A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse

Porensky, Paul; Mitrpant, Chalermchai; McGovern, Vicki L.; Bevan, Adam K.; Foust, Kevin D.; Kaspar, B.; Wilton, Steve D.; Burghes, Arthur H.M.

doi:10.1093/hmg/ddr600

Cited by 235 publications

(253 citation statements)

References 75 publications

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“…Consistent with this interpretation, using a conditional knockout strategy, Park et al (2010) recently found that 70% of mice with selective depletion of SMN in motor neurons survived over a year. Porensky et al (2012) reported that ICV injection of PMO ASO10-29 at a dose of 27, 54, or 81 mg in the SMND7 model (which has a slightly milder phenotype than the severe model that we used here) led to a sixfold to sevenfold survival increase; the investigators proposed that early and sustained increase of SMN in the CNS is essential for SMA therapy. However, the strong survival increase that they reported was less striking than what we obtained in the more severe model with peripheral rescue alone.…”

Section: Discussionmentioning

confidence: 79%

“…In addition, as stated above, some of the ASO injected into the CNS is cleared with CSF into the blood and circulates to peripheral tissues. Porensky et al (2012) reported no statistically significant peripheral effect on SMN2 splicing after ICV injection of the middle dose; however, this may be attributable to the small sample size (n = 2), as an approximately twofold increase in SMN2 full-length mRNA in the liver and heart was actually observed. A more recent study using 25mer PMO (PMO25) confirmed that systemic delivery at high doses robustly rescues severe SMA mice (Zhou et al 2013).…”

Section: Discussionmentioning

confidence: 88%

“…Similarly, necrosis in the tail, ear pinnae, feet, legs, anus, etc. is manifested in severe SMA mice when their survival is extended after treatment with therapeutic drugs (Narver et al 2008;Hua et al 2011;Passini et al 2011;Porensky et al 2012).…”

Section: Discussionmentioning

confidence: 99%

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Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models

et al. 2015

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Survival of motor neuron (SMN) deficiency causes spinal muscular atrophy (SMA), but the pathogenesis mechanisms remain elusive. Restoring SMN in motor neurons only partially rescues SMA in mouse models, although it is thought to be therapeutically essential. Here, we address the relative importance of SMN restoration in the central nervous system (CNS) versus peripheral tissues in mouse models using a therapeutic spliceswitching antisense oligonucleotide to restore SMN and a complementary decoy oligonucleotide to neutralize its effects in the CNS. Increasing SMN exclusively in peripheral tissues completely rescued necrosis in mild SMA mice and robustly extended survival in severe SMA mice, with significant improvements in vulnerable tissues and motor function. Our data demonstrate a critical role of peripheral pathology in the mortality of SMA mice and indicate that peripheral SMN restoration compensates for its deficiency in the CNS and preserves motor neurons. Thus, SMA is not a cell-autonomous defect of motor neurons in SMA mice.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 88%

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Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models

et al. 2015

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“…18,[53][54][55][56] We aimed to test a situation suitable for future patient care and chose oral application beginning on the first day of life (P0). Protein analysis of SMA animals at different disease stages demonstrates that there may be organ as well as time-dependent effects of HDACi treatment on SMN levels.…”

Section: Discussionmentioning

confidence: 99%

Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585

et al. 2012

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Spinal muscular atrophy (SMA) is the leading genetic cause of early childhood death worldwide and no therapy is available today. Many drugs, especially histone deacetylase inhibitors (HDACi), increase SMN levels. As all HDACi tested so far only mildly ameliorate the SMA phenotype or are unsuitable for use in humans, there is still need to identify more potent drugs. Here, we assessed the therapeutic power of the pan-HDACi JNJ-26481585 for SMA, which is currently used in various clinical cancer trials. When administered for 64 h at 100 nM, JNJ-26481585 upregulated SMN levels in SMA fibroblast cell lines, including those from non-responders to valproic acid. Oral treatment of Taiwanese SMA mice and control littermates starting at P0 showed no overt extension of lifespan, despite mild improvements in motor abilities and weight progression. Many treated and untreated animals showed a very rapid decline or unexpected sudden death. We performed exploratory autopsy and histological assessment at different disease stages and found consistent abnormalities in the intestine, heart and lung and skeletal muscle vasculature of SMA animals, which were not prevented by JNJ-26481585 treatment. Interestingly, some of these features may be only indirectly caused by a-motoneuron function loss but may be major life-limiting factors in the course of disease. A better understanding of -primary or secondary -non-neuromuscular organ involvement in SMA patients may improve standard of care and may lead to reassessment of how to investigate SMA patients clinically.

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“…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)(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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A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse

Cited by 235 publications

References 75 publications

Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models

Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models

Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585

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

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