Glucose metabolism and pancreatic defects in spinal muscular atrophy

Bowerman, Mélissa; Swoboda, Kathryn J.; Michalski, John Paul; Wang, Gen Sheng; Reeks, Courtney; Beauvais, Ariane; Murphy, Kelley J.; Woulfe, John; Screaton, Robert A.; Scott, Fraser W.; Kothary, Rashmi

doi:10.1002/ana.23582

Cited by 150 publications

(186 citation statements)

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“…The single most important pathological finding for SMA is the loss of lower motor neurons, and denervation at the NMJ is the earliest pathological change in SMA mice (37)(38)(39)(40)(41). However, reduced SMN expression has also been observed to cause skeletal muscle (13,14,16) and vascular system (19,20,49) defects in SMA mice, and SMN is involved in general cellular functions, including small nuclear ribonucleic protein (snRNP) biogenesis (13,(22)(23)(24) and glucose metabolism (17,18,21). Thus, although delivery to the CNS is primordial for SMA therapy, combined targeting of both the CNS and the periphery has the potential of being the optimal approach.…”

Section: Discussionmentioning

confidence: 99%

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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.

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169

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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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Section: Discussionmentioning

confidence: 99%

“…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.

Self Cite

169

129

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“…In addition, bone defects were reported in both SMA patients and mouse models (Shanmugarajan et al 2007(Shanmugarajan et al , 2009). More recently, Bowerman et al (2012) uncovered abnormal expansion of a cells and shrinkage of b cells in the pancreatic islets of SMA mice, resulting in hyperglucagonemia and defective glucose metabolism. In spite of these global peripheral defects seen in both patients and animal models, their importance in SMA pathogenesis has been largely overlooked.…”

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confidence: 99%

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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“…In addition to its housekeeping function in splicing, SMN is involved in multiple cellular processes such as actin dynamics (19)(20)(21)(22), axonal transport (23), endocytosis (24), and neuromuscular junction maturation (reviewed in [25][26][27][28]. Although SMN deficiency primarily affects motor neurons, SMN-dependent perturbations have also been reported in nonneuronal tissues, including in the muscle, heart, liver, and pancreas of SMA animal models as well as patients (29)(30)(31)(32). Therefore, increasing SMN protein level is the most straightforward approach for SMA therapy, and has been studied for years with different strategies such as correction of SMN2 splicing, modulation of SMN gene expression, prevention of protein degradation, and replacement of SMN1 (reviewed in 3,33-37).…”

Section: Introductionmentioning

confidence: 99%