Intraneural <scp><i>GJB</i></scp><i>1</i> gene delivery improves nerve pathology in a model of <scp>X</scp>‐linked <scp>C</scp>harcot–<scp>M</scp>arie–<scp>T</scp>ooth disease

Sargiannidou, Irene; Kagiava, Alexia; Bashiardes, Stavros; Richter, Jan; Christodoulou, Christina; Scherer, Steven S.; Kleopa, Kleopas A.

doi:10.1002/ana.24441

Cited by 41 publications

(60 citation statements)

References 58 publications

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“…This is in keeping with our previous observations following intraneural delivery of the same vector (8) or with preclinical (37,38) and clinical (39) applications of similar lentiviral vectors. Rarely reported inflammatory responses (26) were attributed to the reporter gene and not to the intrathecal method of gene delivery or to the vector type.…”

Section: Discussionsupporting

confidence: 91%

“…Previously attempted intraneural gene delivery using the same vector resulted in expression restricted to the injected sciatic nerve (8), whereas the intrathecal approach described here led to similar Schwann cell expression rates in sciatic nerves, but also achieved expression in multiple other peripheral nerves and spinal roots. This represents a major breakthrough, given that intrathecal injection is less invasive than other delivery methods and is routinely used in clinical practice for drug administration to treat pain, spasticity, and cancer.…”

Section: Discussionmentioning

confidence: 83%

“…This vector contains the human GJB1 gene, which encodes connexin32 (Cx32), a gap junction protein found in the Schwann cell myelin sheath localized in the noncompact myelin areas, including paranodal loops and Schmidt-Lantermann incisures (13). We previously showed that transgenic expression of human Cx32 can rescue the phenotype in Cx32 KO mice (9), that most CMT1X-associated GJB1 mutations cause a loss of Cx32 function (14), and that sciatic intraneural injection of this vector restores local Cx32 expression in this CMT1X model (8).…”

Section: Establishment Of Intrathecal Gene Delivery Targeting Schwannmentioning

confidence: 99%

“…The number of abnormally myelinated fibers, including demyelinated and remyelinated fibers, was counted and their proportion of the total number of fibers calculated (9,14). Foamy macrophages were also counted (8), and their numbers per 1,000 myelinated fibers were compared (to account for variations in root and nerve size).…”

Section: Improved Pathology In Spinal Roots and Peripheral Nerves Ofmentioning

confidence: 99%

“…We recently reported Schwann cell-specific expression driven by the rat myelin protein zero (Mpz) promoter of a neuropathy gene following intraneural lentiviral vector delivery, alleviating pathological changes in a model of X-linked Charcot-MarieTooth disease (CMT1X) (8). Expression was restricted to the injected sciatic nerve, however, thus limiting its usefulness for clinical applications.…”

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confidence: 99%

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Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy

Kagiava

Sargiannidou

Theophilidis

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Inherited demyelinating peripheral neuropathies are progressive incurable diseases without effective treatment. To develop a gene therapy approach targeting myelinating Schwann cells that can be translatable, we delivered a lentiviral vector using a single lumbar intrathecal injection and a myelin-specific promoter. The human gene of interest, GJB1, which is mutated in X-linked CharcotMarie-Tooth Disease (CMT1X), was delivered intrathecally into adult Gjb1-null mice, a genetically authentic model of CMT1X that develops a demyelinating peripheral neuropathy. We obtained widespread, stable, and cell-specific expression of connexin32 in up to 50% of Schwann cells in multiple lumbar spinal roots and peripheral nerves. Behavioral and electrophysiological analysis revealed significantly improved motor performance, quadriceps muscle contractility, and sciatic nerve conduction velocities. Furthermore, treated mice exhibited reduced numbers of demyelinated and remyelinated fibers and fewer inflammatory cells in lumbar motor roots, as well as in the femoral motor and sciatic nerves. This study demonstrates that a single intrathecal lentiviral gene delivery can lead to Schwann cell-specific expression in spinal roots extending to multiple peripheral nerves. This clinically relevant approach improves the phenotype of an inherited neuropathy mouse model and provides proof of principle for treating inherited demyelinating neuropathies.demyelinating neuropathy | Charcot-Marie-Tooth disease | connexin32 | peripheral nerve | gene therapy

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 83%

Section: Establishment Of Intrathecal Gene Delivery Targeting Schwannmentioning

confidence: 99%

Section: Improved Pathology In Spinal Roots and Peripheral Nerves Ofmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy

Kagiava

Sargiannidou

Theophilidis

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Precision Medicine for Charcot-Marie-Tooth Disease

Pleasure

2016

JAMA Neurol

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Clinical and biophysical characterization of 19 GJB1 mutations

Tsai

Yang

Liao

et al. 2016

Ann Clin Transl Neurol

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ObjectiveCharcot–Marie–Tooth disease type X1 (CMTX1), which is caused by mutations in the gap junction (GJ) protein beta‐1 gene (GJB1), is the second most common form of Charcot–Marie–Tooth disease (CMT). GJB1 encodes the GJ beta‐1 protein (GJB1), which forms GJs within the myelin sheaths of peripheral nerves. The process by which GJB1 mutants cause neuropathy has not been fully elucidated. This study evaluated the biophysical characteristics of GJB1 mutants and their correlations with the clinical features of CMTX1 patients.MethodsAll patients with a validated GJB1 mutation were assessed using the Charcot–Marie–Tooth disease neuropathy score version 2 (CMTNS). The impacts of the mutations on the biophysical functions of GJB1 were characterized by assessing intracellular localization, expression patterns, and GJ Ca2+ permeability.ResultNineteen GJB1 mutations were identified in 24 patients with a clinical diagnosis of CMT. Six are novel mutations: p.L6S, p.I20F, p.I101Rfs*8, p.F153L, p.R215P, and p.D278V. Diverse pathological effects of the mutations were demonstrated, including reduced GJB1 expression, intracellular mislocalization, and altered GJ functions. GJB1 mutations that caused a complete loss of GJ Ca2+ permeability appeared to be associated with an earlier disease onset, whereas those resulting in preservation of GJ permeability and with predominant cell membrane expression tended to have a later onset and a milder phenotype.InterpretationThis study demonstrated that the degree of loss of GJ function caused by the GJB1 mutations might contribute to the onset and severity of neuropathic symptoms in CMTX1.

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Intraneural GJB1 gene delivery improves nerve pathology in a model of X‐linked Charcot–Marie–Tooth disease

Abstract: Gene delivery using a lentiviral vector leads to efficient gene expression specifically in Schwann cells. Restoration of Cx32 expression ameliorates nerve pathology in a disease model and provides a promising approach for future treatments of CMT1X and other inherited neuropathies.

Cited by 41 publications

References 58 publications

Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy

Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy

Precision Medicine for Charcot-Marie-Tooth Disease

Clinical and biophysical characterization of 19 GJB1 mutations

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