Drug treatment for spinal muscular atrophy type I

Wadman, Renske I.; Pol, W. Ludo van der; Bosboom, Wendy MJ; Asselman, Fay‐Lynn; Berg, Leonard H. van den; Iannaccone, Susan T.; Vrancken, Alexander FJE

doi:10.1002/14651858.cd006281.pub5

Cited by 16 publications

(21 citation statements)

References 177 publications

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“…Recently, the antisense oligonucleotide (ASO) nusinersen and the gene replacement therapy by onasemnogene abeparvovec have become available for SMA patients. Moreover, encouraging results from phase II and III clinical trials have raised hope that other therapeutic options will enter soon in clinical practice [ 11 , 12 , 13 , 14 , 15 ]. However, the availability of effective approaches has raised up ethical, medical and financial issues that are routinely faced by the SMA community.…”

Section: Introductionmentioning

confidence: 99%

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

Messina

Sframeli

2020

JCM

112

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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: Introductionmentioning

confidence: 99%

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

Messina

Sframeli

2020

JCM

112

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“…SMN1 encodes survival motor neuron (SMN) protein, which is crucial for the maintenance of motor neurons; insufficient levels of SMN protein lead to motor neuron death and subsequently the signs and symptoms of 5q SMA [atrophy and weakness of the skeletal muscles (including those involved in general movement and breathing) and impaired bulbar function (characterized by difficulties in mouth opening, chewing and swallowing)] [ 1 , 3 ]. Five 5q SMA types have been identified (based on age of symptom onset and maximal acquired motor function) [ 1 , 2 , 4 , 5 ]. Type 0, the most severe form, results in death within weeks of birth even with intensive respiratory support.…”

Section: Introductionmentioning

confidence: 99%

“…Type 4 is the mildest and rarest form of the disease and symptoms often develop in early adulthood. Affected individuals have mild to moderate disability and a normal life expectancy [ 1 , 2 , 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Nusinersen: A Review in 5q Spinal Muscular Atrophy

Hoy

2021

CNS Drugs

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Survival motor neuron 1 ( SMN1 ), located on chromosome 5q, encodes the survival motor neuron (SMN) protein. A deletion or mutation in SMN1 results in a rare neuromuscular disorder: 5q spinal muscular atrophy (SMA). In such patients, SMN protein production relies solely on SMN2 . Nusinersen (Spinraza ® ) is a modified antisense oligonucleotide approved for the treatment of 5q SMA. Administered intrathecally, it modifies SMN2 pre-messenger RNA splicing, thereby increasing full-length SMN protein levels. Interim analyses from an ongoing phase II study suggest substantial clinical benefits with nusinersen initiation in presymptomatic patients. In phase III studies, nusinersen achieved significant and/or clinically relevant improvements in motor function in symptomatic patients with infantile- and later-onset 5q SMA, and significantly improved event-free survival and overall survival in patients with infantile-onset 5q SMA. Longer term (up to a median of ≈ 6 years of available data), motor function was maintained or improved in symptomatic patients. Nusinersen had a favourable safety profile in clinical studies in presymptomatic and symptomatic patients. Real-world experience supports the effectiveness, safety and tolerability of nusinersen in symptomatic patients of all ages. Thus, nusinersen remains an important treatment option among a broad range of 5q SMA patients.

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“…Early studies investigated the therapeutic potential of histone deacetylase inhibitors (HDACIs) and demonstrated their ability to increase SMN2 transcription through the modification of chromatin structure in vitro and in vivo SMA models [34,43]. Several potential HDACIs have been proposed to benefit SMA, including valproic acid, phenylbutyrate, and trichostatin A, which have been demonstrated to activate the SMN2 promotor, driving increased FL SMN [41,44]. However, regardless of any putative effect observed in vitro, no beneficial effect of HDACIs has carried over to clinical trials [45].…”

Section: Previous Smn-dependent Trials With Indefinable Outcomesmentioning

confidence: 99%

New and Developing Therapies in Spinal Muscular Atrophy: From Genotype to Phenotype to Treatment and Where Do We Stand?

Chen

2020

IJMS

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Spinal muscular atrophy (SMA) is a congenital neuromuscular disorder characterized by motor neuron loss, resulting in progressive weakness. SMA is notable in the health care community because it accounts for the most common cause of infant death resulting from a genetic defect. SMA is caused by low levels of the survival motor neuron protein (SMN) resulting from SMN1 gene mutations or deletions. However, patients always harbor various copies of SMN2, an almost identical but functionally deficient copy of the gene. A genotype–phenotype correlation suggests that SMN2 is a potent disease modifier for SMA, which also represents the primary target for potential therapies. Increasing comprehension of SMA pathophysiology, including the characterization of SMN1 and SMN2 genes and SMN protein functions, has led to the development of multiple therapeutic approaches. Until the end of 2016, no cure was available for SMA, and management consisted of supportive measures. Two breakthrough SMN-targeted treatments, either using antisense oligonucleotides (ASOs) or virus-mediated gene therapy, have recently been approved. These two novel therapeutics have a common objective: to increase the production of SMN protein in MNs and thereby improve motor function and survival. However, neither therapy currently provides a complete cure. Treating patients with SMA brings new responsibilities and unique dilemmas. As SMA is such a devastating disease, it is reasonable to assume that a unique therapeutic solution may not be sufficient. Current approaches under clinical investigation differ in administration routes, frequency of dosing, intrathecal versus systemic delivery, and mechanisms of action. Besides, emerging clinical trials evaluating the efficacy of either SMN-dependent or SMN-independent approaches are ongoing. This review aims to address the different knowledge gaps between genotype, phenotypes, and potential therapeutics.

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Drug treatment for spinal muscular atrophy type I

Cited by 16 publications

References 177 publications

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

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

Nusinersen: A Review in 5q Spinal Muscular Atrophy

New and Developing Therapies in Spinal Muscular Atrophy: From Genotype to Phenotype to Treatment and Where Do We Stand?

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