Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy

Bogdanik, Laurent; Osborne, Melissa; Davis, Crystal; Martin, Whitney; Austin, Andrew D.; Rigo, Frank; Bennett, C. Frank; Lutz, Cathleen

doi:10.1073/pnas.1509758112

Cited by 56 publications

(61 citation statements)

References 65 publications

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“…Preclinical research continues to adjust and improve ISS-N1 targeted ASO therapeutics to establish a more efficient and successful compound without adverse effects. In addition, newly developed mouse models have enabled delayed treatment paradigms in order to fully evaluate SMN -targeted ASOs (Bogdanik et al, 2015). …”

Section: Application To Neurodegenerative Diseasesmentioning

confidence: 99%

Antisense Oligonucleotides: Translation from Mouse Models to Human Neurodegenerative Diseases

Schoch

Miller

2017

Neuron

234

254

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Multiple neurodegenerative diseases are characterized by single protein dysfunction and aggregation. Treatment strategies for these diseases have often targeted downstream pathways to ameliorate consequences of protein dysfunction; however, targeting the source of that dysfunction, the affected protein itself, seems most judicious to achieve a highly effective therapeutic outcome. Antisense oligonucleotides (ASOs) are small sequences of DNA able to target RNA transcripts resulting in reduced or modified protein expression. ASOs are ideal candidates for the treatment of neurodegenerative diseases given numerous advancements made to their chemical modifications and delivery methods. Successes achieved in both animal models and human clinical trials have proven ASOs both safe and effective. With proper considerations in mind regarding the human applicability of ASOs, we anticipate ongoing in vivo research and clinical trial development of ASOs for the treatment of neurodegenerative diseases.

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Section: Application To Neurodegenerative Diseasesmentioning

confidence: 99%

Antisense Oligonucleotides: Translation from Mouse Models to Human Neurodegenerative Diseases

Schoch

Miller

2017

Neuron

234

254

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“…ISS-N1-targeted SSOs used to treat presymptomatic severely affected neonatal SMA mice, via systemic or intracerebroventricular administration, extend survival from 10 to >100 d (11,12). Although SSO targeting to the CNS is essential, there is also evidence for a peripheral role for the SMN in SMA (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24).…”

mentioning

confidence: 99%

Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy

Hammond

Hazell

Shabanpoor

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

169

129

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The development of antisense oligonucleotide therapy is an important advance in the identification of corrective therapy for neuromuscular diseases, such as spinal muscular atrophy (SMA). Because of difficulties of delivering single-stranded oligonucleotides to the CNS, current approaches have been restricted to using invasive intrathecal single-stranded oligonucleotide delivery. Here, we report an advanced peptide-oligonucleotide, Pip6a-morpholino phosphorodiamidate oligomer (PMO), which demonstrates potent efficacy in both the CNS and peripheral tissues in severe SMA mice following systemic administration. SMA results from reduced levels of the ubiquitously expressed survival motor neuron (SMN) protein because of loss-of-function mutations in the SMN1 gene. Therapeutic splice-switching oligonucleotides (SSOs) modulate exon 7 splicing of the nearly identical SMN2 gene to generate functional SMN protein. Pip6a-PMO yields SMN expression at high efficiency in peripheral and CNS tissues, resulting in profound phenotypic correction at doses an order-of-magnitude lower than required by standard naked SSOs. Survival is dramatically extended from 12 d to a mean of 456 d, with improvement in neuromuscular junction morphology, down-regulation of transcripts related to programmed cell death in the spinal cord, and normalization of circulating insulin-like growth factor 1. The potent systemic efficacy of Pip6a-PMO, targeting both peripheral as well as CNS tissues, demonstrates the high clinical potential of peptide-PMO therapy for SMA.spinal muscular atrophy | survival motor neuron | antisense oligonucleotide | splice switching oligonucleotide | cell-penetrating peptide S pinal muscular atrophy (SMA), a leading genetic cause of infant mortality primarily due to lower motor neuron degeneration and progressive muscle weakness, results from loss of the ubiquitous survival motor neuron 1 gene (SMN1) (1, 2). Humans have a second nearly identical copy, SMN2, that differs from SMN1 by a crucial nucleotide transition within exon 7 leading to the predominant generation of an alternative exon 7-excluded transcript and only marginally functional protein (3-7). SMN2 therefore fails to compensate for loss of SMN1 unless sufficient copies are present to generate functional levels of full-length SMN protein (2).A rational, gene therapy-based approach for SMA uses singlestranded antisense splice-switching oligonucleotides (SSOs) to enhance SMN2 pre-mRNA exon 7 inclusion via steric block of splice regulatory pre-mRNA elements (8). Targeting the intron splice silencer N1 (ISS-N1) site within intron 7, by deletion or SSOmediated splice switching, improves exon 7 inclusion (9, 10). ISS-N1-targeted SSOs used to treat presymptomatic severely affected neonatal SMA mice, via systemic or intracerebroventricular administration, extend survival from 10 to >100 d (11, 12). Although SSO targeting to the CNS is essential, there is also evidence for a peripheral role for the SMN in SMA (13-24).Although SSO therapy is currently at an advanced stage of de...

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“…13,15,48–54,61–72 Initially, the 2′OMe ISS-N1-targeting ASO 43 increased SMN protein in the central nervous system (CNS) and improved motor function in the Δ7 mouse. 61 This finding led to studies from Krainer and colleagues, and independently from the Burghes (The University of Ohio School of Medicine, Columbus, OH, USA) and Muntoni groups (University College London, London, UK), to further explore the efficacy of the ISS-N1 inhibitor, albeit they used contrasting delivery strategies and ASOs of different lengths and chemistries.…”

Section: In Vivo Studies With Iss-n1-targeting Asosmentioning

confidence: 99%

How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy

et al. 2017

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Spinal muscular atrophy (SMA), a prominent genetic disease of infant mortality, is caused by low levels of survival motor neuron (SMN) protein owing to deletions or mutations of the SMN1 gene. SMN2, a nearly identical copy of SMN1 present in humans, cannot compensate for the loss of SMN1 due to predominant skipping of exon 7 during pre-mRNA splicing. With the recent FDA approval of nusinersen (Spinraza™), the potential for correction of SMN2 exon 7 splicing as a SMA therapy has been affirmed. Nusinersen is an antisense oligonucleotide that targets intronic splicing silencer N1 (ISS-N1) discovered in 2004 at the University of Massachusetts Medical School. ISS-N1 has emerged as the model target for testing the therapeutic efficacy of antisense oligonucleotides using different chemistries as well as different mouse models of SMA. Here we provide a historical account of events that led to the discovery of ISS-N1 and describe the impact of independent validations that raised the profile of ISS-N1 as one of the most potent antisense targets for the treatment of a genetic disease. Recent approval of nusinersen provides a much-needed boost for antisense technology that is just beginning to realize its potential. Beyond treating SMA, the ISS-N1 target offers myriad potentials for perfecting various aspects of the nucleic-acid-based technology for the amelioration of the countless number of pathological conditions.

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Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy

Cited by 56 publications

References 65 publications

Antisense Oligonucleotides: Translation from Mouse Models to Human Neurodegenerative Diseases

Antisense Oligonucleotides: Translation from Mouse Models to Human Neurodegenerative Diseases

Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy

How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy

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