Tolerability and efficacy study of P2X7 inhibition in experimental Charcot-Marie-Tooth type 1A (CMT1A) neuropathy

Sociali, Giovanna; Visigalli, Davide; Prukop, Thomas; Cervellini, Ilaria; Mannino, Elena; Venturi, Consuelo; Bruzzone, Santina; Sereda, Michael W.; Schenone, Angelo

doi:10.1016/j.nbd.2016.07.017

Cited by 29 publications

(31 citation statements)

References 74 publications

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“…n = 3-7 per group; t tests; # p < 0.05 CMT1A placebo versus WT placebo; *p < 0.05 CMT1A PXT3003 versus CMT1A placebo; dot plots and means (c and d) [Color figure can be viewed at wileyonlinelibrary.com] weight and to keep animal numbers as low as needed to minimize animal's burden for ethical reasons. Despite this limitation, using only one sex is considered sufficient since gender differences were not observed in CMT1A rats on disease severity with regard to molecular, electrophysiological, histological, and phenotypical characteristics (Chumakov et al, 2014;Fledrich et al, 2012Fledrich et al, , 2014Fledrich et al, , 2018Meyer zu Horste et al, 2007;Prukop et al, 2019;Sereda et al, 1996;Sereda, Meyer zu Hörste, Suter, Uzma, & Nave, 2003;Sociali et al, 2016). Moreover, no gender effect was reported in male and female CMT1A rats treated independently with Onapristone (Meyer zu Horste et al, 2007;Sereda et al, 2003), and no gender effect was observed in CMT1A patients after therapy with PXT3003 (Attarian et al, 2014) (Clinical Trials Register/Results, 2019.…”

Section: Discussionmentioning

confidence: 99%

Synergistic PXT3003 therapy uncouples neuromuscular function from dysmyelination in male Charcot–Marie–Tooth disease type 1A (CMT1A) rats

Prukop

Wernick

Boussicault

et al. 2020

J of Neuroscience Research

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Charcot–Marie–Tooth disease 1 A (CMT1A) is caused by an intrachromosomal duplication of the gene encoding for PMP22 leading to peripheral nerve dysmyelination, axonal loss, and progressive muscle weakness. No therapy is available. PXT3003 is a low‐dose combination of baclofen, naltrexone, and sorbitol which has been shown to improve disease symptoms in Pmp22 transgenic rats, a bona fide model of CMT1A disease. However, the superiority of PXT3003 over its single components or dual combinations have not been tested. Here, we show that in a dorsal root ganglion (DRG) co‐culture system derived from transgenic rats, PXT3003 induced myelination when compared to its single and dual components. Applying a clinically relevant (“translational”) study design in adult male CMT1A rats for 3 months, PXT3003, but not its dual components, resulted in improved performance in behavioral motor and sensory endpoints when compared to placebo. Unexpectedly, we observed only a marginally increased number of myelinated axons in nerves from PXT3003‐treated CMT1A rats. However, in electrophysiology, motor latencies correlated with increased grip strength indicating a possible effect of PXT3003 on neuromuscular junctions (NMJs) and muscle fiber pathology. Indeed, PXT3003‐treated CMT1A rats displayed an increased perimeter of individual NMJs and a larger number of functional NMJs. Moreover, muscles of PXT3003 CMT1A rats displayed less neurogenic atrophy and a shift toward fast contracting muscle fibers. We suggest that ameliorated motor function in PXT3003‐treated CMT1A rats result from restored NMJ function and muscle innervation, independent from myelination.

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Section: Discussionmentioning

confidence: 99%

Synergistic PXT3003 therapy uncouples neuromuscular function from dysmyelination in male Charcot–Marie–Tooth disease type 1A (CMT1A) rats

Prukop

Wernick

Boussicault

et al. 2020

J of Neuroscience Research

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“…At the present time, the most advanced strategy is a pharmacological treatment that reached the clinical phase III (NCT02579759). Another pharmacological treatment is reaching the clinical phase I (NCT03610334) and several others are in preclinical phases [12,16,34,37,51,58,66].…”

Section: Discussionmentioning

confidence: 99%

Long term AAV2/9-mediated silencing of PMP22 prevents CMT1A disease in rats and validates skin biomarkers as treatment outcome measure

Gautier¹,

Hajjar

Soares

et al. 2020

Preprint

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Charcot-Marie-Tooth disease 1A (CMT1A) results from a duplication of the PMP22 gene leading to an excess of PMP22, a deficit of myelination and an instability of the myelin sheath in peripheral nerves. Patients present with reduced nerve conduction velocity, muscle waste, hand and foot deformations and foot drop walking problems. As gene silencing therapy has been shown to be effective in other monogenic neurological disorders, we evaluated the safety and efficacy of recombinant adeno-associated viral vector serotype 9 (AAV2/9)-based gene therapy for CMT1A. AAV2/9-mediated delivery of eGFP and shRNAs targeting PMP22 mRNA in the sciatic nerve allowed widespread gene expression in myelinating Schwann cells in mouse, rat and nonhuman primate. The treatment restored wild-type PMP22 level, increased myelination and prevented motor and sensory impairment over 12 months in a rat model of CMT1A. Intra-nerve injection limited off-target transduction and immune response to barely detectable levels. A combination of previously characterized human skin biomarkers successfully discriminated treated animals from their untreated littermate controls indicating their potential use as part of outcome measures in future clinical trials. Our results support intra nerve injection of AAV2/9 as an effective strategy for the treatment of CMT1A as well as other demyelinating CMT diseases.

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“…Probably best studied is its central role in NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome activation, cytokine maturation, and inflammation that was originally established in P2X7 knockout ( P2rx7 -/- ) mouse models ( Chessell et al, 2005 ; Solle et al, 2001 ; Di Virgilio et al, 2017 ). A growing body of evidence suggests that an increased P2X7 receptor function plays a role in various diseases of the central nervous system (CNS) and peripheral nervous system (PNS) and further supports its importance as a drug target ( Bhattacharya and Biber, 2016 ; Rassendren and Audinat, 2016 ; Sperlágh and Illes, 2014 ; Sociali et al, 2016 ).…”

Section: Introductionmentioning

confidence: 97%

Re-evaluation of neuronal P2X7 expression using novel mouse models and a P2X7-specific nanobody

Kaczmarek-Hájek

Zhang

Kopp

et al. 2018

eLife

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147

183

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The P2X7 channel is involved in the pathogenesis of various CNS diseases. An increasing number of studies suggest its presence in neurons where its putative functions remain controversial for more than a decade. To resolve this issue and to provide a model for analysis of P2X7 functions, we generated P2X7 BAC transgenic mice that allow visualization of functional EGFP-tagged P2X7 receptors in vivo. Extensive characterization of these mice revealed dominant P2X7-EGFP protein expression in microglia, Bergmann glia, and oligodendrocytes, but not in neurons. These findings were further validated by microglia- and oligodendrocyte-specific P2X7 deletion and a novel P2X7-specific nanobody. In addition to the first quantitative analysis of P2X7 protein expression in the CNS, we show potential consequences of its overexpression in ischemic retina and post-traumatic cerebral cortex grey matter. This novel mouse model overcomes previous limitations in P2X7 research and will help to determine its physiological roles and contribution to diseases.

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Tolerability and efficacy study of P2X7 inhibition in experimental Charcot-Marie-Tooth type 1A (CMT1A) neuropathy

Cited by 29 publications

References 74 publications

Synergistic PXT3003 therapy uncouples neuromuscular function from dysmyelination in male Charcot–Marie–Tooth disease type 1A (CMT1A) rats

Synergistic PXT3003 therapy uncouples neuromuscular function from dysmyelination in male Charcot–Marie–Tooth disease type 1A (CMT1A) rats

Long term AAV2/9-mediated silencing of PMP22 prevents CMT1A disease in rats and validates skin biomarkers as treatment outcome measure

Re-evaluation of neuronal P2X7 expression using novel mouse models and a P2X7-specific nanobody

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