Gene replacement therapy is a rational therapeutic strategy and clinical intervention for neurodegenerative disorders like Canavan disease, a leukodystrophy caused by biallelic mutations in the aspartoacylase () gene. We aimed to investigate whether simultaneous intravenous (i.v.) and intracerebroventricular (i.c.v.) administration of rAAV9-CB6-ASPA provides a safe and effective therapeutic strategy in an open-label, individual-patient, expanded-access trial for Canavan disease. Immunomodulation was given prophylactically prior to adeno-associated virus (AAV) treatment to prevent an immune response to ASPA or the vector capsid. The patient served as his own control, and change from baseline was assessed by clinical pathology tests, vector genomes in the blood, antibodies against ASPA and AAV capsids, levels of cerebrospinal fluid (CSF) -acetylaspartate (NAA), brain water content and morphology, clinical status, and motor function tests. Two years post treatment, the patient’s white matter myelination had increased, motor function was improved, and he remained free of typical severe epilepsy. NAA level was reduced at 3 months and remained stable up to 4 years post treatment. Immunomodulation prior to AAV exposure enables repeat dosing and has prevented an anti-transgene immune response. Dual-route administration of gene therapy may improve treatment outcomes.

中文翻译：

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使用双重给药途径和免疫调节对卡纳万病患者进行腺相关病毒介导的基因治疗

基因替代疗法是针对卡纳万病等神经退行性疾病的合理治疗策略和临床干预，卡纳万病是一种由天冬氨酸酰化酶 () 基因双等位基因突变引起的脑白质营养不良。我们的目的是调查 rAAV9-CB6-ASPA 同时静脉 (iv) 和脑室内 (icv) 给药是否可以在卡纳万病的开放标签、个体患者、扩大访问试验中提供安全有效的治疗策略。在腺相关病毒 (AAV) 治疗之前预防性进行免疫调节，以防止对 ASPA 或载体衣壳的免疫反应。患者作为自己的对照，通过临床病理学测试、血液中的载体基因组、抗 ASPA 和 AAV 衣壳的抗体、脑脊液 (CSF) - 乙酰天冬氨酸 (NAA) 水平、脑含水量和形态来评估相对于基线的变化、临床状态和运动功能测试。治疗两年后，患者的白质髓鞘形成增加，运动功能改善，并且没有出现典型的严重癫痫。 NAA 水平在治疗后 3 个月时降低，并在治疗后 4 年内保持稳定。 AAV 暴露前的免疫调节可以重复给药，并防止抗转基因免疫反应。基因治疗的双途径给药可以改善治疗结果。