scholarly journals Muscle overexpression of Klf15 via an AAV8-Spc5-12 construct does not provide benefits in spinal muscular atrophy mice

Gene Therapy ◽  
2020 ◽  
Vol 27 (10-11) ◽  
pp. 505-515
Author(s):  
Nina Ahlskog ◽  
Daniel Hayler ◽  
Anja Krueger ◽  
Sabrina Kubinski ◽  
Peter Claus ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Treatment Options ◽  
Survival Motor Neuron ◽  
Significant Activity ◽  
Dependent Manner ◽  
Patient Response ◽  
High Gene Expression ◽  
Virus Serotype ◽  
High Gene

AbstractSpinal muscular atrophy (SMA) is a neuromuscular disease caused by loss of the survival motor neuron (SMN) gene. While there are currently two approved gene-based therapies for SMA, availability, high cost, and differences in patient response indicate that alternative treatment options are needed. Optimal therapeutic strategies will likely be a combination of SMN-dependent and -independent treatments aimed at alleviating symptoms in the central nervous system and peripheral muscles. Krüppel-like factor 15 (KLF15) is a transcription factor that regulates key metabolic and ergogenic pathways in muscle. We have recently reported significant downregulation of Klf15 in muscle of presymptomatic SMA mice. Importantly, perinatal upregulation of Klf15 via transgenic and pharmacological methods resulted in improved disease phenotypes in SMA mice, including weight and survival. In the current study, we designed an adeno-associated virus serotype 8 (AAV8) vector to overexpress a codon-optimized Klf15 cDNA under the muscle-specific Spc5-12 promoter (AAV8-Klf15). Administration of AAV8-Klf15 to severe Taiwanese Smn−/−;SMN2 or intermediate Smn2B/− SMA mice significantly increased Klf15 expression in muscle. We also observed significant activity of the AAV8-Klf15 vector in liver and heart. AAV8-mediated Klf15 overexpression moderately improved survival in the Smn2B/− model but not in the Taiwanese mice. An inability to specifically induce Klf15 expression at physiological levels in a time- and tissue-dependent manner may have contributed to this limited efficacy. Thus, our work demonstrates that an AAV8-Spc5-12 vector induces high gene expression as early as P2 in several tissues including muscle, heart, and liver, but highlights the challenges of achieving meaningful vector-mediated transgene expression of Klf15.

scholarly journals Muscle overexpression of Klf15 via an AAV8-Spc5-12 construct does not provide benefits in spinal muscular atrophy mice

2019 ◽  
Author(s):  
Nina Ahlskog ◽  
Daniel Hayler ◽  
Anja Krueger ◽  
Sabrina Kubinski ◽  
Peter Claus ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Treatment Options ◽  
Survival Motor Neuron ◽  
Significant Activity ◽  
Dependent Manner ◽  
Patient Response ◽  
High Gene Expression ◽  
Virus Serotype ◽  
High Gene

ABSTRACTSpinal muscular atrophy (SMA) is a neuromuscular disease caused by loss of the survival motor neuron (SMN) gene. While there are currently two approved gene-based therapies for SMA, availability, high cost, and differences in patient response indicate that alternative treatment options are needed. Optimal therapeutic strategies will likely be a combination of SMN-dependent and -independent treatments aimed at alleviating symptoms in the central nervous system and peripheral muscles. Krüppel-like factor 15 (KLF15) is a transcription factor that regulates key metabolic and ergogenic pathways in muscle. We have recently reported significant downregulation of Klf15 in muscle of pre-symptomatic SMA mice. Importantly, perinatal upregulation of Klf15 via transgenic and pharmacological methods resulted in improved disease phenotypes in SMA mice, including weight and survival. In the current study, we designed an adeno-associated virus serotype 8 (AAV8) vector to overexpress a codon-optimised Klf15 cDNA under the muscle-specific Spc5-12 promoter (AAV8-Klf15). Administration of AAV8-Klf15 to severe Taiwanese Smn−/−;SMN2 or intermediate Smn2B/− SMA mice significantly increased Klf15 expression in muscle. We also observed significant activity of the AAV8-Klf15 vector in liver and heart. AAV8-mediated Klf15 overexpression moderately improved survival in the Smn2B/− model but not in the Taiwanese mice. An inability to specifically induce Klf15 expression at physiological levels in a time- and tissue-dependent manner may have contributed to this limited efficacy. Thus, our work demonstrates that an AAV8-Spc5-12 vector induces high gene expression as early as P2 in several tissues including muscle, heart and liver, but highlights the challenges of achieving meaningful vector-mediated transgene expression of Klf15.

Novel protective modifiers in mouse models of spinal muscular atrophy

2018 ◽  
Author(s):  
◽  
Kevin Andrew Cody Kaifer
Keyword(s):  
Spinal Muscular Atrophy ◽  
Mouse Models ◽  
Muscular Atrophy ◽  
Experimental System ◽  
Homozygous Deletion ◽  
Alpha Synuclein ◽  
Survival Motor Neuron ◽  
Virus Serotype ◽  
Smn Protein

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by the homozygous deletion or mutation in the survival motor neuron-1 (SMN1) gene resulting in extremely low levels of the SMN protein. Without treatment, the majority of SMA cases progress rapidly and lead to mortality by age 2. SMA is uniquely positioned for therapy, however, as a nearly identical gene called SMN2 can be modulated to express the functional SMN protein. A recently approved, highly efficacious therapy called Spinraza adopts this strategy and has brought promise to the SMA patient community. Despite this breakthrough, it is widely hypothesized that a long-term strategy will require a combinatorial approach to address the complexity of this disease, and additional therapeutic strategies need to be established. Towards this aim, the past decade of research has led to the elucidation of key molecular events that contribute to the pathology of SMA as well as several factors that modulate disease severity. Referred to as protective modifiers, these factors represent potential targets for combinatorial therapy. In this work we establish a strategy to identify and characterize novel protective modifiers in mouse models of SMA. Our approach utilizes adenoassociated virus serotype 9 (AAV9) to express putative modifiers in mouse models, effectively allowing us to determine their effects in vivo. Using our experimental system, we confirm that a previously controversial modifier, Plastin-3, reduces severity in mouse models of SMA. We also identify miR-23a, DOK7, and [alpha]-synuclein as novel protective modifiers of SMA. These insights implicate microRNA dysregulation, neuromuscular junction organization, and synaptic transmission as disease modifying pathways that contain potential therapeutic candidates for the treatment of SMA.

scholarly journals Massachusetts’ Findings from Statewide Newborn Screening for Spinal Muscular Atrophy

2021 ◽  
Vol 7 (2) ◽  
pp. 26
Author(s):  
Jaime E. Hale ◽  
Basil T. Darras ◽  
Kathryn J. Swoboda ◽  
Elicia Estrella ◽  
Jin Yun Helen Chen ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Newborn Screening ◽  
New England ◽  
Screening Program ◽  
Muscular Atrophy ◽  
Treatment Options ◽  
Newborn Screening Program ◽  
Treatment Protocols ◽  
Screening Algorithm ◽  
New Treatment

Massachusetts began newborn screening (NBS) for Spinal Muscular Atrophy (SMA) following the availability of new treatment options. The New England Newborn Screening Program developed, validated, and implemented a screening algorithm for the detection of SMA-affected infants who show absent SMN1 Exon 7 by Real-Time™ quantitative PCR (qPCR). We screened 179,467 neonates and identified 9 SMA-affected infants, all of whom were referred to a specialist by day of life 6 (average and median 4 days of life). Another ten SMN1 hybrids were observed but never referred. The nine referred infants who were confirmed to have SMA were entered into treatment protocols. Early data show that some SMA-affected children have remained asymptomatic and are meeting developmental milestones and some have mild to moderate delays. The Massachusetts experience demonstrates that SMA NBS is feasible, can be implemented on a population basis, and helps engage infants for early treatment to maximize benefit.

scholarly journals Salbutamol inhibits ubiquitin-mediated survival motor neuron protein degradation in spinal muscular atrophy cells

2015 ◽  
Vol 4 ◽  
pp. 351-356 ◽  
Author(s):  
Nur Imma Fatimah Harahap ◽  
Dian Kesumapramudya Nurputra ◽  
Mawaddah Ar Rochmah ◽  
Ai Shima ◽  
Naoya Morisada ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Protein Degradation ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Survival Motor Neuron Protein ◽  
Motor Neuron Protein

scholarly journals AAV9-mediated delivery of miR-23a reduces disease severity in Smn2B/−SMA model mice

2019 ◽  
Vol 28 (19) ◽  
pp. 3199-3210 ◽  
Author(s):  
Kevin A Kaifer ◽  
Eric Villalón ◽  
Benjamin S O'Brien ◽  
Samantha L Sison ◽  
Caley E Smith ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Viral Vector ◽  
Muscular Atrophy ◽  
Induced Pluripotent Stem Cell ◽  
Survival Motor Neuron ◽  
Virus Serotype

Abstract Spinal muscular atrophy (SMA) is a neuromuscular disease caused by deletions or mutations in survival motor neuron 1 (SMN1). The molecular mechanisms underlying motor neuron degeneration in SMA remain elusive, as global cellular dysfunction obscures the identification and characterization of disease-relevant pathways and potential therapeutic targets. Recent reports have implicated microRNA (miRNA) dysregulation as a potential contributor to the pathological mechanism in SMA. To characterize miRNAs that are differentially regulated in SMA, we profiled miRNA levels in SMA induced pluripotent stem cell (iPSC)-derived motor neurons. From this array, miR-23a downregulation was identified selectively in SMA motor neurons, consistent with previous reports where miR-23a functioned in neuroprotective and muscle atrophy-antagonizing roles. Reintroduction of miR-23a expression in SMA patient iPSC-derived motor neurons protected against degeneration, suggesting a potential miR-23a-specific disease-modifying effect. To assess this activity in vivo, miR-23a was expressed using a self-complementary adeno-associated virus serotype 9 (scAAV9) viral vector in the Smn2B/− SMA mouse model. scAAV9-miR-23a significantly reduced the pathology in SMA mice, including increased motor neuron size, reduced neuromuscular junction pathology, increased muscle fiber area, and extended survival. These experiments demonstrate that miR-23a is a novel protective modifier of SMA, warranting further characterization of miRNA dysfunction in SMA.

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