Vascular <scp>D</scp>efects and <scp>S</scp>pinal <scp>C</scp>ord <scp>H</scp>ypoxia in <scp> S</scp>pinal <scp>M</scp>uscular <scp>A</scp>trophy

Somers, Eilidh; Lees, Robert D.; Hoban, Katie; Sleigh, James N.; Zhou, Haïyan; Muntoni, Francesco; Talbot, Kevin; Gillingwater, Thomas H.; Parson, Simon H.

doi:10.1002/ana.24549

Cited by 78 publications

(99 citation statements)

References 54 publications

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“…This in turn decreases the proportion of full-length SMN2 transcript, thereby decreasing the level of functional SMN protein, which in turn leads to further motor neuron damage. Consistent with this notion, vascular malformations in muscle and spinal cord have been described in three different SMA mouse models, Taiwanese, SMNΔ7, and Burghes’ severe model (Somers et al 2016; Nobutoki and Ihara 2015; Somers et al 2012; Le et al 2005; Monani et al 2000; Hsieh-Li et al 2000). Somers et al, analyzed muscle capillary beds in the severe Burghes mouse model at PND1, PND3 and PND5.…”

Section: Hypoxic Stresssupporting

confidence: 55%

“…This decreased capillary bed density was similarly observed in the transverse abdominal muscle, that exhibits substantial muscular atrophy, and LAL rostral band (LALr), that shows mild muscular atrophy, indicating decreased capillary bed density did not correlate with only severely affected muscle types (Somers et al 2012). Additionally, the Taiwanese and SMNΔ7 SMA mouse models were also analyzed for capillary bed infiltration in muscle and spinal cord (Somers et al 2016; Le et al 2005; Monani et al 2000). Spinal cord vasculature at pre-symptomatic stages matches that of non-disease littermates.…”

Section: Hypoxic Stressmentioning

confidence: 99%

“…Spinal cord vasculature at pre-symptomatic stages matches that of non-disease littermates. However, over time, capillary beds in control animals grow denser while in SMA mice, they remain sparse, at approximately half the density of the controls (Somers et al 2016). A similar vascular deficiency was observed in human SMA patient muscle biopsies, with a capillary-to-filament ratio approaching 10 fold lower in SMA patients than controls (Somers et al 2016).…”

Section: Hypoxic Stressmentioning

confidence: 99%

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SMN regulation in SMA and in response to stress: new paradigms and therapeutic possibilities

2017

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Low levels of the survival of motor neuron (SMN) protein cause the neurodegenerative disease spinal muscular atrophy (SMA). SMA is a pediatric disease characterized by spinal motor neuron degeneration. SMA exhibits several levels of severity ranging from early antenatal fatality, to only mild muscular weakness and disease prognosis is related directly to the amount of functional SMN protein that a patient is able to express. Current therapies are being developed to increase the production of functional SMN protein, however understanding the effect that natural stresses have on the production and function of SMN is of critical importance to ensuring that these therapies will have the greatest possible effect for patients. Research has shown that SMN, both on the mRNA and protein level, is highly affected by cellular stress. In this review we will summarize the research that highlights the roles of SMN in the disease process and the response of SMN to various environmental stresses.

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Section: Hypoxic Stresssupporting

confidence: 55%

Section: Hypoxic Stressmentioning

confidence: 99%

Section: Hypoxic Stressmentioning

confidence: 99%

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SMN regulation in SMA and in response to stress: new paradigms and therapeutic possibilities

2017

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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%

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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166

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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“…One potential unifying factor may be a deficiency in the development of vasculature in SMA; the resulting hypoxia would likely impact motor neurons as well as skeletal muscle and possibly contribute to the gastrointestinal defects (gastroesophageal reflux, constipation, and delayed gastric emptying) commonly observed in SMA patients 6438, 39, 65…”

Section: How Low Levels Of Smn Cause Smamentioning

confidence: 99%

Emerging therapies and challenges in spinal muscular atrophy

Farrar

Park

Vucic

et al. 2017

Annals of Neurology

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181

170

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Spinal muscular atrophy (SMA) is a hereditary neurodegenerative disease with severity ranging from progressive infantile paralysis and premature death (type I) to limited motor neuron loss and normal life expectancy (type IV). Without disease‐modifying therapies, the impact is profound for patients and their families. Improved understanding of the molecular basis of SMA, disease pathogenesis, natural history, and recognition of the impact of standardized care on outcomes has yielded progress toward the development of novel therapeutic strategies and are summarized. Therapeutic strategies in the pipeline are appraised, ranging from SMN1 gene replacement to modulation of SMN2 encoded transcripts, to neuroprotection, to an expanding repertoire of peripheral targets, including muscle. With the advent of preliminary trial data, it can be reasonably anticipated that the SMA treatment landscape will transform significantly. Advancement in presymptomatic diagnosis and screening programs will be critical, with pilot newborn screening studies underway to facilitate preclinical diagnosis. The development of disease‐modifying therapies will necessitate monitoring programs to determine the long‐term impact, careful evaluation of combined treatments, and further acceleration of improvements in supportive care. In advance of upcoming clinical trial results, we consider the challenges and controversies related to the implementation of novel therapies for all patients and set the scene as the field prepares to enter an era of novel therapies. Ann Neurol 2017;81:355–368

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Vascular Defects and Spinal Cord Hypoxia in Spinal Muscular Atrophy

Abstract: Our results indicate that vascular defects are a major feature of severe forms of SMA, present in both mouse models and patients, resulting in functional hypoxia of motor neurons. Thus, abnormal vascular development and resulting hypoxia may contribute to the pathogenesis of SMA.

Cited by 78 publications

References 54 publications

SMN regulation in SMA and in response to stress: new paradigms and therapeutic possibilities

SMN regulation in SMA and in response to stress: new paradigms and therapeutic possibilities

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

Emerging therapies and challenges in spinal muscular atrophy

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