Spinal muscular atrophy — insights and challenges in the treatment era

Mercuri, Eugenio; Pera, Maria Carmela; Scoto, Mariacristina; Finkel, Richard S.; Muntoni, Francesco

doi:10.1038/s41582-020-00413-4

Cited by 129 publications

(131 citation statements)

References 99 publications

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“…Global regulations of SEs, A3SS, and RI by SF3B1 are well-predictable because SF3B1 has important function in 3 SS recognition of constitutive splicing. Both 5 SS and 3 SS recognitions by spliceosomes are affected by each other [46][47][48]. Thus, although SF3B1 is not able to directly regulate 5 SS, 3 SS recognition by SF3B1 might be able to indirectly affect 5 SS.…”

Section: Discussionmentioning

confidence: 98%

“…Various mechanisms, including abrogation of a positive element, creation of a negative element, and formation of an inhibitory context, have been attributed to C6U transition within SMN2 exon 7 [41]. Therapies for SMA patients include increasing the production of SMN through modifying SMN2 splicing or gene therapy by delivering SMN1 gene [42][43][44][45][46]. Nusinersen is the first FDA-approved drug for SMA, which is an antisense oligonucleotide-based compound targeting the intronic splicing silencer and thereby regulating the splicing of SMN2 exon 7 [46].…”

Section: Introductionmentioning

confidence: 99%

“…Therapies for SMA patients include increasing the production of SMN through modifying SMN2 splicing or gene therapy by delivering SMN1 gene [42][43][44][45][46]. Nusinersen is the first FDA-approved drug for SMA, which is an antisense oligonucleotide-based compound targeting the intronic splicing silencer and thereby regulating the splicing of SMN2 exon 7 [46]. However, nusinersen is not able to cross the blood-brain barrier; thus, repeated intrathecal injection is necessary for therapy [46].…”

Section: Introductionmentioning

confidence: 99%

“…Nusinersen is the first FDA-approved drug for SMA, which is an antisense oligonucleotide-based compound targeting the intronic splicing silencer and thereby regulating the splicing of SMN2 exon 7 [46]. However, nusinersen is not able to cross the blood-brain barrier; thus, repeated intrathecal injection is necessary for therapy [46]. Compared with nusinersen, AVXS-101, an adeno-associated viral vector that forms a double-stranded DNA template to deliver SMN1 to target motor neurons, can cross the blood-brain barrier [46].…”

Section: Introductionmentioning

confidence: 99%

“…However, nusinersen is not able to cross the blood-brain barrier; thus, repeated intrathecal injection is necessary for therapy [46]. Compared with nusinersen, AVXS-101, an adeno-associated viral vector that forms a double-stranded DNA template to deliver SMN1 to target motor neurons, can cross the blood-brain barrier [46]. However, none of the available approaches have the potential to fully cure SMA [47].…”

Section: Introductionmentioning

confidence: 99%

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U2AF65-Dependent SF3B1 Function in SMN Alternative Splicing

Choi

Liu

et al. 2020

Cells

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Splicing factor 3b subunit 1 (SF3B1) is an essential protein in spliceosomes and mutated frequently in many cancers. While roles of SF3B1 in single intron splicing and roles of its cancer-linked mutant in aberrant splicing have been identified to some extent, regulatory functions of wild-type SF3B1 in alternative splicing (AS) are not well-understood yet. Here, we applied RNA sequencing (RNA-seq) to analyze genome-wide AS in SF3B1 knockdown (KD) cells and to identify a large number of skipped exons (SEs), with a considerable number of alternative 5′ splice-site selection, alternative 3′ splice-site selection, mutually exclusive exons (MXE), and retention of introns (RI). Among altered SEs by SF3B1 KD, survival motor neuron 2 (SMN2) pre-mRNA exon 7 splicing was a regulatory target of SF3B1. RT-PCR analysis of SMN exon 7 splicing in SF3B1 KD or overexpressed HCT116, SH-SY5Y, HEK293T, and spinal muscular atrophy (SMA) patient cells validated the results. A deletion mutation demonstrated that the U2 snRNP auxiliary factor 65 kDa (U2AF65) interaction domain of SF3B1 was required for its function in SMN exon 7 splicing. In addition, mutations to lower the score of the polypyrimidine tract (PPT) of exon 7, resulting in lower affinity for U2AF65, were not able to support SF3B1 function, suggesting the importance of U2AF65 in SF3B1 function. Furthermore, the PPT of exon 7 with higher affinity to U2AF65 than exon 8 showed significantly stronger interactions with SF3B1. Collectively, our results revealed SF3B1 function in SMN alternative splicing.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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U2AF65-Dependent SF3B1 Function in SMN Alternative Splicing

Choi

Liu

et al. 2020

Cells

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Nusinersen efficacy data for 24‐month in type 2 and 3 spinal muscular atrophy

Pane

Coratti

Pera

et al. 2022

Ann Clin Transl Neurol

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The study reports real world data in type 2 and 3 SMA patients treated for at least 2 years with nusinersen. Increase in motor function was observed after 12 months and during the second year. The magnitude of change was variable across age and functional subgroup, with the largest changes observed in young patients with higher function at baseline. When compared to natural history data, the difference between study cohort and untreated patients swas significant on both Hammersmith Functional Motor Scale and Revised Upper Limb Module both at 12 months and at 24 months.

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Data sharing to advance gene‐targeted therapies in rare diseases

Lekstrom-Himes

Augustine

Brower

et al. 2023

American J of Med Genetics Pt C

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Recent advancements in gene‐targeted therapies have highlighted the critical role data sharing plays in successful translational drug development for people with rare diseases. To scale these efforts, we need to systematize these sharing principles, creating opportunities for more rapid, efficient, and scalable drug discovery/testing including long‐term and transparent assessment of clinical safety and efficacy. A number of challenges will need to be addressed, including the logistical difficulties of studying rare diseases affecting individuals who may be scattered across the globe, scientific, technical, regulatory, and ethical complexities of data collection, and harmonization and integration across multiple platforms and contexts. The NCATS/NIH Gene‐Targeted Therapies: Early Diagnosis and Equitable Delivery meeting series held during June 2021 included data sharing models that address these issues and framed discussions of areas that require improvement. This article describes these discussions and provides a series of considerations for future data sharing.

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Spinal muscular atrophy — insights and challenges in the treatment era

Cited by 129 publications

References 99 publications

U2AF65-Dependent SF3B1 Function in SMN Alternative Splicing

U2AF65-Dependent SF3B1 Function in SMN Alternative Splicing

Nusinersen efficacy data for 24‐month in type 2 and 3 spinal muscular atrophy

Data sharing to advance gene‐targeted therapies in rare diseases

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