NT-3 promotes nerve regeneration and sensory improvement in CMT1A mouse models and in patients

Sahenk, Zarife; Nagaraja, H. N.; McCracken, B. S.; King, W. M.; Freimer, Miriam; Cedarbaum, Jesse M.; Mendell, Jerry R.

doi:10.1212/01.wnl.0000171978.70849.c5

Cited by 169 publications

(133 citation statements)

References 49 publications

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“…Unfortunately, ascorbic acid failed to show any benefit in clinical trials 16. Other therapeutic strategies described for CMT1A include treatment with neurotrophin‐3,17 neuregulin 1,18, or a combination drug regime containing baclofen, naltrexone, and D‐sorbitol 19…”

Section: Introductionmentioning

confidence: 99%

Cell transplantation strategies for acquired and inherited disorders of peripheral myelin

Muhammad

Kim

Epifantseva

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo investigate transplantation of rat Schwann cells or human iPSC‐derived neural crest cells and derivatives into models of acquired and inherited peripheral myelin damage.MethodsPrimary cultured rat Schwann cells labeled with a fluorescent protein for monitoring at various times after transplantation. Human‐induced pluripotent stem cells (iPSCs) were differentiated into neural crest stem cells, and subsequently toward a Schwann cell lineage via two different protocols. Cell types were characterized using flow cytometry, immunocytochemistry, and transcriptomics. Rat Schwann cells and human iPSC derivatives were transplanted into (1) nude rats pretreated with lysolecithin to induce demyelination or (2) a transgenic rat model of dysmyelination due to PMP22 overexpression.ResultsRat Schwann cells transplanted into sciatic nerves with either toxic demyelination or genetic dysmyelination engrafted successfully, and migrated longitudinally for relatively long distances, with more limited axial migration. Transplanted Schwann cells engaged existing axons and displaced dysfunctional Schwann cells to form normal‐appearing myelin. Human iPSC‐derived neural crest stem cells and their derivatives shared similar engraftment and migration characteristics to rat Schwann cells after transplantation, but did not further differentiate into Schwann cells or form myelin.InterpretationThese results indicate that cultured Schwann cells surgically delivered to peripheral nerve can engraft and form myelin in either acquired or inherited myelin injury, as proof of concept for pursuing cell therapy for diseases of peripheral nerve. However, lack of reliable technology for generating human iPSC‐derived Schwann cells for transplantation therapy remains a barrier in the field.

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Section: Introductionmentioning

confidence: 99%

Cell transplantation strategies for acquired and inherited disorders of peripheral myelin

Muhammad

Kim

Epifantseva

et al. 2018

Ann Clin Transl Neurol

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“…A pilot, double-blind, RCT of 150 g/kg of r-metHuNT-3 three times a week for 24 weeks or placebo in CMT1A, showed encouraging results, with significant improvement in sensory and reflex subsets (but not motor subsets) of the NIS, and increased density of regenerative clusters and single myelinated nerve fibers on pre-and post-treatment nerve biopsies, compared with placebo-treated subjects. 31 NT-3 was well tolerated.…”

Section: Neurotrophin-3mentioning

confidence: 95%

“…31 Human mutant SCs harboring PMP-22 duplications fail to support axonal regeneration of nude mice axons in an injury model. Addition of NT-3, but not brain-derived neurotrophic factor (BDNF) partially corrects the defect in axonal regeneration in a human CMT1A xenograft in nude mice.…”

Section: Neurotrophin-3mentioning

confidence: 99%

“…Addition of NT-3, but not brain-derived neurotrophic factor (BDNF) partially corrects the defect in axonal regeneration in a human CMT1A xenograft in nude mice. 31 NT-3 is known to be important for SC survival and axonal regeneration. A pilot, double-blind, RCT of 150 g/kg of r-metHuNT-3 three times a week for 24 weeks or placebo in CMT1A, showed encouraging results, with significant improvement in sensory and reflex subsets (but not motor subsets) of the NIS, and increased density of regenerative clusters and single myelinated nerve fibers on pre-and post-treatment nerve biopsies, compared with placebo-treated subjects.…”

Section: Neurotrophin-3mentioning

confidence: 99%

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Experimental Therapeutics in Hereditary Neuropathies: The Past, the Present, and the Future

Herrmann

2008

Neurotherapeutics

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Summary:Hereditary neuropathies represent approximately 40% of undiagnosed neuropathies in a tertiary clinic setting. The Charcot-Marie-Tooth neuropathies (CMT) are the most common. Mutations in more than 40 genes have been identified to date in CMT. Approximately 50% of CMT cases are accounted for by CMT type 1A, due to a duplication within the peripheral myelin protein 22 gene (PMP22). Mutations in the gap junction beta 1 gene (GJB1), the myelin protein zero gene (MPZ), and the mitofusin 2 gene (MFN2) account for a substantial proportion of other genetically definable CMT. Some 15% of demyelinating CMT and 70% of axonal CMT await genetic clarification. Other hereditary neuropathies include the hereditary sensory and autonomic neuropathies, the familial amyloid polyneuropathies, and multisystem disorders (e.g., lipid storage diseases and inherited ataxias) that have peripheral neuropathy as a major or minor component. This review surveys the challenges of developing effective therapies for hereditary neuropathies in terms of past, present, and future experimental therapeutics in CMT.

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“…It has been documented that NT-3 has a strong effect on neurite outgrowth (Markus, Patel et al 2002;Sahenk, Nagaraja et al 2005). Additionally, some studies using genetically modified Schwann cells to overexpress the NT-3 gene have examined the role of NT-3 in the neuron survival and axonal regeneration/remyelination (Zhang, Zeng et al 2007;Pettingill, Minter et al 2008).…”

Section: Lipus Stimulation Induced An Alteration In Schwann Cell Funcmentioning

confidence: 99%

Effect of Low-Intensity Pulsed Ultrasound on Nerve Repair

Li¹,

Zhang²,

Ren³

2012

Tissue Regeneration - From Basic Biology to Clinical Application

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NT-3 promotes nerve regeneration and sensory improvement in CMT1A mouse models and in patients

Abstract: Neurotrophin-3 augments nerve regeneration in animal models for CMT1A and may benefit patients clinically, but these results need further confirmation.

Cited by 169 publications

References 49 publications

Cell transplantation strategies for acquired and inherited disorders of peripheral myelin

Cell transplantation strategies for acquired and inherited disorders of peripheral myelin

Experimental Therapeutics in Hereditary Neuropathies: The Past, the Present, and the Future

Effect of Low-Intensity Pulsed Ultrasound on Nerve Repair

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