AAV-mediated expression of galactocerebrosidase in brain results in attenuated symptoms and extended life span in murine models of globoid cell leukodystrophy
AAV-mediated expression of galactocerebrosidase in brain results in attenuated symptoms and extended life span in murine models of globoid cell leukodystrophy
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DOI：
10.1016/j.ymthe.2004.12.020
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发表时间：
2005-05-01
影响因子：
12.4
通讯作者：
Wenger, DA
中科院分区：
文献类型：
--
作者：
Rafi, MA;Rao, HZ;Wenger, DA
球样细胞脑白质营养不良（GLD）或克拉伯病是一种神经退行性疾病引起的缺乏半乳糖苷酶（GALC）的活动。半乳糖神经酰胺、精神病肽和可能的其他半乳糖脂的溶酶体降解需要GALC。这个过程在活跃的髓鞘形成过程中非常重要。在没有功能性GALC的情况下，精神分裂素积累，导致髓鞘产生细胞的凋亡性死亡。虽然大多数患者是婴儿谁不生存超过2岁，一些老年患者也被诊断。造血干细胞移植已被证明对一些迟发性克拉伯病患者的病程有积极影响。这种疾病的小鼠模型提供了一个很好的机会，以评估包括基因治疗的治疗方案。在这项研究中，我们使用血清型1腺相关病毒表达小鼠GALC的人巨细胞病毒启动子的控制下。将这些病毒颗粒直接给予患有GLD的新生小鼠的脑中，导致GALC活性的持续表达，髓鞘形成改善，症状减轻，寿命延长。虽然这种治疗也导致了显著的病理学改善，但治疗的小鼠死亡时症状与未治疗的小鼠相似。在动物模型和人类患者中，可能需要采取额外的措施来预防疾病的发作并逆转疾病的进程。
Globoid cell leukodystrophy (GLD) or Krabbe disease is a neurodegenerative disorder caused by a deficiency of galactocerebrosidase (GALC) activity. GALC is required for the lysosomal degradation of galactosylceramide, psychosine, and possibly other galactolipids. This process is extremely important during active myelination. In the absence of functional GALC, psychosine accumulates, resulting in the apoptotic death of myelin-producing cells. While most patients are infants who do not survive beyond 2 years of age, some older patients are also diagnosed. Hematopoietic stem cell transplantation has proven to have a positive effect on the course of some patients with late-onset Krabbe disease. Murine models of this disease provide an excellent opportunity to evaluate therapeutic alternatives including gene therapy. In this study we used serotype 1 AAV to express mouse GALC under the control of the human cytomegalovirus promoter. Direct administration of these viral particles into the brains of neonatal mice with GLD resulted in sustained expression of GALC activity, improved myelination, attenuated symptoms, and prolonged life span. While this treatment also resulted in significant pathological improvements, the treated mice died with symptoms similar to those of the untreated mice. Additional initiatives may be required to prevent the onset of disease and reverse the course of the disease in animal models and human patients.