Survival Motor Neuron (SMN) protein is required for normal mouse liver development

Szunyogova, Eva; Zhou, Haïyan; Maxwell, Gillian K.; Powis, Rachael A.; Muntoni, Francesco; Gillingwater, Thomas H.; Parson, Simon H.

doi:10.1038/srep34635

Cited by 58 publications

(59 citation statements)

References 72 publications

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“…These include functional and structural cardiac defects,66 abnormal development of the gastrointestinal tract, liver, and spleen,64, 67, 68 and irregular bone remodeling and skeletal pathology 69. These findings suggest that successful treatment of SMA may require systemic targeting of a range of affected tissues.…”

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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173

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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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

Self Cite

173

170

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“…Interestingly, impaired liver development, iron overload and embryonic lethality were the main features of Smn conditional knockout restricted to the liver 35. Recently, iron homeostasis defects were also observed in the Taiwanese mouse model of SMA 36. Whether the spleen is causative of iron dysregulation, and potential cross‐talk between the liver and the spleen exists to regulate the pool of iron remains to be determined.…”

Section: Potential Functional Consequences Of Lymphoid Organ Defects mentioning

confidence: 99%

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

Deguise

Kothary

2017

Ann Clin Transl Neurol

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Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by motor neuron degeneration, although defects in multiple cell types and tissues have also been implicated. Three independent laboratories recently identified immune organ defects in SMA. We therefore propose a novel pathogenic mechanism contributory to SMA, resulting in higher susceptibility to infection and exacerbated disease progression caused by neuroinflammation. Overall, compromised immune function could significantly affect survival and quality of life of SMA patients. We highlight the recent findings in immune organ defects, their potential consequences on patients, our understanding of neuroinflammation in SMA, and new research hypotheses in SMA pathogenesis.

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“…Subsequent years also witnessed a series of in vivo studies employing phosphorodiamidate morpholino oligonucleotides (PMOs) targeting ISS-N1. 13,15,51–54 These studies provided additional independent validations of the efficacy of ISS-N1-targeting ASOs.…”

Section: Defining Features Of the Iss-n1 Targetmentioning

confidence: 90%

“…13,15,48–54,61–72 Initially, the 2′OMe ISS-N1-targeting ASO 43 increased SMN protein in the central nervous system (CNS) and improved motor function in the Δ7 mouse. 61 This finding led to studies from Krainer and colleagues, and independently from the Burghes (The University of Ohio School of Medicine, Columbus, OH, USA) and Muntoni groups (University College London, London, UK), to further explore the efficacy of the ISS-N1 inhibitor, albeit they used contrasting delivery strategies and ASOs of different lengths and chemistries.…”

Section: In Vivo Studies With Iss-n1-targeting Asosmentioning

confidence: 99%

How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy

et al. 2017

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Spinal muscular atrophy (SMA), a prominent genetic disease of infant mortality, is caused by low levels of survival motor neuron (SMN) protein owing to deletions or mutations of the SMN1 gene. SMN2, a nearly identical copy of SMN1 present in humans, cannot compensate for the loss of SMN1 due to predominant skipping of exon 7 during pre-mRNA splicing. With the recent FDA approval of nusinersen (Spinraza™), the potential for correction of SMN2 exon 7 splicing as a SMA therapy has been affirmed. Nusinersen is an antisense oligonucleotide that targets intronic splicing silencer N1 (ISS-N1) discovered in 2004 at the University of Massachusetts Medical School. ISS-N1 has emerged as the model target for testing the therapeutic efficacy of antisense oligonucleotides using different chemistries as well as different mouse models of SMA. Here we provide a historical account of events that led to the discovery of ISS-N1 and describe the impact of independent validations that raised the profile of ISS-N1 as one of the most potent antisense targets for the treatment of a genetic disease. Recent approval of nusinersen provides a much-needed boost for antisense technology that is just beginning to realize its potential. Beyond treating SMA, the ISS-N1 target offers myriad potentials for perfecting various aspects of the nucleic-acid-based technology for the amelioration of the countless number of pathological conditions.

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Survival Motor Neuron (SMN) protein is required for normal mouse liver development

Cited by 58 publications

References 72 publications

Emerging therapies and challenges in spinal muscular atrophy

Emerging therapies and challenges in spinal muscular atrophy

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy

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