Improved behavior and neuropathology in the mouse model of Sanfilippo type IIIB disease after adeno-associated virus-mediated gene transfer in the striatum
Improved behavior and neuropathology in the mouse model of Sanfilippo type IIIB disease after adeno-associated virus-mediated gene transfer in the striatum
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DOI：
10.1523/jneurosci.3558-04.2004
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发表时间：
2004-11-10
影响因子：
5.3
通讯作者：
Heard, JM
中科院分区：
文献类型：
--
作者：
Cressant, A;Desmaris, N;Heard, JM
Sanfilippo综合征是由溶酶体酶缺陷中断硫酸乙酰肝素降解途径引起的粘多糖样变性（MPS）。受影响的儿童发展多动症，侵略性，发育迟缓，严重的神经病理。我们观察了Sanfilippo综合征B型（MPSIIII B）小鼠模型的相关行为，其中编码α-N-乙酰氨基葡萄糖苷酶（NaGlu）的基因无效。我们讨论了基因治疗在这些动物中的可行性。在45只6周龄MPSIIIB小鼠的壳核中的单个位点注射源自编码NaGlu的腺相关病毒血清型2（AAV2）或5（AAV5）的载体。在处理的小鼠中观察到正常行为。在大脑中测量到远高于生理水平的高NaGlu活性，并持续到38周龄。在神经元胞内细胞器，包括溶酶体中检测到NaGlu免疫反应。酶活性扩散到载体扩散区以外。用两种载体类型可重复地获得向整个脑的递送。与AAV2-NaGlu载体相比，AAV5-NaGlu载体的NaGlu活性更高并且分布更广。各种溶酶体酶活性的代偿性增加得到改善。治疗前存在并可能参与神经病理学的神经节苷脂GM2和GM3的积累被逆转。在小胶质细胞，血管周围细胞和神经元，这是突出的治疗年龄之前，特征性空泡消失的地区，其中NaGlu是本。然而，在一些动物中仅部分改善，与高NaGlu活性相反。这些结果表明，来自脑内来源的NaGlu递送能够减轻MPSIIIB小鼠模型中的大多数疾病表现。
Sanfilippo syndrome is a mucopolysaccharidosis ( MPS) caused by a lysosomal enzyme defect interrupting the degradation pathway of heparan sulfates. Affected children develop hyperactivity, aggressiveness, delayed development, and severe neuropathology. We observed relevant behaviors in the mouse model of Sanfilippo syndrome type B ( MPSIIIB), in which the gene coding for alpha-N-acetylglucosaminidase ( NaGlu) is invalidated. We addressed the feasibility of gene therapy in these animals. Vectors derived from adeno-associated virus serotype 2 ( AAV2) or 5 ( AAV5) coding for NaGlu were injected at a single site in the putamen of 45 6-week-old MPSIIIB mice. Normal behavior was observed in treated mice. High NaGlu activity, far above physiological levels, was measured in the brain and persisted at 38 weeks of age. NaGlu immunoreactivity was detected in neuron intracellular organelles, including lysosomes. Enzyme activity spread beyond vector diffusion areas. Delivery to the entire brain was reproducibly obtained with both vector types. NaGlu activity was higher and distribution was broader with AAV5-NaGlu than with AAV2-NaGlu vectors. The compensatory increase in the activity of various lysosomal enzymes was improved. The accumulation of gangliosides GM2 and GM3 present before treatment and possibly participating in neuropathology was reversed. Characteristic vacuolations in microglia, perivascular cells, and neurons, which were prominent before the age of treatment, disappeared in areas in which NaGlu was present. However, improvement was only partial in some animals, in contrast to high NaGlu activity. These results indicate that NaGlu delivery from intracerebral sources has the capacity to alleviate most disease manifestations in the MPSIIIB mouse model.