Discovery of a CNS penetrant small molecule SMN2 splicing modulator with improved tolerability for spinal muscular atrophy

Ando, Shiori; Suzuki, Shunya; Okubo, Shoichi; Ohuchi, Kazuki; Takahashi, Kei; Nakamura, Shinsuke; Shimazawa, Masamitsu; Fuji, Koji; Hara, Hideaki

doi:10.1038/s41598-020-74346-9

Cited by 34 publications

(24 citation statements)

References 44 publications

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“…135,141 Two more small molecules, PK4C9 and TEC-1, have been recently reported to enhance SMN2 exon 7 inclusion with high specificity (Figure 2). 142,143 TEC-1 has been found to be permeable to the central nervous system and confer therapeutic efficacy in a mouse model of SMA. 142 While the mechanism of TEC-1 action has not yet been examined, PK4C9 has been shown to interact with a structural element, namely the tri-loop of TSL2.…”

Section: Resultsmentioning

confidence: 99%

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

2020

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Spinal muscular atrophy (SMA) is 1 of the leading causes of infant mortality. SMA is mostly caused by low levels of Survival Motor Neuron (SMN) protein due to deletion of or mutation in the SMN1 gene. Its nearly identical copy, SMN2, fails to compensate for the loss of SMN1 due to predominant skipping of exon 7. Correction of SMN2 exon 7 splicing by an antisense oligonucleotide (ASO), nusinersen (Spinraza™), that targets the intronic splicing silencer N1 (ISS-N1) became the first approved therapy for SMA. Restoration of SMN levels using gene therapy was the next. Very recently, an orally deliverable small molecule, risdiplam (Evrysdi™), became the third approved therapy for SMA. Here we discuss how these therapies are positioned to meet the needs of the broad phenotypic spectrum of SMA patients.

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Section: Resultsmentioning

confidence: 99%

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

2020

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“…Moreover, the drug called TEC-1 (2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-6-(4-methylpiperazin-1-yl)quinazolin-4(3H)-one) another SMN2 splicing modulator, was recently identified in a screening on SMA patient-derived fibroblasts. The drug's effects were then confirmed in SMA-MN-iPSCs (Ando et al, 2020).…”

Section: Drug Screening For Neuromuscular and Motor Neuron Disorders In A Dish From Research Efforts To Clinical Applicationmentioning

confidence: 90%

The Potential of Induced Pluripotent Stem Cells to Test Gene Therapy Approaches for Neuromuscular and Motor Neuron Disorders

Cappella

Elouej

Biferi

2021

Front. Cell Dev. Biol.

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The reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) represents a major advance for the development of human disease models. The emerging of this technique fostered the concept of “disease in a dish,” which consists into the generation of patient-specific models in vitro. Currently, iPSCs are used to study pathological molecular mechanisms caused by genetic mutations and they are considered a reliable model for high-throughput drug screenings. Importantly, precision-medicine approaches to treat monogenic disorders exploit iPSCs potential for the selection and validation of lead candidates. For example, antisense oligonucleotides (ASOs) were tested with promising results in myoblasts or motor neurons differentiated from iPSCs of patients affected by either Duchenne muscular dystrophy or Amyotrophic lateral sclerosis. However, the use of iPSCs needs additional optimization to ensure translational success of the innovative strategies based on gene delivery through adeno associated viral vectors (AAV) for these diseases. Indeed, to establish an efficient transduction of iPSCs with AAV, several aspects should be optimized, including viral vector serotype, viral concentration and timing of transduction. This review will outline the use of iPSCs as a model for the development and testing of gene therapies for neuromuscular and motor neuron disorders. It will then discuss the advantages for the use of this versatile tool for gene therapy, along with the challenges associated with the viral vector transduction of iPSCs.

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“…Together, the results of our work emphasize the importance of AS in determining the plasticity and functional status of the skeletal muscle transcriptome. Considering the current development of novel treatment methods for atrophic musculoskeletal diseases using small-molecule splicing modulators (Jarecki et al, 2005; Cheung et al, 2018; Ando et al, 2020), it is possible that further characterization of microgravity-induced AS targets will allow for the development of small-molecule splicing modulator-based therapies to prevent microgravity-induced muscle atrophy and other detrimental physiologic adaptations to spaceflight.…”

Section: Discussionmentioning

confidence: 99%

Alternative splicing regulates the physiological adaptation of the mouse hind limb postural and phasic muscles to microgravity

Henrich¹,

P²,

Js³

et al. 2021

Preprint

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Muscle atrophy and fiber type alterations are well-characterized physiological adaptations to microgravity with both understood to be primarily regulated by differential gene expression (DGE). While microgravity-induced DGE has been extensively investigated, adaptations to microgravity due to alternative splicing (AS) have not been studied in a mammalian model. We sought to comprehensively elucidate the transcriptomic underpinnings of microgravity-induced muscle phenotypes in mice by evaluating both DGE and changes in AS due to extended spaceflight. Tissue sections and total RNA were isolated from the gastrocnemius and quadriceps, postural and phasic muscles of the hind limb, respectively, of 32-week-old female BALB/c mice exposed to microgravity or ground control conditions for nine weeks. Immunohistochemistry disclosed muscle type-specific physiological adaptations to microgravity that included i) a pronounced reduction in muscle fiber cross-sectional area in both muscles and ii) a prominent slow-to-fast fiber type transition in the gastrocnemius. RNA sequencing revealed that DGE and AS varied across postural and phasic muscle types with preferential employment of DGE in the gastrocnemius and AS in the quadriceps. Gene ontology analysis indicated that DGE and AS regulate distinct molecular processes. Various non-differentially expressed transcripts encoding musculoskeletal proteins (Tnnt3, Tnnt1, Neb, Ryr1, and Ttn) and muscle-specific RNA binding splicing regulators (Mbnl1 and Rbfox1) were found to have significant changes in AS that altered critical functional domains of their protein products. In striking contrast, microgravity-induced differentially expressed genes were associated with lipid metabolism and mitochondrial function. Our work serves as the first comprehensive investigation of coordinate changes in DGE and AS in large limb muscles across spaceflight. We propose that substantial remodeling of pre-mRNA by AS is a major component of transcriptomic adaptation of skeletal muscle to microgravity. The alternatively spliced genes identified here could be targeted by small molecule splicing regulator therapies to address microgravity-induced changes in muscle during spaceflight.

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Discovery of a CNS penetrant small molecule SMN2 splicing modulator with improved tolerability for spinal muscular atrophy

Cited by 34 publications

References 44 publications

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

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

The Potential of Induced Pluripotent Stem Cells to Test Gene Therapy Approaches for Neuromuscular and Motor Neuron Disorders

Alternative splicing regulates the physiological adaptation of the mouse hind limb postural and phasic muscles to microgravity

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