The First Orally Deliverable Small Molecule for the Treatment of Spinal Muscular Atrophy

Singh, Ravindra; Ottesen, Eric W.; Singh, Natalia N.

doi:10.1177/2633105520973985

Cited by 67 publications

(64 citation statements)

References 147 publications

(210 reference statements)

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“…Due to upcoming orally available splicing-modulating drugs for SMA, daily medication administration will become possible [ 30 ]. However, some off-target effects were discussed related to risdiplam [ 31 ]. Trials allowing for direct comparisons of intrathecally and orally administered splicing modulators are missing so far.…”

Section: Discussionmentioning

confidence: 99%

Nusinersen Wearing-Off in Adult 5q-Spinal Muscular Atrophy Patients

2021

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The antisense oligonucleotide nusinersen was the first drug treatment available for all types of 5q-spinal muscular atrophy (SMA). The dosing regime has been derived from pivotal clinical trials in infants and children. The efficacy of nusinersen in severely affected adult SMA patients is still questionable, as no placebo-controlled trials have been conducted. In the present study, we systematically examined wearing-off phenomena during nusinersen maintenance dosing using a patient-centered approach. We found that adult SMA patients perceived wearing-off after nearly half of 51 investigated nusinersen administrations, primarily within the last month prior to the next administration. Symptoms and functions affected were mainly general strength and arm and leg muscle function next to endurance and independence in daily routine. Lack of walking ability and higher body mass index were characteristic phenotypic features in patients with consistent wearing-off effects. We assume that specific SMA phenotypes might benefit from higher dosing, shorter treatment intervals, change of treatment administration or a combination of all. Efforts towards treatment optimization may result in higher efficacy in distinct phenotypes.

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Section: Discussionmentioning

confidence: 99%

Nusinersen Wearing-Off in Adult 5q-Spinal Muscular Atrophy Patients

2021

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“…[ 18 , 31 ]. Various clinical SMA drug has been approved recent years by the Food and Drug Administration (FDA), such as antisense oligo nucleotides (ASOs) drug Nusinersen (Spinraza) by correction of SMN2 exon 7 splicing, gene therapy targeting SMN1 using AAV [ 31 ], and an orally deliverable small molecule drug-risdiplam (Evrysdi) that the therapeutic effect would be able to reach to all organs [ 32 ]. In this regard, augmenting SMN levels may prove to be a viable strategy to rescue/improve the spermatogenesis efficiencies ex vivo or in vivo for NOA patients.…”

Section: Discussionmentioning

confidence: 99%

Effects of Survival Motor Neuron Protein on Germ Cell Development in Mouse and Human

Chang

Peng

Hsu

et al. 2021

IJMS

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Survival motor neuron (SMN) is ubiquitously expressed in many cell types and its encoding gene, survival motor neuron 1 gene (SMN1), is highly conserved in various species. SMN is involved in the assembly of RNA spliceosomes, which are important for pre-mRNA splicing. A severe neurogenic disease, spinal muscular atrophy (SMA), is caused by the loss or mutation of SMN1 that specifically occurred in humans. We previously reported that SMN plays roles in stem cell biology in addition to its roles in neuron development. In this study, we investigated whether SMN can improve the propagation of spermatogonia stem cells (SSCs) and facilitate the spermatogenesis process. In in vitro culture, SSCs obtained from SMA model mice showed decreased growth rate accompanied by significantly reduced expression of spermatogonia marker promyelocytic leukemia zinc finger (PLZF) compared to those from heterozygous and wild-type littermates; whereas SMN overexpressed SSCs showed enhanced cell proliferation and improved potency. In vivo, the superior ability of homing and complete performance in differentiating progeny was shown in SMN overexpressed SSCs in host seminiferous tubule of transplant experiments compared to control groups. To gain insights into the roles of SMN in clinical infertility, we derived human induced pluripotent stem cells (hiPSCs) from azoospermia patients (AZ-hiPSCs) and from healthy control (ct-hiPSCs). Despite the otherwise comparable levels of hallmark iPCS markers, lower expression level of SMN1 was found in AZ-hiPSCs compared with control hiPSCs during in vitro primordial germ cell like cells (PGCLCs) differentiation. On the other hand, overexpressing hSMN1 in AZ-hiPSCs led to increased level of pluripotent markers such as OCT4 and KLF4 during PGCLC differentiation. Our work reveal novel roles of SMN in mammalian spermatogenesis and suggest new therapeutic targets for azoospermia treatment.

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“…RNA immunoprecipitation demonstrated that risdiplam analogs preferentially bind to a GA-rich sequence that matched the sequence of exon 7 +22 to +30 [ 28 ]. The analysis of other risdiplam-sensitive genes in splicing demonstrated that the GA-rich sequence was slightly enriched at the 3′ splice site but does not have a strong consensus in all sequences [ 109 , 110 ]. PK4C9 is another small molecule reported as an SMN2 splicing modifier ( Figure 5 b).…”

Section: Known Rna-targeting Splicing Modifiers For the Treatment Of Human Diseasesmentioning

confidence: 99%

RNA-Targeting Splicing Modifiers: Drug Development and Screening Assays

et al. 2021

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RNA splicing is an essential step in producing mature messenger RNA (mRNA) and other RNA species. Harnessing RNA splicing modifiers as a new pharmacological modality is promising for the treatment of diseases caused by aberrant splicing. This drug modality can be used for infectious diseases by disrupting the splicing of essential pathogenic genes. Several antisense oligonucleotide splicing modifiers were approved by the U.S. Food and Drug Administration (FDA) for the treatment of spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). Recently, a small-molecule splicing modifier, risdiplam, was also approved for the treatment of SMA, highlighting small molecules as important warheads in the arsenal for regulating RNA splicing. The cellular targets of these approved drugs are all mRNA precursors (pre-mRNAs) in human cells. The development of novel RNA-targeting splicing modifiers can not only expand the scope of drug targets to include many previously considered “undruggable” genes but also enrich the chemical-genetic toolbox for basic biomedical research. In this review, we summarized known splicing modifiers, screening methods for novel splicing modifiers, and the chemical space occupied by the small-molecule splicing modifiers.

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The First Orally Deliverable Small Molecule for the Treatment of Spinal Muscular Atrophy

Cited by 67 publications

References 147 publications

Nusinersen Wearing-Off in Adult 5q-Spinal Muscular Atrophy Patients

Nusinersen Wearing-Off in Adult 5q-Spinal Muscular Atrophy Patients

Effects of Survival Motor Neuron Protein on Germ Cell Development in Mouse and Human

RNA-Targeting Splicing Modifiers: Drug Development and Screening Assays

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