AAV9-DOK7 gene therapy reduces disease severity in Smn SMA model mice

Kaifer, Kevin A.; Villalón, Eric; Smith, Caley E.; Simon, Madeline; Marquez, José; Hopkins, Abigail E.; Morcos, Toni I.; Lorson, Christian L.

doi:10.1016/j.bbrc.2020.07.031

Cited by 21 publications

(16 citation statements)

References 48 publications

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“…The identification of impaired U7 snRNP assembly as the upstream trigger of a cascade leading to motor neuron denervation and muscle atrophy in SMA mice raised the question as to which downstream effector(s) could directly mediate the distal effects of U7 dysfunction at the NMJ. A candidate emerging from recent studies [28][29][30][31] was Agrin -an essential NMJ organizer that promotes clustering of post-synaptic acetylcholine receptors (AChR) during development 32,33 and is also required for postnatal NMJ maintenance 34 . Since increasing Agrin levels or its associated signaling cascade has been shown to ameliorate NMJ pathology of SMA mice in a manner similar to Lsm10/11 co-expression 28-31 , we sought to investigate possible links between Agrin and SMNregulated U7 snRNP assembly.…”

Section: Smn Regulates Agrin Expression At the Nmj Through U7 Snrnpmentioning

confidence: 99%

SMN controls neuromuscular junction integrity through U7 snRNP

Tisdale

Alstyne

Simon

et al. 2021

Preprint

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The neuromuscular junction (NMJ) is an essential synapse for animal survival whose loss is a key hallmark of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). While insights into the function of the causative genes implicate RNA dysregulation in NMJ pathogenesis, the RNA-mediated mechanisms controlling the biology of this specialized synapse that go awry in disease remain elusive. Here, we show that activity of the SMA-determining SMN protein in the assembly of U7 small nuclear ribonucleoprotein (snRNP), which functions in the 3'-end processing of replication-dependent histone mRNAs, is required for NMJ integrity. AAV9-mediated gene delivery of U7-specific Lsm10 and Lsm11 proteins selectively enhances U7 snRNP assembly, corrects histone mRNA processing defects, and rescues key structural and functional abnormalities of neuromuscular pathology in SMA mice - including NMJ denervation, reduced synaptic transmission, and skeletal muscle atrophy. Furthermore, U7 snRNP dysfunction induced by SMN deficiency drives selective loss of the synaptic organizing protein Agrin at NMJs innervating vulnerable axial muscles of SMA mice, revealing an unanticipated link between U7-dependent histone mRNA processing and motor neuron-derived expression of an essential factor for NMJ biology. Together, these findings establish a direct contribution of U7 snRNP dysfunction to the neuromuscular phenotype in SMA and the requirement of RNA-mediated histone gene regulation for maintaining functional synaptic connections between motor neurons and muscles.

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Section: Smn Regulates Agrin Expression At the Nmj Through U7 Snrnpmentioning

confidence: 99%

SMN controls neuromuscular junction integrity through U7 snRNP

Tisdale

Alstyne

Simon

et al. 2021

Preprint

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“…Augmenting MuSK expression in mdx animals via an adeno-associated virus (AAV) vector reduced neuromuscular failure from eccentric muscle damage and elevated DAPC/UAPC components [16] . Furthermore, AAV induction of downstream effector proteins rapsyn and Dok7 conferred unique neuromuscular alterations in several disparate models of NMDs, including DMD [16] , CMS [82] , SMA [83] , and amyotrophic lateral sclerosis [84] . Thus, these pre-clinical data indicate that targeting the agrin/LRP4/MuSK cascade may eventually yield promising therapeutic effects in DMD patients.…”

Section: Synaptic Biology In Dmd and Therapies Targeting The Nmjmentioning

confidence: 99%

Recent insights into neuromuscular junction biology in Duchenne muscular dystrophy: Impacts, challenges, and opportunities

Ljubicic

2020

EBioMedicine

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Duchenne muscular dystrophy (DMD) is the most common and relentless form of muscular dystrophy. The pleiotropic effects of dystrophin deficiency include remarkable impacts on neuromuscular junction (NMJ) structure and function. Some of these alterations contribute to the severe muscle wasting and weakness that distinguish DMD, while others attempt to compensate for them. Experimental approaches that correct NMJ biology in pre-clinical models of DMD attenuate disease progression and improve functional outcomes, which suggests that targeting the NMJ may be an effective therapeutic strategy for DMD patients. The objectives of this review are to 1) survey the distinctions in NMJ structure, function, and gene expression in the dystrophic context as compared to the healthy condition, and 2) summarize the efforts, opportunities and challenges to correct NMJ biology in DMD. This information will expand our basic understanding of neuromuscular biology and may be useful for designing novel NMJ-targeted drug or behavioural strategies to mitigate the dystrophic pathology and other disorders of the neuromuscular system.

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“…Furthermore, upregulation of Z+ agrin by a genetic approach [ 29 ] or by a pharmacological treatment [ 30 ] increases NMJ area, muscle fiber size, and innervation at NMJs of SMA mice. Similarly, enhancing DOK7 by AAV9 delivery also improved NMJ architecture and reduced muscle atrophy [ 31 ]. These findings suggest that NMJ defects can be alleviated by enhancing postsynaptic differentiation in SMA mice.…”

Section: Introductionmentioning

confidence: 99%

Activation of Muscle-Specific Kinase (MuSK) Reduces Neuromuscular Defects in the Delta7 Mouse Model of Spinal Muscular Atrophy (SMA)

Feng

Lam

Tenn

et al. 2021

IJMS

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Spinal muscular atrophy (SMA) is a motor neuron disease caused by insufficient levels of the survival motor neuron (SMN) protein. One of the most prominent pathological characteristics of SMA involves defects of the neuromuscular junction (NMJ), such as denervation and reduced clustering of acetylcholine receptors (AChRs). Recent studies suggest that upregulation of agrin, a crucial NMJ organizer promoting AChR clustering, can improve NMJ innervation and reduce muscle atrophy in the delta7 mouse model of SMA. To test whether the muscle-specific kinase (MuSK), part of the agrin receptor complex, also plays a beneficial role in SMA, we treated the delta7 SMA mice with an agonist antibody to MuSK. MuSK agonist antibody #13, which binds to the NMJ, significantly improved innervation and synaptic efficacy in denervation-vulnerable muscles. MuSK agonist antibody #13 also significantly increased the muscle cross-sectional area and myofiber numbers in these denervation-vulnerable muscles but not in denervation-resistant muscles. Although MuSK agonist antibody #13 did not affect the body weight, our study suggests that preservation of NMJ innervation by the activation of MuSK may serve as a complementary therapy to SMN-enhancing drugs to maximize the therapeutic effectiveness for all types of SMA patients.

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AAV9-DOK7 gene therapy reduces disease severity in Smn SMA model mice

Cited by 21 publications

References 48 publications

SMN controls neuromuscular junction integrity through U7 snRNP

SMN controls neuromuscular junction integrity through U7 snRNP

Recent insights into neuromuscular junction biology in Duchenne muscular dystrophy: Impacts, challenges, and opportunities

Activation of Muscle-Specific Kinase (MuSK) Reduces Neuromuscular Defects in the Delta7 Mouse Model of Spinal Muscular Atrophy (SMA)

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