Neonatal brain-directed gene therapy rescues a mouse model of neurodegenerative CLN6 Batten disease
Neonatal brain-directed gene therapy rescues a mouse model of neurodegenerative CLN6 Batten disease
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新生儿大脑定向基因治疗拯救神经退行性 CLN6 Batten 病小鼠模型
DOI：
10.1101/673848
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Holthaus S
中科院分区：
文献类型：
--
作者：
Holthaus S
神经元蜡样质脂褐质沉积症（NCL），更常被称为Batten病，是一组遗传性溶酶体贮积症，表现为神经变性、视力丧失和过早死亡。至少有13种遗传上不同的NCL形式。酶替代疗法和基因补充的临床前研究已显示出对溶酶体酶缺乏引起的NCL有希望的结果。针对跨膜蛋白缺陷引起的脑NCL的基因疗法的开发更具挑战性，迄今为止在动物模型中仅实现了有限的治疗效果。在这里，我们描述了一种腺相关病毒（AAV）介导的基因疗法的发展，以治疗神经退行性病变的小鼠模型CLN6疾病，一种形式的NCL与膜结合蛋白CLN6的缺陷。我们表明，新生儿双侧脑室内注射携带CLN6的AAV9可使寿命延长90%以上，维持运动技能和运动协调性，并在载体给药后23个月内减少Cln6缺陷小鼠的神经病理学标志。这些数据表明，脑定向基因治疗是治疗CLN6疾病神经退行性变的有效策略，并可能在未来应用于由跨膜蛋白缺陷引起的其他形式的NCL。
The neuronal ceroid lipofuscinoses (NCLs), more commonly referred to as Batten disease, are a group of inherited lysosomal storage disorders that present with neurodegeneration, loss of vision and premature death. There are at least 13 genetically distinct forms of NCL. Enzyme replacement therapies and pre-clinical studies on gene supplementation have shown promising results for NCLs caused by lysosomal enzyme deficiencies. The development of gene therapies targeting the brain for NCLs caused by defects in transmembrane proteins has been more challenging and only limited therapeutic effects in animal models have been achieved so far. Here, we describe the development of an adeno-associated virus (AAV)-mediated gene therapy to treat the neurodegeneration in a mouse model of CLN6 disease, a form of NCL with a deficiency in the membrane-bound protein CLN6. We show that neonatal bilateral intracerebroventricular injections with AAV9 carryingCLN6increase lifespan by more than 90%, maintain motor skills and motor coordination and reduce neuropathological hallmarks ofCln6-deficient mice up to 23 months post vector administration. These data demonstrate that brain-directed gene therapy is a valid strategy to treat the neurodegeneration of CLN6 disease and may be applied to other forms of NCL caused by transmembrane protein deficiencies in the future.
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影响因子：
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