Thus, early diagnosis followed by swift initiation of treatment is fundamental for the treatment response and consequently long-term prognosis in SMA type 1, and probably SMA type 2. The same principle similarly applies to the milder phenotypes. All three therapies are relatively novel, with risdiplam being the latest addition. Except for nusinersen, real-world data are still scarce, and long-term data are quite naturally lacking.

Safety and efficacy of growth-friendly instrumentation for early-onset scoliosis in patients with spinal muscular atrophy type 1 in the disease-modifying treatment era

“…4 The natural course of SMA has improved since the development of disease-modifying treatment (DMT) options, such as mRNA splicing modifiers (nusinersen and risdiplam) and gene therapies (onasemnogene abeparvovec). 5 Nusinersen and risdiplam act by increasing the levels of SMN2 through different mechanisms, and onasemnogene abeparvovec is a gene therapy that is delivered via intravenous infusion, which uses a viral vector to introduce new functioning copies of SMN1 into the cell. Nusinersen is delivered intrathecally, while risdiplam can be taken orally.…”

“…Both these splicing modifiers require continuous usage, and onasemnogene abeparvovec has the advantage of being single-use. 5 Early-onset scoliosis (EOS) is one of the most common orthopedic manifestations in children with SMA, and as a historical cohort reports, virtually all nonambulatory patients develop scoliosis of varying degrees. 6 Due to expected poor natural history with very high mortality within the first 2 years of life, patients with SMA type 1 were rarely seen as candidates for surgery, and their spinal deformities were either not seen or not treated.…”

Emerging Gene Therapy Approaches in the Management of Spinal Muscular Atrophy (SMA): An Overview of Clinical Trials and Patent Landscape

“…breathing difficulties and their life span is shortened to 18 months in 95% of cases with treatment due to respiratory complications [7].…”

A Mixed-method Approach to Develop an Ambulatory Module of the SMA Independence Scale

“…With the approval of three DMTs, the natural history of SMA is changing, with individuals stabilizing or achieving new motor abilities. In addition, with the evolution of classical phenotypes of SMA, current clinical care guidelines are shifting from the traditional SMA disease classification towards classification by functional status (non-sitters, sitters, walkers) [19,20]. Treated individuals with SMA and their families describe changes in ADLs that have historically not been fully captured by existing performance outcome measures [21,22].…”