scholarly journals Onasemnogene Abeparvovec (AVXS-101) for the Treatment of Spinal Muscular Atrophy

2021 ◽  
Vol 26 (5) ◽  
pp. 437-444
Author(s):  
Aimen Naveed ◽  
Hillary Calderon
Keyword(s):  
Gene Therapy ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Clinical Studies ◽  
Viral Vector ◽  
Muscular Atrophy ◽  
Protein Deficiency ◽  
Smn2 Gene ◽  
Smn Gene ◽  
Smn Protein

Spinal muscular atrophy (SMA) is a debilitating disorder characterized by degeneration of large motor neurons. It is a heterogeneous group of disorders caused by a homozygous deletion in the survival motor neuron (SMN) gene on chromosome 5, resulting in a SMN protein deficiency. Small amounts of SMN protein are also produced by the SMN2 gene, which that differs from SMN1 by a single nucleotide. Spinal muscular atrophy types and phenotypic severity depend on the number of variations of the SMN2 gene and the amount of SMN2 protein produced. Because the SMN protein deficiency is the root cause of the disease, treatment strategies for SMA revolve around increasing SMN protein production. Nusinersen (Spinraza, Biogen, Cambridge, MA) was the only treatment option available for SMA until the FDA approved onasemnogene abeparvovec-xioi (Zolgensma, AveXis Inc, Bannockburn, IL), a one-time–administered adeno-associated viral vector–based gene therapy that delivers the SMN gene to the motor neuron cells. Data from clinical studies show significant improvement in motor milestone achievements and ventilator-free survival but are limited by approximately 5 years' worth of results. This one-time intravenous injection of this new gene therapy also bears a hefty price tag; however, it may be more cost effective in the long run versus the multiple intrathecal administrations needed with nusinersen. Drug access and use are hindered by drug cost, payer reimbursement issues, and lack of long-term data from clinical studies. Questions also remain regarding the safety and efficacy of repeated drug administration for patients with advanced disease.

scholarly journals Short-duration splice promoting compound enables a tunable mouse model of spinal muscular atrophy

2020 ◽  
Vol 4 (1) ◽  
pp. e202000889
Author(s):  
Anne Rietz ◽  
Kevin J Hodgetts ◽  
Hrvoje Lusic ◽  
Kevin M Quist ◽  
Erkan Y Osman ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Antisense Oligonucleotides ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Potential Drug ◽  
Transgenic Mouse Models ◽  
Fda Approval ◽  
Smn Protein

Spinal muscular atrophy (SMA) is a motor neuron disease and the leading genetic cause of infant mortality. SMA results from insufficient survival motor neuron (SMN) protein due to alternative splicing. Antisense oligonucleotides, gene therapy and splicing modifiers recently received FDA approval. Although severe SMA transgenic mouse models have been beneficial for testing therapeutic efficacy, models mimicking milder cases that manifest post-infancy have proven challenging to develop. We established a titratable model of mild and moderate SMA using the splicing compound NVS-SM2. Administration for 30 d prevented development of the SMA phenotype in severe SMA mice, which typically show rapid weakness and succumb by postnatal day 11. Furthermore, administration at day eight resulted in phenotypic recovery. Remarkably, acute dosing limited to the first 3 d of life significantly enhanced survival in two severe SMA mice models, easing the burden on neonates and demonstrating the compound as suitable for evaluation of follow-on therapies without potential drug–drug interactions. This pharmacologically tunable SMA model represents a useful tool to investigate cellular and molecular pathogenesis at different stages of disease.

scholarly journals CIM Journal Club: Gene therapy for spinal muscular atrophy Comment on Mendell et al. N Engl J Med 2017;377:1713-22.

2018 ◽  
pp. E31-E33 ◽  
Author(s):  
Raphael Schneider
Keyword(s):  
Gene Therapy ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Viral Vector ◽  
Muscular Atrophy ◽  
Journal Club ◽  
Dna Encoding ◽  
Motor Neuron Diseases ◽  
Motor Neuron Protein ◽  
Survival Of Motor Neuron

In their landmark paper, Mendell et al. show that infants with spinal muscular atrophy (SMA) reached important motor milestones and survived longer when treated with AVXS-101 (AveXis), a viral vector containing DNA encoding the survival of motor neuron protein (SMN). Patients not only crawled, stood and walked independently, but learned to speak. These results are very encouraging for patients with SMA and offer hope for pediatric and adult patients with other types of motor neuron diseases.

scholarly journals A transgene carrying an A2G missense mutation in the SMN gene modulates phenotypic severity in mice with severe (type I) spinal muscular atrophy

2003 ◽  
Vol 160 (1) ◽  
pp. 41-52 ◽  
Author(s):  
Umrao R. Monani ◽  
Matthew T. Pastore ◽  
Tatiana O. Gavrilina ◽  
Sibylle Jablonka ◽  
Thanh T. Le ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Autosomal Recessive Disorder ◽  
Type I ◽  
Missense Mutations ◽  
Smn2 Gene ◽  
Smn Gene

5q spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans and the leading genetic cause of infantile death. Patients lack a functional survival of motor neurons (SMN1) gene, but carry one or more copies of the highly homologous SMN2 gene. A homozygous knockout of the single murine Smn gene is embryonic lethal. Here we report that in the absence of the SMN2 gene, a mutant SMN A2G transgene is unable to rescue the embryonic lethality. In its presence, the A2G transgene delays the onset of motor neuron loss, resulting in mice with mild SMA. We suggest that only in the presence of low levels of full-length SMN is the A2G transgene able to form partially functional higher order SMN complexes essential for its functions. Mild SMA mice exhibit motor neuron degeneration, muscle atrophy, and abnormal EMGs. Animals homozygous for the mutant transgene are less severely affected than heterozygotes. This demonstrates the importance of SMN levels in SMA even if the protein is expressed from a mutant allele. Our mild SMA mice will be useful in (a) determining the effect of missense mutations in vivo and in motor neurons and (b) testing potential therapies in SMA.

scholarly journals Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

2016 ◽  
Vol 10 ◽  
pp. JEN.S33122 ◽  
Author(s):  
Saif Ahmad ◽  
Kanchan Bhatia ◽  
Annapoorna Kannan ◽  
Laxman Gangwani
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Skeletal Muscle Atrophy ◽  
Spinal Motor Neurons ◽  
Low Levels ◽  
Smn Protein

Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease with a high incidence and is the most common genetic cause of infant mortality. SMA is primarily characterized by degeneration of the spinal motor neurons that leads to skeletal muscle atrophy followed by symmetric limb paralysis, respiratory failure, and death. In humans, mutation of the Survival Motor Neuron 1 (SMN1) gene shifts the load of expression of SMN protein to the SMN2 gene that produces low levels of full-length SMN protein because of alternative splicing, which are sufficient for embryonic development and survival but result in SMA. The molecular mechanisms of the (a) regulation of SMN gene expression and (b) degeneration of motor neurons caused by low levels of SMN are unclear. However, some progress has been made in recent years that have provided new insights into understanding of the cellular and molecular basis of SMA pathogenesis. In this review, we have briefly summarized recent advances toward understanding of the molecular mechanisms of regulation of SMN levels and signaling mechanisms that mediate neurodegeneration in SMA.

Spinal Muscular Atrophy

2017 ◽  
Author(s):  
Arthur H. M. Burghes ◽  
Vicki L. McGovern
Keyword(s):  
Motor Neuron ◽  
Gene Locus ◽  
Autosomal Recessive ◽  
Muscular Atrophy ◽  
Autosomal Recessive Disorder ◽  
Clinical Testing ◽  
Smn1 Gene ◽  
Smn2 Gene ◽  
Spinal Muscular Atrophies ◽  
Smn Gene

Spinal muscular atrophies affect the lower motor neuron. The most common SMA maps to 5q is an autosomal recessive disorder. SMA is caused by loss or mutation of the SMN1 gene and retention of the SMN2 gene, and these genes lie in a complex area of the genome. Mild missense alleles of SMN1 work to complement SMN2 to give function and therapeutics that restore SMN levels are in clinical testing. Modifiers that lie outside the SMN gene locus and influence severity clearly exist, but what they are remains unknown as do the critical genes affected by SMN deficiency.

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