Embryonic motor axon development in the severe SMA mouse

McGovern, Vicki L.; Gavrilina, Tatiana O.; Beattie, Christine E.; Burghes, Arthur H.M.

doi:10.1093/hmg/ddn189

Cited by 136 publications

(129 citation statements)

References 58 publications

Supporting

Mentioning

117

Contrasting

Order By: Relevance

“…1F). Impaired maturation of neuromuscular junctions (NMJs) is a hallmark of SMA, notable by small endplate area and complexity, denervation, poor terminal arborization, and neurofilament accumulation at the presynaptic nerve terminal (37)(38)(39)(40)(41). We therefore studied the morphology of NMJs in the transversus abdominis (TVA), one of the most severely affected muscles, between untreated and treated SMA pups at PND12 (42).…”

Section: Resultsmentioning

confidence: 99%

“…Multiple studies in SMA mouse models have generated conflicting data regarding the importance of systemic versus CNS-only treatment (11,12,43,44,47,48). 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).…”

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.

163

129

View full text Add to dashboard Cite

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...

show abstract

Section: Resultsmentioning

confidence: 99%

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.

163

129

View full text Add to dashboard Cite

show abstract

“…62,65 Interestingly, the phenotypes observed in SMA mouse models all show first perturbations of the neuromuscular junctions, before an actual cell death can be confirmed in the spinal cord. [69][70][71][72][73][74][75][76] This strongly favours a dying mouse Smn and expressing human SMN2. 79,100,101 However, a study performed with SMA patients showed no increase of SMN.…”

Section: The Architecture Of Smn Genes With Regard To Exon 7 Definitionmentioning

confidence: 99%

Repair of pre-mRNA splicing

2010

View full text Add to dashboard Cite

“…Disruption of neuronal growth, axon branching, and neuromuscular connectivity was observed in zebrafish [122]. While developmental processes were maintained in mouse models, denervation was evident during embryogenesis and early in the postnatal course, around the time of disease onset [86,123]. In SMA mouse models the temporal requirement for SMN protein encompasses the early postnatal course, with depletion of SMN in adults having minimal effect, coinciding with relative maturity of the neuromuscular junction [82,124].…”

Section: Challenges Is Smn1-related Sma Therapeuticsmentioning

confidence: 99%

The Genetics of Spinal Muscular Atrophy: Progress and Challenges

2015

View full text Add to dashboard Cite

Spinal muscular atrophies (SMAs) are a group of inherited disorders characterized by motor neuron loss in the spinal cord and lower brainstem, muscle weakness, and atrophy. The clinical and genetic phenotypes incorporate a wide spectrum that is differentiated based on age of onset, pattern of muscle involvement, and inheritance pattern. Over the past several years, rapid advances in genetic technology have accelerated the identification of causative genes and provided important advances in understanding the molecular and biological basis of SMA and insights into the selective vulnerability of the motor neuron. Common pathophysiological themes include defects in RNA metabolism and splicing, axonal transport, and motor neuron development and connectivity. Together these have revealed potential novel treatment strategies, and extensive efforts are being undertaken towards expedited therapeutics. While a number of promising therapies for SMA are emerging, defining therapeutic windows and developing sensitive and relevant biomarkers are critical to facilitate potential success in clinical trials. This review incorporates an overview of the clinical manifestations and genetics of SMA, and describes recent advances in the understanding of mechanisms of disease pathogenesis and development of novel treatment strategies.

show abstract

Embryonic motor axon development in the severe SMA mouse

Cited by 136 publications

References 58 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

Repair of pre-mRNA splicing

The Genetics of Spinal Muscular Atrophy: Progress and Challenges

Contact Info

Product

Resources

About