Responses to Fasting and Glucose Loading in a Cohort of Well Children with Spinal Muscular Atrophy Type II

Davis, Rebecca Hurst; Miller, Elizabeth A.; Zhang, Ren Zhe; Swoboda, Kathryn J.

doi:10.1016/j.jpeds.2015.09.023

Cited by 42 publications

(42 citation statements)

References 43 publications

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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%

See 1 more Smart Citation

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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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.

169

129

View full text Add to dashboard Cite

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“…Metabolic defects in SMA have been reported previously. Pancreatic defects were observed in mouse models of SMA and in SMA patients . These alterations appear to be the cause of abnormal glucose homeostasis .…”

Section: Introductionmentioning

confidence: 99%

Abnormal fatty acid metabolism is a core component of spinal muscular atrophy

Deguise

Baranello

Mastella

et al. 2019

Ann Clin Transl Neurol

125

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Objective Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder leading to paralysis and subsequent death in young children. Initially considered a motor neuron disease, extra‐neuronal involvement is increasingly recognized. The primary goal of this study was to investigate alterations in lipid metabolism in SMA patients and mouse models of the disease. Methods We analyzed clinical data collected from a large cohort of pediatric SMA type I–III patients as well as SMA type I liver necropsy data. In parallel, we performed histology, lipid analysis, and transcript profiling in mouse models of SMA. Results We identify an increased susceptibility to developing dyslipidemia in a cohort of 72 SMA patients and liver steatosis in pathological samples. Similarly, fatty acid metabolic abnormalities were present in all SMA mouse models studied. Specifically, Smn2B/‐ mice displayed elevated hepatic triglycerides and dyslipidemia, resembling non‐alcoholic fatty liver disease (NAFLD). Interestingly, this phenotype appeared prior to denervation. Interpretation This work highlights metabolic abnormalities as an important feature of SMA, suggesting implementation of nutritional and screening guidelines in patients, as such defects are likely to increase metabolic distress and cardiovascular risk. This study emphasizes the need for a systemic therapeutic approach to ensure maximal benefits for all SMA patients throughout their life.

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“…In contrast, most NAFLD patients have metabolic syndrome, which includes features of obesity, dyslipidemia, insulin resistance, hyperglycemia, hyperinsulinemia [10]. Note that it is unclear whether the Smn 2B/mice develop insulin resistance as gold standard studies are not logistically feasible in this model, but SMA patients appear prone to insulin resistance [32]. Smn 2B/mice show some difficulties in glucose handling during intra-peritoneal glucose tolerance challenge [31].…”

Section: Discussionmentioning

confidence: 99%

“…Hormonal contribution to NAFLD in Smn 2B/mice Insulin insensitivity plays a major role in the development of NAFLD. Smn 2B/mice show abnormal glucose handling in intra-peritoneal glucose tolerance test [31] and small cohort of SMA patients showed susceptibility to insulin resistance [32]. Surprisingly, the Smn 2B/mice show sustained hypoglycemia with age in a normoinsulinemic state and a trend towards diminished Cpeptide production at P19 ( Fig 5A-C).…”

Section: Assessment Of Mitochondrial Function In Livers Of Smn 2b/micementioning

confidence: 93%

A mouse model for spinal muscular atrophy provides insights into non-alcoholic fatty liver disease pathogenesis

Deguise

Pileggi

Beauvais

et al. 2020

Preprint

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Charles Best CIHR Doctoral Research Award. contrast to typical NAFLD/NASH, the Smn 2B/mice lose weight due to their neurological condition, develop hypoglycemia and do not develop hepatic fibrosis. ConclusionThe Smn 2B/mice represent a good model of microvesicular steatohepatitis. Like other models, it is not representative of the complete NAFLD/NASH spectrum. Nevertheless, it offers a reliable, low-cost, early onset model that is not dependent on diet to identify molecular players in NAFLD pathogenesis and can serve as one of the very few models of microvesicular steatohepatitis for both adult and pediatric populations.

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Responses to Fasting and Glucose Loading in a Cohort of Well Children with Spinal Muscular Atrophy Type II

Cited by 42 publications

References 43 publications

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

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

Abnormal fatty acid metabolism is a core component of spinal muscular atrophy

A mouse model for spinal muscular atrophy provides insights into non-alcoholic fatty liver disease pathogenesis

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