AAV1.NT-3 gene therapy for X-linked Charcot–Marie–Tooth neuropathy type 1

Özeş, Burçak; Myers, Morgan; Moss, Kyle; McKinney, Jennifer L.; Ridgley, Alicia; Chen, Lei; Bai, Shasha; Abrams, Charles K.; Freidin, Mona M.; Mendell, Jerry R.; Sahenk, Zarife

doi:10.1038/s41434-021-00231-3

Cited by 30 publications

(33 citation statements)

References 33 publications

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“…Nerve conduction studies were performed on the right sciatic using a Nicolet Viasys Viking Select EMG EP System (Nicolet Biomedical, Wisconsin, USA); 27 G disposable needle electrodes were used for both stimulation and recording as described previously. 28 …”

Section: Methodsmentioning

confidence: 99%

“…Five randomly selected areas (one from the centre and four from each quadrant) were photographed at ×100 magnification and axon diameter measurements were obtained from the computer screen image frames using BioQuant Life Sciences imaging software as previously described (2014, V15.5.6; BioQuant Image Analysis Corporation, Nashville, Tennessee). 28 A total of 0.0502 mm 2 of endoneurial area per mouse was analysed. Composites of fibre size distribution histograms expressed as number per 0.01 mm 2 of endoneurial areas and mean myelinated fibre (MF) densities (mean ± SEM, number/0.1 mm 2 ) were generated.…”

Section: Methodsmentioning

confidence: 99%

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AAV1.NT-3 gene therapy in a CMT2D model: phenotypic improvements in GarsP278KY/+ mice

Özeş

Moss

Myers

et al. 2021

Brain Communications

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Glycyl tRNA synthetase (GARS) mutations are associated to the Charcot-Marie-Tooth type-2D. The GarsP278KY/+ model for Charcot-Marie-Tooth type-2D is known best for its early onset severe neuropathic phenotype with findings including reduced axon size, slow conduction velocities and abnormal neuromuscular junction. Muscle involvement remains largely unexamined. We tested the efficacy of neurotrophin 3 (NT-3) gene transfer therapy in two Gars mutants with severe (GarsP278KY/+) and milder (GarsΔETAQ/+) phenotypes via intramuscular injection of adeno-associated virus setoype-1, triple tandem muscle creatine kinase promoter, NT-3 (AAV1.tMCK.NT-3) at 1x1011 vg dose. In the GarsP278KY/+ mice, the treatment efficacy was assessed at 12 weeks post-injection using rotarod test, electrophysiology, and detailed quantitative histopathological studies of the peripheral nervous system including neuromuscular junction, and muscle. NT-3 gene transfer therapy in GarsP278KY/+ mice resulted in significant functional and electrophysiological improvements, supported with increases in myelin thickness and improvements in the denervated status of neuromuscular junctions as well as increases in muscle fiber size along with attenuation of myopathic changes. Improvements in the milder phenotype GarsΔETAQ/+ was less pronounced. Furthermore, oxidative enzyme histochemistry in muscles from Gars mutants revealed alterations in the content and distribution of oxidative enzymes with increased expression levels of Pgc1a. Cox1, Cox3 and Atp5d transcripts were significantly decreased suggesting that the muscle phenotype might be related to mitochondrial dysfunction. NT-3 gene therapy attenuated these abnormalities in muscle. This study shows that NT-3 gene transfer therapy has disease modifying effect in a mouse model for Charcot-Marie-Tooth type-2D, leading to meaningful improvements in peripheral nerve myelination and neuromuscular junction integrity as well as in a unique myopathic process, associated with mitochondria dysfunction, all in combination contributing to functional outcome. Based on the multiple biological effects of this versatile molecule, we predict NT-3 has the potential to be beneficial in other aminoacyl-tRNA synthetase (ARS)-linked CMT subtypes.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

AAV1.NT-3 gene therapy in a CMT2D model: phenotypic improvements in GarsP278KY/+ mice

Özeş

Moss

Myers

et al. 2021

Brain Communications

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“…Since both neurons as well as SCs targeted by CMT therapies are highly differentiated and not proliferating, the episomal persistence of AAVs without integration into the hosts’ genome will not affect the stability of the treatment. AAV vectors have been employed in promising preclinical research for treating CMT neuropathies either by expression of trophic factors or by targeting the responsible genes in neurons or SCs [ 29 , 30 , 31 , 32 , 33 , 34 ]. AAV1 is already used for a CMT1A clinical trial (NCT03520751), while other serotypes such as AAV9 have been clinically implemented for other neuromuscular diseases, most notably for spinal muscular atrophy (NCT03306277).…”

Section: Overview Of Therapeutic Approaches For Cmt Neuropathiesmentioning

confidence: 99%

“…Similarly to CMT1A (above), NT-3 was recently employed as a potential treatment also for CMT1X [ 33 ]. NT-3 based gene therapy of CMT1X, resulted in significant improvement of the demyelinating neuropathy in the pre-onset Gjb1 -null model as indicated by electrophysiological and morphological improvements.…”

Section: Emerging Treatments For Demyelinating Cmt Neuropathiesmentioning

confidence: 99%

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Emerging Therapies for Charcot-Marie-Tooth Inherited Neuropathies

Stavrou

Sargiannidou

Georgiou

et al. 2021

IJMS

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Inherited neuropathies known as Charcot-Marie-Tooth (CMT) disease are genetically heterogeneous disorders affecting the peripheral nerves, causing significant and slowly progressive disability over the lifespan. The discovery of their diverse molecular genetic mechanisms over the past three decades has provided the basis for developing a wide range of therapeutics, leading to an exciting era of finding treatments for this, until now, incurable group of diseases. Many treatment approaches, including gene silencing and gene replacement therapies, as well as small molecule treatments are currently in preclinical testing while several have also reached clinical trial stage. Some of the treatment approaches are disease-specific targeted to the unique disease mechanism of each CMT form, while other therapeutics target common pathways shared by several or all CMT types. As promising treatments reach the stage of clinical translation, optimal outcome measures, novel biomarkers and appropriate trial designs are crucial in order to facilitate successful testing and validation of novel treatments for CMT patients.

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Charcot‐Marie‐Tooth disease in children

Saylam,

Ramani,

Duvuru

et al. 2024

Annals of the Child Neurology Society

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Charcot‐Marie‐Tooth (CMT) disease represents a diverse group of inherited neuropathies with a broad spectrum of symptoms. It is the most prevalent inherited neuropathy, with an estimated prevalence ranging from 9.7 to 82 cases per 100,000 individuals. Despite this, CMT comprises only 118 of 853 inherited neuropathy entries in the Online Mendelian Inheritance in Man (OMIM) database. This comprehensive review offers a thorough examination of CMT's clinical features, subtypes, genetic underpinnings, and pathomechanisms in pediatric cases. CMT typically manifests as progressively worsening muscle weakness and atrophy, primarily affecting the distal extremities. Patients may also experience foot and ankle deformities, hand atrophy, and other systemic issues. To accurately diagnose CMT, a detailed family history, comprehensive clinical evaluation, nerve conduction studies, and relevant genetic testing are essential. Importantly, establishing a differential diagnosis is crucial during evaluation to rule out other conditions with similar presentations. This review aims to provide clinicians with a valuable resource for diagnosing and managing CMT, emphasizing the need for a streamlined and standardized approach considering advancements in genetic testing and the identification of various subtypes.

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AAV1.NT-3 gene therapy for X-linked Charcot–Marie–Tooth neuropathy type 1

Cited by 30 publications

References 33 publications

AAV1.NT-3 gene therapy in a CMT2D model: phenotypic improvements in GarsP278KY/+ mice

AAV1.NT-3 gene therapy in a CMT2D model: phenotypic improvements in GarsP278KY/+ mice

Emerging Therapies for Charcot-Marie-Tooth Inherited Neuropathies

Charcot‐Marie‐Tooth disease in children

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