BACKGROUND Danon disease is a rare, X-linked, monogenic cardiomyopathy caused by mutations in the lysosomal-associated membrane 2 gene (LAMP2), which encodes the LAMP2 protein. In male patients, the predominant phenotype is progressive cardiac hypertrophy, cardiac dysfunction, and early death. There are no directed therapies for the disease. METHODS In this phase 1 study, we evaluated the safety and efficacy of a single infusion of RP-A501, a recombinant adeno-associated virus serotype 9 containing the transgene LAMP2B, which encodes an isoform of LAMP2. The primary outcomes were the safety and toxic effects of RP-A501, myocardial LAMP2 transduction and protein expression, stabilization of or reduction in heart-failure symptoms, and stabilization of or improvement in cardiac structure and function. Key secondary outcomes were sustained reduction in or stabilization of symptoms, immunologic response to RP-A501, end-stage heart failure, and overall survival. Exploratory outcomes included improvement in serologic markers of cardiac disease, patient-reported outcomes, and quality-of-life assessments. RESULTS RP-A501 infusion was administered to seven male patients with Danon disease: five who were 15 years of age or older and two who were between 11 and 14 years of age. All the patients received a transient immunomodulatory regimen of prednisone, tacrolimus or sirolimus, and rituximab. Phase 1 data over 24 to 54 months, including interim data from a long-term follow-up study, are reported here. One patient had complement-mediated thrombotic microangiopathy (grade 4) with thrombocytopenia and acute kidney injury. Three patients had glucocorticoid-related exacerbation (grade 3) of Danon disease-related skeletal myopathy. One patient with left ventricular systolic dysfunction at baseline had progressive heart failure and underwent transplantation 5 months after infusion. In the six patients with normal left ventricular ejection fraction at baseline, we observed cardiac LAMP2 protein expression and a reduction from baseline in or stabilization of the left ventricular mass index, preservation of left ventricular ejection fraction, and reduction in or stabilization of the levels of cardiac troponin I and N-terminal pro-B-type natriuretic peptide. At 24 to 54 months, all the patients were alive, with complete resolution of side effects. CONCLUSIONS A single infusion of RP-A501 appeared to be safe and was associated with cardiac LAMP2 expression and evidence of clinical improvement over a period of 24 to 54 months. (Funded by Rocket Pharmaceuticals; ClinicalTrials.gov number, NCT03882437.).

中文翻译：

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AAV9 的 1 期研究。Danon 病中的 LAMP2B 基因治疗。


背景 Danon 病是一种罕见的 X 连锁单基因心肌病，由编码 LAMP2 蛋白的溶酶体相关膜 2 基因 （LAMP2） 突变引起。在男性患者中，主要表型是进行性心脏肥大、心功能不全和早逝。没有针对该疾病的定向疗法。方法 在这项 1 期研究中，我们评估了单次输注 RP-A501 的安全性和有效性，RP-A501 是一种重组腺相关病毒血清型 9，含有编码 LAMP2 亚型的转基因 LAMP2B。主要结局是 RP-A501 的安全性和毒性作用、心肌 LAMP2 转导和蛋白表达、心力衰竭症状的稳定或减轻，以及心脏结构和功能的稳定或改善。关键的次要结局是症状的持续减轻或稳定、对 RP-A501 的免疫反应、终末期心力衰竭和总生存期。探索性结局包括心脏病血清学标志物的改善、患者报告的结局和生活质量评估。结果 RP-A501 输注对 7 名男性 Danon 病患者进行输注： 5 名年龄在 15 岁或以上，2 名年龄在 11 至 14 岁之间。所有患者都接受了泼尼松、他克莫司或西罗莫司和利妥昔单抗的瞬时免疫调节方案。此处报告了 24 至 54 个月的 1 期数据，包括来自长期随访研究的中期数据。1 例患者患有补体介导的血栓性微血管病 （4 级），伴有血小板减少症和急性肾损伤。3 例患者出现 Danon 病相关骨骼肌病的糖皮质激素相关加重 （3 级）。 1 例基线时左心室收缩功能障碍的患者患有进行性心力衰竭，输注后 5 个月接受了移植。在基线时左心室射血分数正常的 6 例患者中，我们观察到心脏 LAMP2 蛋白表达和左心室质量指数从基线降低或稳定，左心室射血分数保留，心肌肌钙蛋白 I 和 N 末端 B 型利钠肽前体水平降低或稳定。在 24 至 54 个月时，所有患者都存活，副作用完全消退。结论 单次输注 RP-A501 似乎是安全的，并且在 24 至 54 个月的时间内与心脏 LAMP2 表达和临床改善的证据相关。（由 Rocket Pharmaceuticals 资助;ClinicalTrials.gov 号，NCT03882437 号）。