Overturning the Paradigm of Spinal Muscular Atrophy as Just a Motor Neuron Disease

Yeo, Crystal Jing Jing; Darras, Basil T.

doi:10.1016/j.pediatrneurol.2020.01.003

Cited by 110 publications

(77 citation statements)

References 68 publications

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“…While the intrathecal administration route of nusinersen mainly limits its effect to motoneurons of the central nervous system, the systemic distribution demonstrated in preclinical studies with risdiplam by oral administration allows to hypothesize a possible effect in other tissues. This is of relevance, as numerous studies in human and murine models indicate that SMA may actually be considered as a multi-system disorder with an involvement of neuromuscular junction, gastrointestinal-tract, cardio-vascular system, lung and liver [ 34 , 35 ].…”

Section: Smn —Dependent Gene Therapiesmentioning

confidence: 99%

New Treatments in Spinal Muscular Atrophy: Positive Results and New Challenges

Messina

Sframeli

2020

JCM

117

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Spinal muscular atrophy (SMA) is one of the most common autosomal recessive diseases with progressive weakness of skeletal and respiratory muscles, leading to significant disability. The disorder is caused by mutations in the survival motor neuron 1 (SMN1) gene and a consequent decrease in the SMN protein leading to lower motor neuron degeneration. Recently, Food and Drug Administration (FDA) and European Medical Agency (EMA) approved the antisense oligonucleotide nusinersen, the first SMA disease-modifying treatment and gene replacement therapy by onasemnogene abeparvovec. Encouraging results from phase II and III clinical trials have raised hope that other therapeutic options will enter soon in clinical practice. However, the availability of effective approaches has raised up ethical, medical and financial issues that are routinely faced by the SMA community. This review covers the available data and the new challenges of SMA therapeutic strategies.

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Section: Smn —Dependent Gene Therapiesmentioning

confidence: 99%

New Treatments in Spinal Muscular Atrophy: Positive Results and New Challenges

Messina

Sframeli

2020

JCM

117

View full text Add to dashboard Cite

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“…Additionally, other abnormalities have been reported, including abnormalities in autonomic, sensory, gastrointestinal, and endocrine systems [22,24,26,[181][182][183][184]. In animal models, a number of organ phenotypes have been noted, including abnormalities in cardiac, lymphatic, kidney, liver, pancreas, spleen, vasculature, bone and connective tissues (thoroughly reviewed in Yeo and Darras (2020) [185]). These non-canonical pathologies are generally only reported in patients with the most severe forms of SMA, suggesting that even low expression levels of SMN (achieved by 2-3 functional copies of SMN2) is sufficient for vitality in these tissues.…”

Section: Additional Susceptible Cell and Tissue Typesmentioning

confidence: 99%

In Search of a Cure: The Development of Therapeutics to Alter the Progression of Spinal Muscular Atrophy

2021

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Until the recent development of disease-modifying therapeutics, spinal muscular atrophy (SMA) was considered a devastating neuromuscular disease with a poor prognosis for most affected individuals. Symptoms generally present during early childhood and manifest as muscle weakness and progressive paralysis, severely compromising the affected individual’s quality of life, independence, and lifespan. SMA is most commonly caused by the inheritance of homozygously deleted SMN1 alleles with retention of one or more copies of a paralog gene, SMN2, which inversely correlates with disease severity. The recent advent and use of genetically targeted therapies have transformed SMA into a prototype for monogenic disease treatment in the era of genetic medicine. Many SMA-affected individuals receiving these therapies achieve traditionally unobtainable motor milestones and survival rates as medicines drastically alter the natural progression of this disease. This review discusses historical SMA progression and underlying disease mechanisms, highlights advances made in therapeutic research, clinical trials, and FDA-approved medicines, and discusses possible second-generation and complementary medicines as well as optimal temporal intervention windows in order to optimize motor function and improve quality of life for all SMA-affected individuals.

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“…Nusinersen is an antisense oligonucleotide able to enhance the synthesis of a functional SMN protein in the central nervous system [1]. This molecule has shown to prolong survival after 2 years of age in different populations of infants with spinal muscular atrophy (SMA) [2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Do we always need to treat patients with spinal muscular atrophy? A personal view and experience

Agosto

Salamon

Divisic

et al. 2021

Orphanet J Rare Dis

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Background We report the clinical outcomes observed in our patients with SMA type 1 or 2 receiving nusinersen, and we comment on the ethical implications of this treatment, in line with our results and those reported by Audic et al. in their analysis published in the Orphanet Journal of Rare Diseases. Methods We analyzed records of all children with a genetically diagnosed SMA and clinically confirmed diagnosis of SMA Type 1 or 2 to whom nusinersen was offered. Follow-up lasted 30 months. Results Among the 17 children with SMA type 1, 6 interrupted treatment with nusinersen due to adverse events or lack of efficacy. Of the remaining 11 patients, 9 are responding to therapy, though multidisciplinary complex care is still required. All those children started nusinersen at a very early age. Eighteen patients with SMA type 2 received nusinersen; five required treatment interruption. The other 13 patients are still on nusinersen therapy, and 6 are responders. Among the seven non-responders, only two met the inclusion criteria of the pivotal trial. Conclusions Our analysis further supports the findings reported in the study by Audic et al. We believe that a wider use of nusinersen in clinical practice would require a comprehensive assessment of its actual benefits weighed against the discomfort caused to patients, as well as the identification of the patients who may obtain the best benefits from this treatment.

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Overturning the Paradigm of Spinal Muscular Atrophy as Just a Motor Neuron Disease

Cited by 110 publications

References 68 publications

New Treatments in Spinal Muscular Atrophy: Positive Results and New Challenges

New Treatments in Spinal Muscular Atrophy: Positive Results and New Challenges

In Search of a Cure: The Development of Therapeutics to Alter the Progression of Spinal Muscular Atrophy

Do we always need to treat patients with spinal muscular atrophy? A personal view and experience

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