2022
DOI: 10.1002/glia.24140
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Astrocyte‐targeting RNA interference against mutated superoxide dismutase 1 induces motoneuron plasticity and protects fast‐fatigable motor units in a mouse model of amyotrophic lateral sclerosis

Abstract: In amyotrophic lateral sclerosis (ALS) caused by SOD1 gene mutations, both cellautonomous and noncell-autonomous mechanisms lead to the selective degeneration of motoneurons (MN). Here, we evaluate the therapeutic potential of gene therapy targeting mutated SOD1 in mature astrocytes using mice expressing the mutated SOD1 G93A protein. An AAV-gfaABC 1 D vector encoding an artificial microRNA is used to deliver RNA interference against mutated SOD1 selectively in astrocytes. The treatment leads to the progressiv… Show more

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Cited by 13 publications
(9 citation statements)
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“…We injected SOD1 G93A mice at 60 days of age (pre- symptomatic stage) with AAV serotype 9 encoding for GFP and FGF4 intrathecally (Figure 4a). To restrict the expression of the candidate transgenes specifically to astrocytes, we used the gfaABC1D promoter [32, 33]. The spinal cord of mice from different cohorts was collected at 140 days (symptomatic stage [34]).…”
Section: Resultsmentioning
confidence: 99%
“…We injected SOD1 G93A mice at 60 days of age (pre- symptomatic stage) with AAV serotype 9 encoding for GFP and FGF4 intrathecally (Figure 4a). To restrict the expression of the candidate transgenes specifically to astrocytes, we used the gfaABC1D promoter [32, 33]. The spinal cord of mice from different cohorts was collected at 140 days (symptomatic stage [34]).…”
Section: Resultsmentioning
confidence: 99%
“…There is a rich literature on motor neuron plasticity in this preparation, some of which reports PKC-dependent mechanisms (Cai et al, 2008; Fulton et al, 2008; Glanzman, 2008; Villareal et al, 2009; Reissner et al, 2010; Jin et al, 2011; Bougie et al, 2012; Choi et al, 2014; Hu et al, 2015, 2017a; Ferguson et al, 2019; Alexandrescu and Carew, 2020). Also in mammals (including humans) motor neuron plasticity in the spinal cord is a readily observable phenomenon in non-clinical and clinical settings (Wolpaw and Lee, 1989; Wolpaw et al, 1989; Carp and Wolpaw, 1994; Carp et al, 2001; Wang et al, 2006; Wolpaw, 2012; Eftekhar et al, 2018; Kaneko et al, 2022; Rochat et al, 2022; Simonyan et al, 2022). The discovery of aPKC-dependent plasticity in Drosophila motor neurons expands this body of literature to a genetically tractable organism and inasmuch as clinical practice relies on motor neuron plasticity, may even help instruct the development of clinical applications.…”
Section: Discussionmentioning
confidence: 99%
“…Similarly, transplantation of wild-type astrocyte precursors in the cervical spinal cord of SOD1 G93A mice extended their survival, slowed the decline in motor performance, and partially prevented motor neuron loss in these mice [128]. Moreover, astrocyte-selective RNA interference against mutant SOD1 G93A significantly improved the neuromuscular function of SOD1 G93A mice and rescued a small population of fast-fatigable motor neurons [129]. Conversely, transplantation of SOD1 G93A astrocyte precursors in wild-type mice reduced neuromuscular functions and induced motor neuron death [130].…”
Section: Glial Studies From Sod1 Rodent Modelsmentioning
confidence: 93%