Enzyme replacement in the CSF to treat metachromatic leukodystrophy in mouse model using single intracerebroventricular injection of self-complementary AAV1 vector.
Enzyme replacement in the CSF to treat metachromatic leukodystrophy in mouse model using single intracerebroventricular injection of self-complementary AAV1 vector.
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DOI：
10.1038/srep13104
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发表时间：
2015-08-18
影响因子：
4.6
通讯作者：
Shimada T
中科院分区：
文献类型：
--
作者：
Hironaka K;Yamazaki Y;Hirai Y;Yamamoto M;Miyake N;Miyake K;Okada T;Morita A;Shimada T
异染性脑白质营养不良（MLD）是由人芳基硫酸酯酶A（hASA）的功能缺陷引起的溶酶体储存疾病。我们最近报道，室管膜细胞和脉络丛的选择性转导脑室内（ICV）注射腺相关病毒血清型1（AAV 1）载体，并作为一个生物水库分泌溶酶体酶到脑脊液（CSF）。在本研究中，我们研究了这种AAV介导的基因治疗治疗MLD模型小鼠的可行性。初步实验显示，ICV注射自身互补（sc）AAV 1后CSF中的hASA水平远高于注射单链AAV 1或scAAV 9的小鼠。然而，当用scAAV 1的ICV注射处理18周龄MLD小鼠时，CSF中的hASA浓度逐渐降低，并且在注射后12周时检测不到，这可能是由于抗hASA抗体的产生。结果，与未治疗的MLD小鼠相比，治疗的MLD小鼠脑组织中的硫苷脂水平仅略有降低。这些结果表明，这种方法对于治疗MLD是潜在有希望的，但是控制免疫应答对于CSF中治疗性蛋白质的长期表达似乎是至关重要的。
Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by a functional deficiency in human arylsulfatase A (hASA). We recently reported that ependymal cells and the choroid plexus are selectively transduced by intracerebroventricular (ICV) injection of adeno-associated virus serotype 1 (AAV1) vector and serve as a biological reservoir for the secretion of lysosomal enzymes into the cerebrospinal fluid (CSF). In the present study, we examined the feasibility of this AAV-mediated gene therapy to treat MLD model mice. Preliminary experiments showed that the hASA level in the CSF after ICV injection of self-complementary (sc) AAV1 was much higher than in mice injected with single-stranded AAV1 or scAAV9. However, when 18-week-old MLD mice were treated with ICV injection of scAAV1, the concentration of hASA in the CSF gradually decreased and was not detectable at 12 weeks after injection, probably due to the development of anti-hASA antibodies. As a result, the sulfatide levels in brain tissues of treated MLD mice were only slightly reduced compared with those of untreated MLD mice. These results suggest that this approach is potentially promising for treating MLD, but that controlling the immune response appears to be crucial for long-term expression of therapeutic proteins in the CSF.