静脉基因治疗改善 Sandhoff 病猫模型的寿命与临床结局
Intravenous gene therapy improves life span and clinical outcomes in a feline model of Sandhoff disease
Sandhoff 病是一种因 β-氨基己糖苷酶缺乏导致 GM2 神经节苷脂在溶酶体中蓄积的致死性神经退行性疾病。此前已有通过脑内和脑脊液途径递送 AAV 基因治疗用于患儿的扩展可及和 1/2 期试验；本研究改为静脉给药，在症状出现前（1 月龄）治疗 Sandhoff 病猫模型。未治疗猫存活 4.3±0.2 个月，低剂量和高剂量治疗组分别存活 8.3±1.2 和 12.4±2.7 个月，呈剂量依赖效果。治疗还减少了脑脊液和血清中中枢神经损伤标志物，影像学显示结构病理部分恢复，GM2 蓄积减少、酶活性回升。该结果支持静脉途径基因治疗向患者转化。
为什么推荐给您：首次验证静脉途径AAV基因治疗在Sandhoff病大型动物模型中剂量依赖性延长寿命，支持新给药途径的临床转化
不需要生物学背景，多打比方
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摘要Abstract
Sandhoff disease (SD) is a fatal neurodegenerative disorder caused by the absence of β-N-acetylhexosaminidase (Hex) and subsequent accumulation of GM2 ganglioside in lysosomes. Previous studies have led to the development of an adeno-associated virus (AAV) vector-delivered gene therapy for children with GM2 gangliosidosis in both expanded access and phase 1/2 clinical trials through intrathalamic and cerebrospinal fluid-based delivery. This study investigated intravenous delivery of a bicistronic AAV vector-based gene therapy that has not yet been tested in clinical trials to a feline model of SD, treated presymptomatically at 1 month of age. Whereas untreated SD cats lived to 4.3 ± 0.2 months, SD cats treated with low or high doses of the gene therapy lived to 8.3 ± 1.2 or 12.4 ± 2.7 months, respectively. In-life assessments revealed a clinical benefit of AAV treatment, with marked improvements seen in the prevention of overt full-body tremors; cerebrospinal fluid and serum markers of central nervous system damage were also reduced. Magnetic resonance imaging and spectroscopy indicated that the structural pathology and metabolite abnormalities seen in untreated SD cats were partially normalized by treatment. Ultrasound elastography showed improvement in the livers of cats in the high-dose treatment group. Dose-dependent reductions of GM2 ganglioside storage and increases in Hex activity were documented, associated with reduced neuroinflammatory cell populations and partial correction of myelin deficits. These data support the dose-dependent efficacy of intravenous-delivered gene therapy for restoration of Hex activity and preservation of clinical metrics, supporting potential for translation to patients with SD.