Evaluation of an AAV9-mini-dystrophin gene therapy candidate in a rat model of Duchenne muscular dystrophy,Molecular Therapy - Methods & Clinical Development

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Evaluation of an AAV9-mini-dystrophin gene therapy candidate in a rat model of Duchenne muscular dystrophy
Molecular Therapy - Methods & Clinical Development ( IF 4.6 ) Pub Date : 2023-05-18 , DOI: 10.1016/j.omtm.2023.05.017
Caroline Le Guiner ₁ , Xiao Xiao ₂ , Thibaut Larcher ₃ , Aude Lafoux ₄ , Corinne Huchet _{1,

4} , Gilles Toumaniantz _{4,

5} , Oumeya Adjali ₁ , Ignacio Anegon ₆ , Séverine Remy ₆ , Josh Grieger ₇ , Juan Li ₈ , Vahid Farrokhi ₉ , Hendrik Neubert ₉ , Jane Owens ₁₀ , Maritza McIntyre ₇ , Philippe Moullier ₁ , R Jude Samulski ₂

Affiliation

Duchenne muscular dystrophy (DMD) is an X-linked disease caused by loss-of-function mutations in the gene and is characterized by muscle wasting and early mortality. Adeno-associated virus-mediated gene therapy is being investigated as a treatment for DMD. In the nonclinical study documented here, we determined the effective dose of fordadistrogene movaparvovec, a clinical candidate adeno-associated virus serotype 9 vector carrying a human mini-dystrophin transgene, after single intravenous injection in a dystrophin-deficient (DMD) rat model of DMD. Overall, we found that transduction efficiency, number of muscle fibers expressing the human mini-dystrophin polypeptide, improvement of the skeletal and cardiac muscle tissue architecture, correction of muscle strength and fatigability, and improvement of diastolic and systolic cardiac function were directly correlated with the amount of vector administered. The effective dose was then tested in older DMD rats with a more dystrophic phenotype similar to the pathology observed in older patients with DMD. Except for a less complete rescue of muscle function in the oldest cohort, fordadistrogene movaparvovec was also found to be therapeutically effective in older DMD rats, suggesting that this product may be appropriate for evaluation in patients with DMD at all stages of disease.

中文翻译：

在杜氏肌营养不良症大鼠模型中评估 AAV9-微型肌营养不良蛋白基因治疗候选药物

杜氏肌营养不良症 (DMD) 是一种由基因功能丧失突变引起的 X 连锁疾病，其特征是肌肉萎缩和早期死亡。腺相关病毒介导的基因疗法正在研究作为 DMD 的治疗方法。在此记录的非临床研究中，我们在肌营养不良蛋白缺陷 (DMD) 大鼠模型中进行单次静脉注射后，确定了 fordadistrogene movaparvovec（一种携带人微型肌营养不良蛋白转基因的临床候选腺相关病毒血清型 9 载体）的有效剂量。。总体而言，我们发现转导效率、表达人微型肌营养不良蛋白多肽的肌纤维数量、骨骼和心肌组织结构的改善、肌肉力量和疲劳性的校正以及舒张和收缩心脏功能的改善与施用的载体的量。然后在老年 DMD 大鼠中测试有效剂量，这些大鼠的营养不良表型与老年 DMD 患者中观察到的病理相似。除了在最古老的队列中对肌肉功能的挽救不太完全外，还发现 fordadistrogene movaparvovec 对老年 DMD 大鼠具有治疗效果，这表明该产品可能适合于对处于疾病各个阶段的 DMD 患者进行评估。

更新日期：2023-05-18

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