192PGNT0004, Genethon's AAV-based gene therapy for Duchenne muscular dystrophy: long-term follow-up of ambulatory boys enrolled in the dose-escalation phase of GNT-016-MDYF

IF 2.8 4区医学 Q2 CLINICAL NEUROLOGY

Neuromuscular Disorders Pub Date : 2025-09-01 DOI:10.1016/j.nmd.2025.105545

V. Laugel , S. De Lucia , J. Davion , N. Daniele , F. Cao , M. Sanz , L. BUSCARA , S. Blaie , L. Thibaut , M. Sagot , A. Riviere , E. Creoff , M. Lelait , A. Valent , G. Perret , S. Braun , F. Muntoni

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Abstract

GNT0004 is an AAV-8 based gene therapy, containing a shortened functional dystrophin gene (hMD1) with a Spc5.12 promoter, targeting skeletal and cardiac muscles for treating Duchenne muscular dystrophy (DMD). GNT0004 is being evaluated in the international all-in-one (phase 1/2/3) clinical trial GNT-016-MDYF, including a first-in-human dose escalation (Part 1), a placebo-controlled pivotal Phase 3 (Part 2), and a long-term follow-up (Part 3). Ambulatory boys with DMD, aged 6 to 10 years, with a stable or early decline in their North Star Ambulatory Assessment (NSAA) score are included. Participants are on stable corticosteroid treatment and have been followed for at least 6 months in the natural history (NH) study GNT-014-MDYF. Long-term data from Part 1 patients receiving Dose 2 (3 × 10¹³ vg/kg, selected for Part 2) are presented. A comparison with an external control group from the NH study was conducted to explore clinical efficacy. Five patients were enrolled in Part 1, three of whom received Dose 2. At week 8, biopsy results showed a mean of 53% hMD1-positive fibers at Dose 2. A significant decrease in serum creatine kinase (CK) levels was observed post-dose that remains persistently low from week 8 and up to 2 years. At one year, the mean CK level was 5,306 IU/L, representing a mean decrease of -68% compared to baseline (mean: 19,175 IU/L). Clinically, functional outcomes were stable or improving, clearly differentiating from the NH progression across all efficacy parameters (e.g., a delta of 4.7-point on NSAA scale and of 0.1 m/s on the Stride velocity 95th centile (SV95C) at one year). No serious adverse events reported at Dose 2. GNT0004 at Dose 2 was well-tolerated and provided long-term stabilization of the sarcolemma, as evidenced by persistent low levels of CK, with a clear clinical benefit. These effects will need to be confirmed in Part 2 with 64 DMD patients to be enrolled.

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192PGNT0004， Genethon基于aav的杜氏肌营养不良基因治疗：对GNT-016-MDYF剂量递增阶段的流动男孩的长期随访

GNT0004是一种基于AAV-8的基因疗法，含有一个缩短的功能性肌营养不良蛋白基因（hMD1），其启动子为Spc5.12，靶向骨骼肌和心肌治疗杜氏肌营养不良症（DMD）。GNT0004正在国际一体化（1/2/3期）临床试验GNT-016-MDYF中进行评估，包括首次人体剂量递增（第1部分）、安慰剂对照关键3期（第2部分）和长期随访（第3部分）。包括6至10岁的DMD流动男孩，其北星流动评估（NSAA）评分稳定或早期下降。参与者接受稳定的皮质类固醇治疗，并在自然历史（NH）研究GNT-014-MDYF中随访至少6个月。本文给出了第1部分接受剂量2（3 × 10¹³vg/kg，为第2部分选择）患者的长期数据。并与NH研究的外部对照组进行比较，探讨临床疗效。第一部分纳入了5名患者，其中3名接受了剂量2。在第8周，活检结果显示，剂量2时平均53%的hmd1阳性纤维。在给药后观察到血清肌酸激酶（CK）水平显著降低，从第8周到2年持续保持低水平。一年后，平均CK水平为5,306 IU/L，与基线（平均值：19,175 IU/L）相比，平均下降了-68%。临床上，功能结果稳定或改善，在所有疗效参数上与NH进展明显不同（例如，NSAA量表上的delta为4.7点，一年内步幅速度第95百分位（SV95C）为0.1 m/s）。剂量2未报告严重不良事件。2剂量的GNT0004耐受性良好，并提供了长期的肌膜稳定，证明了持续低水平的CK，具有明显的临床益处。这些效果需要在第2部分的64名DMD患者中得到证实。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neuromuscular Disorders 医学-临床神经学

CiteScore

4.60

自引率

3.60%

发文量

543

审稿时长

53 days

期刊介绍： This international, multidisciplinary journal covers all aspects of neuromuscular disorders in childhood and adult life (including the muscular dystrophies, spinal muscular atrophies, hereditary neuropathies, congenital myopathies, myasthenias, myotonic syndromes, metabolic myopathies and inflammatory myopathies). The Editors welcome original articles from all areas of the field: • Clinical aspects, such as new clinical entities, case studies of interest, treatment, management and rehabilitation (including biomechanics, orthotic design and surgery). • Basic scientific studies of relevance to the clinical syndromes, including advances in the fields of molecular biology and genetics. • Studies of animal models relevant to the human diseases. The journal is aimed at a wide range of clinicians, pathologists, associated paramedical professionals and clinical and basic scientists with an interest in the study of neuromuscular disorders.