This clinical trial is an open-label one-time injection dose study in which scAAV1.tMCK.NTF3 will be administered by intramuscular injections into muscles in both legs in CMT1A subjects with PMP22 gene duplication. Three subjects ages 18 to 35 years receiving (8.87e11 vg/kg) will be enrolled.

开始日期2025-04-01

申办/合作机构

Nationwide Children's Hospital

100 项与 scAAV1.tMCK.NTF3(Nationwide Children's Hospital) 相关的临床结果

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100 项与 scAAV1.tMCK.NTF3(Nationwide Children's Hospital) 相关的转化医学

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100 项与 scAAV1.tMCK.NTF3(Nationwide Children's Hospital) 相关的专利（医药）

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项与 scAAV1.tMCK.NTF3(Nationwide Children's Hospital) 相关的文献（医药）

2024-10-30·Brain Communications

AAV1.tMCK.NT-3 gene therapy improves phenotype in Sh3tc2−/− mouse model of Charcot–Marie–Tooth Type 4C

Article

作者: Moss, Kyle ; Morrison, Lilye ; Sahenk, Zarife ; Ozes, Burcak ; Attia, Zayed ; Tong, Lingying ; Myers, Morgan

AbstractCharcot–Marie–Tooth Type 4C (CMT4C) is associated with mutations in the SH3 domain and tetratricopeptide repeats 2 (SH3TC2) gene, primarily expressed in Schwann cells (SCs). Neurotrophin-3 (NT-3) is an important autocrine factor for SC survival and differentiation, and it stimulates neurite outgrowth and myelination. In this study, scAAV1.tMCK.NT-3 was delivered intramuscularly to 4-week-old Sh3tc2−/− mice, a model for CMT4C, and treatment efficacy was assessed at 6-month post-gene delivery. Efficient transgene production was verified with the detection of NT-3 in serum from the treated cohort. NT-3 gene therapy improved functional and electrophysiological outcomes including rotarod, grip strength and nerve conduction velocity. Qualitative and quantitative histopathological studies showed that hypomyelination of peripheral nerves and denervated status of neuromuscular junctions at lumbrical muscles were also improved in the NT-3-treated mice. Morphometric analysis in mid-sciatic and tibial nerves showed treatment-induced distally prominent regenerative activity in the nerve and an increase in the estimated SC density. This indicates that SC proliferation and differentiation, including the promyelination stage, are normal in the Sh3tc2−/− mice, consistent with the previous findings that Sh3tc2 is not involved in the early stages of myelination. Moreover, in size distribution histograms, the number of myelinated axons within the 3- to 6-µm diameter range increased, suggesting that treatment resulted in continuous radial growth of regenerating axons over time. In conclusion, this study demonstrates the efficacy of AAV1.NT-3 gene therapy in the Sh3tc2−/− mouse model of CMT4C, the most common recessively inherited demyelinating CMT subtype.

2022-04-01·Gene Therapy3区 · 医学

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

3区 · 医学

Article

作者: Sahenk, Zarife ; Moss, Kyle ; Freidin, Mona M ; Abrams, Charles K ; Chen, Lei ; Mckinney, Jennifer ; Ridgley, Alicia ; Myers, Morgan ; Ozes, Burcak ; Mendell, Jerry R ; Bai, Shasha

AbstractX-linked Charcot-Marie-Tooth neuropathy (CMTX) is caused by mutations in the gene encoding Gap Junction Protein Beta-1 (GJB1)/Connexin32 (Cx32) in Schwann cells. Neurotrophin-3 (NT-3) is an important autocrine factor supporting Schwann cell survival and differentiation and stimulating axon regeneration and myelination. Improvements in these parameters have been shown previously in a CMT1 model, TremblerJ mouse, with NT-3 gene transfer therapy. For this study, scAAV1.tMCK.NT-3 was delivered to the gastrocnemius muscle of 3-month-old Cx32 knockout (KO) mice. Measurable levels of NT-3 were found in the serum at 6-month post gene delivery. The outcome measures included functional, electrophysiological and histological assessments. At 9-months of age, NT-3 treated mice showed no functional decline with normalized compound muscle action potential amplitudes. Myelin thickness and nerve conduction velocity significantly improved compared with untreated cohort. A normalization toward age-matched wildtype histopathological parameters included increased number of Schmidt-Lanterman incisures, and muscle fiber diameter. Collectively, these findings suggest a translational application to CMTX1.

2021-11-01·Journal of Biomedical Materials Research Part A3区 · 工程技术

Surface modification of neurotrophin‐3 loaded PCL/chitosan nanofiber/net by alginate hydrogel microlayer for enhanced biocompatibility in neural tissue engineering

3区 · 工程技术

Article

作者: Mohammadi, Parvin ; Andalib, Sina ; Forouzideh, Narges ; Habibizadeh, Mina ; Fattahi, Ali ; Rostamizadeh, Kobra ; Nadri, Samad ; Hamidi, Mehrdad

AbstractThis study prepared a novel three‐dimensional nanocomposite scaffold by the surface modification of PCL/chitosan nanofiber/net with alginate hydrogel microlayer, hoping to have the privilege of both nanofibers and hydrogels simultaneously. Bead free randomly oriented nanofiber/net (NFN) structure composed of chitosan and polycaprolactone (PCL) was fabricated by electrospinning method. The low surface roughness, good hydrophilicity, and high porosity were obtained from the NFN structure. Then, the PCL/chitosan nanofiber/net was coated with a microlayer of alginate containing neurotrophin‐3 (NT‐3) and conjunctiva mesenchymal stem cells (CJMSCs) as a new stem cell source. According to the cross‐sectional FESEM, the scaffold shows a two‐layer structure with interconnected pores in the range of 20 μm diameter. The finding revealed that the surface modification of nanofiber/net by alginate hydrogel microlayer caused lower inflammatory response and higher proliferation of CJMSCs than the unmodified scaffold. The initial burst release of NT‐3 was 69% in 3 days which followed by a sustained release up to 21 days. The RT‐PCR analysis showed that the expression of Nestin, MAP‐2, and β‐tubulin III genes were increased 6, 5.4, and 8.8‐fold, respectively. The results revealed that the surface‐modified biomimetic scaffold possesses enhanced biocompatibility and could successfully differentiate CJMSCs to the neuron‐like cells.

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