Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy

Lutz, Cathleen; Kariya, Shingo; Patruni, Sunita; Osborne, Melissa; Liu, Don; Henderson, Chris; Li, Darrick K.; Pellizzoni, Livio; Rojas, José Luis Vázquez; Valenzuela, David M.; Murphy, Andrew; Winberg, Margaret L.; Monani, Umrao R.

doi:10.1172/jci57291

Cited by 152 publications

(136 citation statements)

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“…Although mice that received only two injections at PND 1 and PND 3 developed necrosis, repeated s.c. injections also prevented this necrosis. We previously reported a postsymptomatic therapeutic window in the severe Δ7 mouse model, where restoration of SMN expression via a tamoxifeninducible genetic rescue allele provided the greatest benefit with respect to survival if it was induced before PND 8 (17). Although the Δ7 mutants have a mean survival of 17 d, the Burgheron mutants, with a mean survival of 89 d, offered an unprecedented opportunity to test the efficacy of restoring SMN levels much later after the onset of the phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…Although the severe models have been valuable research tools, their rapid phenotype progression presents several obstacles to preclinical testing of therapeutics. Among these is the narrow window for testing therapeutic interventions, as the short overall survival time of these mice limits the study of postonset interventions (11,(15)(16)(17). In these severe SMA mice, several studies have demonstrated that successful intervention in the disease course is limited to the early postnatal days (PNDs) (10,17,18).…”

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confidence: 99%

“…Among these is the narrow window for testing therapeutic interventions, as the short overall survival time of these mice limits the study of postonset interventions (11,(15)(16)(17). In these severe SMA mice, several studies have demonstrated that successful intervention in the disease course is limited to the early postnatal days (PNDs) (10,17,18). Whether this observation holds true in milder models of SMA remains to be answered but is a critical question, as type II/III patients represent the majority currently awaiting treatment.…”

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confidence: 99%

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Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy

Bogdanik

Osborne

Davis

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Clinical presentation of spinal muscular atrophy (SMA) ranges from a neonatal-onset, very severe disease to an adult-onset, milder form. SMA is caused by the mutation of the Survival Motor Neuron 1 (SMN1) gene, and prognosis inversely correlates with the number of copies of the SMN2 gene, a human-specific homolog of SMN1. Despite progress in identifying potential therapies for the treatment of SMA, many questions remain including how late after onset treatments can still be effective and what the target tissues should be. These questions can be addressed in part with preclinical animal models; however, modeling the array of SMA severities in the mouse, which lacks SMN2, has proven challenging. We created a new mouse model for the intermediate forms of SMA presenting with a delay in neuromuscular junction maturation and a decrease in the number of functional motor units, all relevant to the clinical presentation of the disease. Using this new model, in combination with clinical electrophysiology methods, we found that administering systemically SMN-restoring antisense oligonucleotides (ASOs) at the age of onset can extend survival and rescue the neurological phenotypes. Furthermore, these effects were also achieved by administration of the ASOs late after onset, independent of the restoration of SMN in the spinal cord. Thus, by adding to the limited repertoire of existing mouse models for type II/III SMA, we demonstrate that ASO therapy can be effective even when administered after onset of the neurological symptoms, in young adult mice, and without being delivered into the central nervous system.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy

Bogdanik

Osborne

Davis

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Studies to determine how late SMN might be restored in severe SMA demonstrated that an incremental benefit accrues the earlier the protein is augmented [78,79]. The extent of rescue appears to correlate tightly with the extent of damage at the NMJ.…”

Section: Defining When Smn Is Requiredmentioning

confidence: 99%

Spinal Muscular Atrophy: Journeying From Bench to Bedside

2014

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Spinal muscular atrophy (SMA) is a frequently fatal neuromuscular disorder and the most common inherited cause of infant mortality. SMA results from reduced levels of the survival of motor neuron (SMN) protein. Although the disease was first described more than a century ago, a precise understanding of its genetics was not obtained until the SMA genes were cloned in 1995. This was followed in rapid succession by experiments that assigned a role to the SMN protein in the proper splicing of genes, novel animal models of the disease, and the eventual use of the models in the pre clinical development of rational therapies for SMA. These successes have led the scientific and clinical communities to the cusp of what are expected to be the first truly promising treatments for the human disorder. Yet, important questions remain, not the least of which is how SMN paucity triggers a predominantly neuromuscular phenotype. Here we review how our understanding of the disease has evolved since the SMA genes were identified. We begin with a brief description of the genetics of SMA and the proposed roles of the SMN protein. We follow with an examination of how the genetics of the disease was exploited to develop genetically faithful animal models, and highlight the insights gained from their analysis. We end with a discussion of ongoing debates, future challenges, and the most promising treatments to have emerged from our current knowledge of the disease.

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“…Some pre-clinical studies support the existence of a critical therapeutic window, since increases in SMN levels at post-natal day 1 (P1) rescue the majority of SMA mice, but this rescue is absent if SMN levels are restored later [Foust et al, 2010; Le et al, 2011]. However, other studies did not confirm these findings [Lutz et al, 2011]. Arguing against the existence of a therapeutic window is the observation that the loss of MNs is a late and end-stage event in SMA mouse models [Monani et al, 2000;Cifuentes Diaz et al, 2002].…”

Section: Smn: How Much Is Enough?mentioning

confidence: 99%

Solving the puzzle of spinal muscular atrophy: What are the missing pieces?

Tiziano

Melki

Simard

2013

American J of Med Genetics Pt A

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Spinal muscular atrophy (SMA) is an autosomal recessive, lower motor neuron disease. Clinical heterogeneity is pervasive: three infantile (type I-III) and one adult-onset (type IV) forms are recognized. Type I SMA is the most common genetic cause of death in infancy and accounts for about 50% of all patients with SMA. Most forms of SMA are caused by mutations of the survival motor neuron (SMN1) gene. A second gene that is 99% identical to SMN1 (SMN2) is located in the same region. The only functionally relevant difference between the two genes identified to date is a C ! T transition in exon 7 of SMN2, which determines an alternative spliced isoform that predominantly excludes exon 7. Thus, SMN2 genes do not produce sufficient full length SMN protein to prevent the onset of the disease. Since the identification of the causative mutation, biomedical research of SMA has progressed by leaps and bounds: from clues on the function of SMN protein, to the development of different models of the disease, to the identification of potential treatments, some of which are currently in human trials. The aim of this review is to elucidate the current state of knowledge, emphasizing how close we are to the solution of the puzzle that is SMA, and, more importantly, to highlight the missing pieces of this puzzle. Filling in these gaps in our knowledge will likely accelerate the development and delivery of efficient treatments for SMA patients and be a prerequisite towards achieving our final goal, the cure of SMA. Ó 2013 Wiley Periodicals, Inc. Key words: spinal muscular atrophy; SMN INTRODUCTIONSpinal muscular atrophy (SMA) is a lower motor neuron disease that predominantly affects spinal cord anterior horn cells and brain stem nuclei [Dubowitz, 1995; reviewed in Hamilton and Gillingwater, 2013]. Alpha-motor neuron cell degeneration results in progressive, symmetrical skeletal muscle atrophy of limbs and trunk, spreading proximal to distal [Crawford and Pardo, 1996]. Clinical heterogeneity is pervasive: based on the age of onset and on the maximum motor achievement of patients, three infantile (type I-III) and one adult-onset (type IV) forms are commonly recognized. Classification criteria are summarized in Table I. However, this rigid classification does not accurately depict the range of SMA clinical phenotypes, which display a more continuous spectrum, ranging from prenatal onset to almost asymptomatic patients. SMA is a common autosomal recessive disorder (incidence is $1 in 6,000 in most ethnicities). Type I SMA is the most common genetic cause of death in infancy and accounts for about 50% of all patients with SMA [Crawford and Pardo, 1996;Prior, 2010].Most forms of SMA are caused by mutations in the survival motor neuron (SMN) gene, which was isolated in 1995 in chromosome 5q13 harboring a segmental duplication [Lefebvre et al., 1995]. Mutations in SMN1 are responsible for the four forms of SMA [Wirth, 2000;Alías et al., 2009]. A second gene that is 99% identical to SMN1, the SMN2 gene, is located in the same region [Le...

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Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy

Cited by 152 publications

References 56 publications

Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy

Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy

Spinal Muscular Atrophy: Journeying From Bench to Bedside

Solving the puzzle of spinal muscular atrophy: What are the missing pieces?

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