A translatable RNAi-driven gene therapy silences PMP22/Pmp22 genes and improves neuropathy in CMT1A mice

Stavrou, Marina; Kagiava, Alexia; Choudury, Sarah G; Jennings, Matthew J.; Wallace, Lindsay; Fowler, Allison M.; Heslegrave, Amanda; Richter, Jan; Tryfonos, Christina; Christodoulou, Christina; Zetterberg, Henrik; Horváth, Rita; Harper, Scott Q.; Kleopa, Kleopas A.

doi:10.1172/jci159814

Cited by 28 publications

(40 citation statements)

References 114 publications

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“…Proof‐of‐principle of AAV9‐mediated gene therapy at the preclinical level has been provided in animal models of both demyelinating and axonal CMT neuropathies 67,68 . For the demyelinating forms, intrathecal route of administration has been used in CMT1A and CMT1X to target Schwann cells 11,12,68 . Of note, intrathecal and intravenous routes of administration have been recently compared in adult mice using AAV9 carrying an Mpz (myelin protein zero) Schwann cell‐specific promoter and similar efficiency of Schwann cell transduction has been observed 69 .…”

Section: Gene Therapy For Cmtmentioning

confidence: 99%

“…67,68 For the demyelinating forms, intrathecal route of administration has been used in CMT1A and CMT1X to target Schwann cells. 11,12,68 Of note, intrathecal and intravenous routes of administration have been recently compared in adult mice using AAV9 carrying an Mpz (myelin protein zero) Schwann cellspecific promoter and similar efficiency of Schwann cell transduction has been observed. 69 However, intraneural injection has been found to be the most efficient route of administration to specifically target Schwann cells in the demyelinating CMT1A.…”

Section: Gene Therapy For Cmtmentioning

confidence: 99%

“…Two very promising preclinical studies have recently reported proof‐of‐principle data of the efficacy of gene therapy‐based strategies to lower PMP22 levels 10,11 . RNA interference (RNAi) is a fundamental process of gene silencing mediated by endogenous miRNA (microRNAs), small non‐coding molecules that negatively regulate gene expression at post‐transcriptional level 77,78 .…”

Section: Gene Therapy For Cmtmentioning

confidence: 99%

“…A second very interesting study by Stavrou et al recently reported beneficial effects of scAAV9‐miRNA, targeting both mouse and human Pmp22 / PMP22 gene, delivered in the C61 mouse model of CMT1A, that carries four copies of the human PMP22 gene 11 . Viral vectors were administered intrathecally at P60 by performing lumbar injection and outcome measures were scored after 4 and 8 months.…”

Section: Gene Therapy For Cmtmentioning

confidence: 99%

See 3 more Smart Citations

Recent advances in the treatment of Charcot‐Marie‐Tooth neuropathies

Bolino

D’Antonio

2023

J Peripheral Nervous Sys

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Charcot‐Marie‐Tooth (CMT) neuropathies are one of the most common neuromuscular disorders. However, despite the identification of more than 100 causative genes, therapeutic options are still missing. The generation of authentic animal models and the increasing insights into the understanding of disease mechanisms, in addition to extraordinary developments in gene and molecular therapies, are quickly changing this scenario, and several strategies are currently being translated, or are getting close to, clinical trials. Here, we provide an overview of the most recent advances for the therapy of CMT at both the preclinical and clinical levels. For clarity, we have grouped the approaches in three different categories: gene therapy based on viral‐mediated delivery, molecular therapies based on alternative delivery systems, and pharmacological therapies.

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Section: Gene Therapy For Cmtmentioning

confidence: 99%

Section: Gene Therapy For Cmtmentioning

confidence: 99%

Section: Gene Therapy For Cmtmentioning

confidence: 99%

Section: Gene Therapy For Cmtmentioning

confidence: 99%

See 2 more Smart Citations

Recent advances in the treatment of Charcot‐Marie‐Tooth neuropathies

Bolino

D’Antonio

2023

J Peripheral Nervous Sys

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“…Finding additional biomarkers, and determining whether they correlate with disease severity, predict changes over time, and normalize after treatment in CMT patients is an important, feasible goal. In a CMT1A mouse model treated with microRNA gene therapy targeting PMP22 mRNA, elevated NfL levels returned towards normal accompanying clinical improvement, 48 and “CMT4C mice” treated with Sh3tc2 gene replacement showed similar findings 49 . Moreover, reductions in elevated plasma NfL levels accompany clinical improvement in treated human patients afflicted with neuropathy as part of variant transthyretin amyloidosis 50 .…”

mentioning

confidence: 94%

Trials for Slowly Progressive Neurogenetic Diseases Need Surrogate Endpoints

Reilly

Herrmann

Pareyson

et al. 2023

Annals of Neurology

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Heritable neurological disorders provide insights into disease mechanisms that permit development of novel therapeutic approaches including antisense oligonucleotides, RNA interference, and gene replacement. Many neurogenetic diseases are rare and slowly progressive making it challenging to measure disease progression within short time frames. We share our experience developing clinical outcome assessments and disease biomarkers in the inherited peripheral neuropathies. We posit that carefully developed biomarkers from imaging, plasma, or skin can predict meaningful progression in functional and patient reported outcome assessments such that clinical trials of less than 2 years will be feasible for these rare and ultra‐rare disorders. ANN NEUROL 2023;93:906–910

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Lumbar Intrathecal Injection in Adult and Neonatal Mice

Stavrou,

Georgiou,

Kleopa

2024

Current Protocols

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This article describes a step‐by‐step process of lumbar intrathecal injection of Evans blue dye and AAV9‐EGFP in adult (2‐month‐old) and neonatal (postnatal day 10) mice. Intrathecal injection is a clinically translatable technique that has already been extensively applied in humans. In mice, intrathecal injection is considered a challenging procedure that requires a trained and experienced researcher. For both adult and neonatal mice, lumbar intrathecal injection is directed into the L5‐L6 intervertebral space. Intrathecally injected material enters the cerebrospinal fluid (CSF) within the intrathecal space from where it can directly access the central nervous system (CNS) parenchyma. Simultaneously, intrathecally injected material exits the CSF with pressure gradient and enters the endoneurial fluid and ultimately the peripheral nerves. While in the CSF, the injectable material also enters the bloodstream and systemic circulation through the arachnoid villi. A successful lumbar intrathecal injection results in adequate biodistribution of the injectable material in the CNS, PNS, and peripheral organs. When correctly applied, this technique is considered as minimally invasive and non‐disruptive and can be used for the lumbar delivery of any solute. © 2024 Wiley Periodicals LLC.Basic Protocol 1: C57BL/6 adult and P10 mice lumbar intrathecal injectionBasic Protocol 2: Tissue collection and preparation for evaluating Evans blue dye diffusionBasic Protocol 3: Tissue collection and preparation for immunohistochemistry stainingBasic Protocol 4: Tissue collection and vector genome copy number analysis

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A translatable RNAi-driven gene therapy silences PMP22/Pmp22 genes and improves neuropathy in CMT1A mice

Cited by 28 publications

References 114 publications

Recent advances in the treatment of Charcot‐Marie‐Tooth neuropathies

Recent advances in the treatment of Charcot‐Marie‐Tooth neuropathies

Trials for Slowly Progressive Neurogenetic Diseases Need Surrogate Endpoints

Lumbar Intrathecal Injection in Adult and Neonatal Mice

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