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Abstract：
BACKGROUND: X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital muscle disease caused by mutations in the MTM1 gene that result in profound muscle weakness, significant respiratory insufficiency, and high infant mortality. There is no approved disease-modifying therapy for XLMTM. Resamirigene bilparvovec (AT132; rAAV8-Des-hMTM1) is an investigational adeno-associated virus (AAV8)-mediated gene replacement therapy designed to deliver MTM1 to skeletal muscle cells and achieve long-term correction of XLMTM-related muscle pathology. The clinical trial ASPIRO (NCT03199469) investigating resamirigene bilparvovec in XLMTM is currently paused while the risk:benefit balance associated with this gene therapy is further investigated.
METHODS: Muscle biopsies were taken before treatment and 24 and 48 weeks after treatment from ten boys with XLMTM in a clinical trial of resamirigene bilparvovec (ASPIRO; NCT03199469). Comprehensive histopathological analysis was performed.
RESULTS: Baseline biopsies uniformly showed findings characteristic of XLMTM, including small myofibres, increased internal or central nucleation, and central aggregates of organelles. Biopsies taken at 24 weeks post-treatment showed marked improvement of organelle localisation, without apparent increases in myofibre size in most participants. Biopsies taken at 48 weeks, however, did show statistically significant increases in myofibre size in all nine biopsies evaluated at this timepoint. Histopathological endpoints that did not demonstrate statistically significant changes with treatment included the degree of internal/central nucleation, numbers of triad structures, fibre type distributions, and numbers of satellite cells. Limited (predominantly mild) treatment-associated inflammatory changes were seen in biopsy specimens from five participants.
CONCLUSIONS: Muscle biopsies from individuals with XLMTM treated with resamirigene bilparvovec display statistically significant improvement in organelle localisation and myofibre size during a period of substantial improvements in muscle strength and respiratory function. This study identifies valuable histological endpoints for tracking treatment-related gains with resamirigene bilparvovec, as well as endpoints that did not show strong correlation with clinical improvement in this human study.
BACKGROUND: Astellas Gene Therapies (formerly Audentes Therapeutics, Inc.).
METHODS: Muscle biopsies were taken before treatment and 24 and 48 weeks after treatment from ten boys with XLMTM in a clinical trial of resamirigene bilparvovec (ASPIRO; NCT03199469). Comprehensive histopathological analysis was performed.
RESULTS: Baseline biopsies uniformly showed findings characteristic of XLMTM, including small myofibres, increased internal or central nucleation, and central aggregates of organelles. Biopsies taken at 24 weeks post-treatment showed marked improvement of organelle localisation, without apparent increases in myofibre size in most participants. Biopsies taken at 48 weeks, however, did show statistically significant increases in myofibre size in all nine biopsies evaluated at this timepoint. Histopathological endpoints that did not demonstrate statistically significant changes with treatment included the degree of internal/central nucleation, numbers of triad structures, fibre type distributions, and numbers of satellite cells. Limited (predominantly mild) treatment-associated inflammatory changes were seen in biopsy specimens from five participants.
CONCLUSIONS: Muscle biopsies from individuals with XLMTM treated with resamirigene bilparvovec display statistically significant improvement in organelle localisation and myofibre size during a period of substantial improvements in muscle strength and respiratory function. This study identifies valuable histological endpoints for tracking treatment-related gains with resamirigene bilparvovec, as well as endpoints that did not show strong correlation with clinical improvement in this human study.
BACKGROUND: Astellas Gene Therapies (formerly Audentes Therapeutics, Inc.).
摘要：
背景：X连锁肌管肌病（XLMTM）是一种罕见的，由MTM1基因突变引起的危及生命的先天性肌肉疾病，导致严重的肌肉无力，显著呼吸功能不全,婴儿死亡率高。没有批准的XLMTM疾病改善疗法。Resamirigenebilparvovec（AT132;rAAV8-Des-hMTM1）是一种研究性腺相关病毒（AAV8）介导的基因替代疗法，旨在将MTM1递送至骨骼肌细胞并实现XLMTM相关肌肉病理的长期校正。研究XLMTM中的resamirigenebilparvovovec的临床试验ASPIRO（NCT03199469）目前已暂停，同时进一步研究了与该基因疗法相关的风险：收益平衡。
方法：在治疗前和治疗后24周和48周，对10名XLMTM男孩进行了肌肉活检，该研究是在resamirigenebilparvovec（ASPIRO;NCT03199469）的临床试验中进行的。进行了全面的组织病理学分析。
结果：基线活检均显示XLMTM的特征性发现，包括小肌纤维，增加内部或中心成核，和细胞器的中央聚集体。治疗后24周的活检显示细胞器定位明显改善，大多数参与者的肌纤维大小没有明显增加。48周时做的活检,然而,在该时间点评估的所有9例活检中，肌纤维大小均显示出统计学上的显着增加。组织病理学终点没有显示出统计学上显著的变化与治疗包括内部/中央成核的程度，三合会结构的数量，纤维类型分布，和卫星细胞的数量。在五名参与者的活检标本中观察到有限的（主要是轻度的）治疗相关的炎症变化。
结论：在肌肉力量和呼吸功能的显著改善期间，来自XLMTM患者的肌肉活检显示出细胞器定位和肌纤维大小的统计学显著改善。这项研究确定了有价值的组织学终点，用于追踪与治疗相关的增益，以及在这项人体研究中与临床改善没有强相关性的终点。
背景：Astellas基因疗法(前身为AudentesTherapeutics，Inc.).
方法：在治疗前和治疗后24周和48周，对10名XLMTM男孩进行了肌肉活检，该研究是在resamirigenebilparvovec（ASPIRO;NCT03199469）的临床试验中进行的。进行了全面的组织病理学分析。
结果：基线活检均显示XLMTM的特征性发现，包括小肌纤维，增加内部或中心成核，和细胞器的中央聚集体。治疗后24周的活检显示细胞器定位明显改善，大多数参与者的肌纤维大小没有明显增加。48周时做的活检,然而,在该时间点评估的所有9例活检中，肌纤维大小均显示出统计学上的显着增加。组织病理学终点没有显示出统计学上显著的变化与治疗包括内部/中央成核的程度，三合会结构的数量，纤维类型分布，和卫星细胞的数量。在五名参与者的活检标本中观察到有限的（主要是轻度的）治疗相关的炎症变化。
结论：在肌肉力量和呼吸功能的显著改善期间，来自XLMTM患者的肌肉活检显示出细胞器定位和肌纤维大小的统计学显著改善。这项研究确定了有价值的组织学终点，用于追踪与治疗相关的增益，以及在这项人体研究中与临床改善没有强相关性的终点。
背景：Astellas基因疗法(前身为AudentesTherapeutics，Inc.).
