Critical period of neuromuscular development: Importance for a new treatment of SMA

Vrbová, Gerta; Sławińska, Urszula

doi:10.1016/j.nmd.2018.03.007

Cited by 8 publications

(7 citation statements)

References 62 publications

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“…Generally speaking, in this report we aim to provide a molecular level discussion ranging from chemical structures to action mechanisms as a foundation for the rational design of these active molecules. Therefore, our review complements previous accounts − that put special emphasis on SMA clinical studies, − SMA history, − the assembly of small nuclear ribonucleoproteins (snRNPs), ASO therapy, the approved drugs Spinraza (nusinersen) , and Evrysdi (risdiplam), SMN-independent approaches, , and general advances in targeting RNA by small molecules. − Finally, we also include challenges and possible future directions in SMA treatment.…”

Section: Introductionmentioning

confidence: 82%

A Chemical Biology Perspective to Therapeutic Regulation of RNA Splicing in Spinal Muscular Atrophy (SMA)

2022

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Manipulation of RNA splicing machinery has emerged as a drug modality. Here, we illustrate the potential of this novel paradigm to correct aberrant splicing events focused on the recent therapeutic advances in spinal muscular atrophy (SMA). SMA is an incurable neuromuscular disorder and at present the primary genetic cause of early infant death. This Review summarizes the exciting journey from the first reported SMA cases to the currently approved splicing-switching treatments, i.e., antisense oligonucleotides and small-molecule modifiers. We emphasize both chemical structures and molecular bases for recognition. We briefly discuss the advantages and disadvantages of these treatments and include the remaining challenges and future directions. Finally, we also predict that these success stories will contribute to further therapies for human diseases by RNA-splicing control.

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Section: Introductionmentioning

confidence: 82%

A Chemical Biology Perspective to Therapeutic Regulation of RNA Splicing in Spinal Muscular Atrophy (SMA)

2022

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“…It has already been tested in SMA mouse models where it showed significant benefits in terms of neuromuscular transmission and muscle strength [ 222 ]. However, both drugs also need to be administered during a critical period of NMJ development [ 308 ]. Thus, restoring intracellular Ca 2+ -homeostasis by external stimuli might be a therapeutic option for SMA, together with current ASO therapies, small molecules or adenoviral SMN1 -gene transfer.…”

Section: Approved Therapies For Smamentioning

confidence: 99%

Therapy development for spinal muscular atrophy: perspectives for muscular dystrophies and neurodegenerative disorders

Jablonka

Hennlein

Sendtner

2022

Neurol. Res. Pract.

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Background Major efforts have been made in the last decade to develop and improve therapies for proximal spinal muscular atrophy (SMA). The introduction of Nusinersen/Spinraza™ as an antisense oligonucleotide therapy, Onasemnogene abeparvovec/Zolgensma™ as an AAV9-based gene therapy and Risdiplam/Evrysdi™ as a small molecule modifier of pre-mRNA splicing have set new standards for interference with neurodegeneration. Main body Therapies for SMA are designed to interfere with the cellular basis of the disease by modifying pre-mRNA splicing and enhancing expression of the Survival Motor Neuron (SMN) protein, which is only expressed at low levels in this disorder. The corresponding strategies also can be applied to other disease mechanisms caused by loss of function or toxic gain of function mutations. The development of therapies for SMA was based on the use of cell culture systems and mouse models, as well as innovative clinical trials that included readouts that had originally been introduced and optimized in preclinical studies. This is summarized in the first part of this review. The second part discusses current developments and perspectives for amyotrophic lateral sclerosis, muscular dystrophies, Parkinson's and Alzheimer's disease, as well as the obstacles that need to be overcome to introduce RNA-based therapies and gene therapies for these disorders. Conclusion RNA-based therapies offer chances for therapy development of complex neurodegenerative disorders such as amyotrophic lateral sclerosis, muscular dystrophies, Parkinson’s and Alzheimer’s disease. The experiences made with these new drugs for SMA, and also the experiences in AAV gene therapies could help to broaden the spectrum of current approaches to interfere with pathophysiological mechanisms in neurodegeneration.

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“…Similar to other SMN-independent approaches discussed in this review, these neuromuscular-targeted medications are unlikely to immensely benefit SMA patients when used as a stand-alone therapy. In particular, these drug interventions occur after the critical period of neurotransmission-regulated NMJ development, and thus are unlikely to reverse established neuromuscular defects [276]. However, if neuromuscular-targeted medicines are utilized during the critical period of NMJ development, they may provide long-term and substantial therapeutic benefits, as described below.…”

Section: Drugs Targeting Neuromuscular Functionmentioning

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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Critical period of neuromuscular development: Importance for a new treatment of SMA

Cited by 8 publications

References 62 publications

A Chemical Biology Perspective to Therapeutic Regulation of RNA Splicing in Spinal Muscular Atrophy (SMA)

A Chemical Biology Perspective to Therapeutic Regulation of RNA Splicing in Spinal Muscular Atrophy (SMA)

Therapy development for spinal muscular atrophy: perspectives for muscular dystrophies and neurodegenerative disorders

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

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