Neonatal Systemic AAV Induces Tolerance to CNS Gene Therapy in MPS I Dogs and Nonhuman Primates
Neonatal Systemic AAV Induces Tolerance to CNS Gene Therapy in MPS I Dogs and Nonhuman Primates
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DOI：
10.1038/mt.2015.99
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发表时间：
2015-08-01
影响因子：
12.4
通讯作者：
Wilson, James M.
中科院分区：
文献类型：
--
作者：
Hinderer, Christian;Bell, Peter;Wilson, James M.
宿主对非自身蛋白的潜在免疫反应对针对隐性疾病的基因治疗提出了根本性的挑战。我们在狗和非人灵长类动物中证明，使用腺相关病毒（AAV）载体在新生儿中进行肝脏定向基因转移可诱导对转基因产物的持续免疫耐受状态，从而大大提高随后靶向中枢神经系统（CNS）的载体给药的效果。我们将这种方法应用于粘多糖病I型（MPS I）犬模型，这是一种由酶α -l-伊杜糖醛酸酶（IDUA）活性不足引起的进行性神经性溶酶体贮积病。MPS I犬在出生后第一周用表达犬IDUA的载体进行系统治疗，没有产生针对该酶的抗体，并且在1月龄时鞘内AAV递送时在中枢神经系统中表现出强劲的表达，导致脑储存病变完全纠正。用表达人IDUA的AAV载体对新生恒河猴进行系统治疗后，新生恒河猴对转基因产生了耐受性，导致脑脊液（CSF）中IDUA的高表达，并且在随后的CNS基因治疗后无抗体诱导。这些发现表明，在免疫发育的关键时期诱导对转基因产物的耐受性可以提高基因治疗的有效性和安全性。
The potential host immune response to a nonself protein poses a fundamental challenge for gene therapies targeting recessive diseases. We demonstrate in both dogs and nonhuman primates that liver-directed gene transfer using an adeno-associated virus (AAV) vector in neonates induces a persistent state of immunological tolerance to the transgene product, substantially improving the efficacy of subsequent vector administration targeting the central nervous system (CNS). We applied this approach to a canine model of mucopolysaccharidosis type I (MPS I), a progressive neuropathic lysosomal storage disease caused by deficient activity of the enzyme alpha-l-iduronidase (IDUA). MPS I dogs treated systemically in the first week of life with a vector expressing canine IDUA did not develop antibodies against the enzyme and exhibited robust expression in the CNS upon intrathecal AAV delivery at 1 month of age, resulting in complete correction of brain storage lesions. Newborn rhesus monkeys treated systemically with AAV vector expressing human IDUA developed tolerance to the transgene, resulting in high cerebrospinal fluid (CSF) IDUA expression and no antibody induction after subsequent CNS gene therapy. These findings suggest that inducing tolerance to the transgene product during a critical period in immunological development can improve the efficacy and safety of gene therapy.