Gene therapy of the brain in the dog model of Hurler's syndrome
Gene therapy of the brain in the dog model of Hurler's syndrome
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DOI：
10.1002/ana.20870
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发表时间：
2006-08-01
影响因子：
11.2
通讯作者：
Heard, Jean-Michel
中科院分区：
文献类型：
--
作者：
Ciron, Carine;Desmaris, Nathalie;Heard, Jean-Michel
目的：溶酶体酶α-L-艾杜糖醛酸酶（IDUA）的缺陷中断了I型粘多糖沉积症中糖胺聚糖的降解，导致Hurler综合征患儿出现严重的神经系统表现。通过立体定向注射编码IDUA的腺相关病毒载体来递送缺失的酶可预防受影响小鼠的神经病理学。我们研究了这种方法在酶缺乏dogs.Methods的有效性和安全性：由于缺乏犬提高抗体IDUA在输液反应，脑内载体注射相结合的免疫抑制regimeneration.Results：治疗耐受性良好。我们观察到载体基因组在有效免疫抑制狗的大脑中广泛分布。将IDUA递送至大面积（可覆盖整个大脑）可防止糖胺聚糖和继发性神经节苷脂蓄积。这种情况与整个脑的神经病理学急剧减少有关。与此相反，载体注射结合部分免疫抑制与亚急性脑炎，生产抗IDUA抗体在脑组织中，并消除转基因celles.Interpretation：基因治疗针对整个大脑是可行的，可能是有益的儿童赫尔勒综合征。亚急性脑炎的可能性强调了预防针对IDUA的免疫反应的重要性，这是在其他遗传缺陷的类似治疗中需要考虑的问题。
Objective: A defect of the lysosomal enzyme alpha-L-iduronidase (IDUA) interrupts the degradation of glycosaminoglycans in mucopolysaccharidosis type I, causing severe neurological manifestations in children with Hurler's syndrome. Delivery of the missing enzyme through stereotactic injection of adeno-associated virus vectors coding for IDUA prevents neuropathology in affected mice. We examined the efficacy and the safety of this approach in enzyme-deficient dogs.Methods: Because deficient dogs raise antibodies against IDUA in response to infusion, intracerebral vector injections were combined with an immunosuppressive regimen.Results: Treatment was tolerated well. We observed broad dispersion of vector genomes in the brain of efficiently immuno-suppressed dogs. The delivery of IDUA to large areas, which could encompass the entire brain, prevented glycosaminoglycan and secondary ganglioside accumulations. This condition was associated with drastic reduction of neuropathology throughout the encephalon. In contrast, vector injection combined with partial immunosuppression was associated with subacute encephalitis, production of antibodies against IDUA in brain tissues, and elimination of genetically modified cells.Interpretation: Gene therapy directed to the entire brain is feasible and may be beneficial to children with Hurler's syndrome. The possibility of subacute encephalitis emphasizes the importance of preventing immune response against IDUA, a problem that needs to be considered in similar therapies for other genetic defects.