Nusinersen for spinal muscular atrophy

Wurster, Claudia D.; Ludolph, Albert C.

doi:10.1177/1756285618754459

Cited by 77 publications

(72 citation statements)

References 9 publications

(15 reference statements)

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“…Thus, Antisense technology is gaining upcoming relevance in the field of therapeutic applications [2,[4][5][6][7][8]. A recent example is Nusinersen, a successful FDA-approved ASO and the first compound for treating spinal muscular atrophy [7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Antisense Oligonucleotide in LNA-Gapmer Design Targeting TGFBR2—A Key Single Gene Target for Safe and Effective Inhibition of TGFβ Signaling

Kuespert

Heydn

Peters

et al. 2020

IJMS

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Antisense Oligonucleotides (ASOs) are an emerging drug class in gene modification. In our study we developed a safe, stable, and effective ASO drug candidate in locked nucleic acid (LNA)-gapmer design, targeting TGFβ receptor II (TGFBR2) mRNA. Discovery was performed as a process using state-of-the-art library development and screening. We intended to identify a drug candidate optimized for clinical development, therefore human specificity and gymnotic delivery were favored by design. A staggered process was implemented spanning in-silico-design, in-vitro transfection, and in-vitro gymnotic delivery of small batch syntheses. Primary in-vitro and in-vivo toxicity studies and modification of pre-lead candidates were also part of this selection process. The resulting lead compound NVP-13 unites human specificity and highest efficacy with lowest toxicity. We particularly focused at attenuation of TGFβ signaling, addressing both safety and efficacy. Hence, developing a treatment to potentially recondition numerous pathological processes mediated by elevated TGFβ signaling, we have chosen to create our data in human lung cell lines and human neuronal stem cell lines, each representative for prospective drug developments in pulmonary fibrosis and neurodegeneration. We show that TGFBR2 mRNA as a single gene target for NVP-13 responds well, and that it bears great potential to be safe and efficient in TGFβ signaling related disorders.

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Section: Introductionmentioning

confidence: 99%

Antisense Oligonucleotide in LNA-Gapmer Design Targeting TGFBR2—A Key Single Gene Target for Safe and Effective Inhibition of TGFβ Signaling

Kuespert

Heydn

Peters

et al. 2020

IJMS

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“…Following these positive outcomes, nusinersen has been approved as SMA treatment by the US Food and Drug Administration (FDA) in 2016 and by the European Medicines Agency in 2017 [100]. Ongoing studies are evaluating the long-term safety and tolerability of nusinersen and its effects on presymptomatic patients [101].…”

Section: Aon-mediated Exon Inclusionmentioning

confidence: 99%

Targeting Alternative Splicing as a Potential Therapy for Episodic Ataxia Type 2

et al. 2020

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Episodic ataxia type 2 (EA2) is an autosomal dominant neurological disorder characterized by paroxysmal attacks of ataxia, vertigo, and nausea that usually last hours to days. It is caused by loss-of-function mutations in CACNA1A, the gene encoding the pore-forming α1 subunit of P/Q-type voltage-gated Ca2+ channels. Although pharmacological treatments, such as acetazolamide and 4-aminopyridine, exist for EA2, they do not reduce or control the symptoms in all patients. CACNA1A is heavily spliced and some of the identified EA2 mutations are predicted to disrupt selective isoforms of this gene. Modulating splicing of CACNA1A may therefore represent a promising new strategy to develop improved EA2 therapies. Because RNA splicing is dysregulated in many other genetic diseases, several tools, such as antisense oligonucleotides, trans-splicing, and CRISPR-based strategies, have been developed for medical purposes. Here, we review splicing-based strategies used for genetic disorders, including those for Duchenne muscular dystrophy, spinal muscular dystrophy, and frontotemporal dementia with Parkinsonism linked to chromosome 17, and discuss their potential applicability to EA2.

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“…3C). We previously showed that ASO administration at concentrations of 3-10 µM without transfection reagents can stably suppress gene expression in iPSC-derived cultures for >1 week, and clinical studies show that a single administration of ASOs with similar chemical modifications can suppress gene expression for several months in vivo (Becker et al, 2017;Shi et al, 2019;Shi et al, 2018;Wurster and Ludolph, 2018). Because HAND1 and POU5F1 are dispensable for endoderm differentiation (Sherwood et al, 2009;Tsankov et al, 2015), we chose to administer the ASOs at the beginning of the differentiation protocol and used either a 10 µM concentration for either HAND1 and POU5F1 alone, or a 3 µM concentration when using ASOs targeting both genes simultaneously (Fig.…”

Section: Aso-mediated Suppression Of Hand1 and Pou5f1 Enhance Endodermentioning

confidence: 99%

Single Cell Transcriptomics-guided Antisense Treatment Improves Endoderm Differentiation of iPSCs

Hor

Punj

Borok

et al. 2020

Preprint

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Directed differentiation of induced pluripotent stem cells (iPSCs) enables the production of relevant cell types for studies of human biology, disease-modeling, and efforts towards cellular therapy and transplantation. However, the low yield and purity of desired cell types can limit the utility of this approach. Enhancing differentiation purity can require extensive optimization of morphogen treatments, and this can still be ineffective for iPSC lines with biased or aberrant differentiation propensities. To address these limitations, we have developed a new approach for increasing the purity of iPSC directed differentiation cultures called RNA sequencing and Antisense-assisted Differentiation (RAD). We performed trajectory analysis of single cell RNA sequencing during iPSC differentiation into endoderm to identify transcription factors responsible for committing cells to undesired, non-endodermal fates. Specific suppression of these transcription factors using antisense oligonucleotides (ASOs) increased the percentage of endodermal cells by up to 20-fold in 3 different iPSC lines that exhibited poor endoderm differentiation. Moreover, this approach required minimal culture manipulation. Thus, RAD improves the utility of iPSCs for basic and translational studies.

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Nusinersen for spinal muscular atrophy

Cited by 77 publications

References 9 publications

Antisense Oligonucleotide in LNA-Gapmer Design Targeting TGFBR2—A Key Single Gene Target for Safe and Effective Inhibition of TGFβ Signaling

Antisense Oligonucleotide in LNA-Gapmer Design Targeting TGFBR2—A Key Single Gene Target for Safe and Effective Inhibition of TGFβ Signaling

Targeting Alternative Splicing as a Potential Therapy for Episodic Ataxia Type 2

Single Cell Transcriptomics-guided Antisense Treatment Improves Endoderm Differentiation of iPSCs

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