作者：生物谷来源：Nature2010-3-8 10:41:30分享到： 0
关键词： 基因疗法 视力
视觉正常的人类视网膜图像显示了视盘和斑点。
资料来源: 《科学》/美国科学促进会
据3月4日的《科学-转化医学 》杂志报道说，一项新的动物研究凸显了用基因疗法来治疗Leber先天性黑矇症(LCA)的潜力。该疾病是一种会导致到成年的时候完全失明的无法治愈的遗传性疾病。
研究的结果阐明了这种能够治疗双眼的基因疗法的安全性和功效。 去年，一个开拓型的临床试验通过基因疗法帮助了一组儿童战胜了他们的几近完全失明疾病。这种基因疗法将一个突变的基因进行了替换，并使所有12名患者的一只眼睛的视力得到了部分的恢复。 正如人们所料，这一成功恢复视力的基因疗法试验使得患者争相要求对他们的第二只眼睛做进一步的治疗。 现在，同一团队的研究人员已经朝着向这些患者提供相同的恢复其第二只眼睛视力的治疗迈出了重要的一步。
在大多数的基因疗法研究中，人们用一种被称作载体的分子来将一种“有功能”的基因传送到患者的细胞之中。载体通常是在基因上被改变的病毒核酸分子的主链，它们携带有正常人的DNA。尽管最近用于临床实验的腺病毒相关病毒载体成功地逆转了LCA患者一只眼睛的失明，但人们不确定的是，鉴于在第一次注射了病毒之后有可能出现一种令病情加重的免疫反应，因此用同样的方式治疗第二只眼睛是否安全。
在本次研究中，Defne Amado及其同僚显示，在犬和猴子（它们是眼睛的大小和结构与人类似的动物）的第二只眼睛中再次给予含有该基因的腺病毒载体既安全而且有效。此外，即使是在那些先前就已经存在有针对该病毒载体的免疫性的动物之中，这种治疗也是安全的；而这一免疫特性却使某些患者被挡在了该基因疗法的试验之外。这些结果使得合格接受该项治疗的患者的范围变得更宽；那些因为预先存在免疫性的患者也许能够接受对其第一只眼睛的治疗，而那些第一只眼睛已经接受过基因疗法的患者也许有机会恢复他们第二只眼睛的视力。（生物谷Bioon.com）
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生物谷推荐原始出处：
Sci Transl Med 3 March 2010: DOI: 10.1126/scitranslmed.3000659
Safety and Efficacy of Subretinal Readministration of a Viral Vector in Large Animals to Treat Congenital Blindness
Defne Amado1,*, Federico Mingozzi2,*, Daniel Hui2, Jeannette L. Bennicelli1, Zhangyong Wei1, Yifeng Chen2,3, Erin Bote4, Rebecca L. Grant4, Jeffrey A. Golden5,6, Kristina Narfstrom7, Nasreen A. Syed8, Stephen E. Orlin9, Katherine A. High2,3, Albert M. Maguire1,2 and Jean Bennett1,2,?
1F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
2Center for Cellular and Molecular Therapeutics, Children’s Hospital of Philadelphia, Abramson Pediatric Research Center, Philadelphia, PA 19014, USA.
3Howard Hughes Medical Institute, Philadelphia, PA 19104, USA.
4Nonhuman Primate Research Program, University of Pennsylvania, Department of Pathology and Laboratory Medicine, Gene Therapy Program, Translational Research Laboratories, Philadelphia, PA 19104-3402, USA.
5Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
6Developmental Biology Program for Pediatric Disorders, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA.
7College of Veterinary Medicine and Mason Eye Institute, University of Missouri-Columbia, Columbia, MO 65212, USA.
8Departments of Ophthalmology and Visual Sciences and Pathology, University of Iowa, Iowa City, IA 52242-1007, USA.
9Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Leber’s congenital amaurosis (LCA) is a group of severe inherited retinal degenerations that are symptomatic in infancy and lead to total blindness in adulthood. Recent clinical trials using recombinant adeno-associated virus serotype 2 (rAAV2) successfully reversed blindness in patients with LCA caused by RPE65 mutations after one subretinal injection. However, it was unclear whether treatment of the second eye in the same manner would be safe and efficacious, given the potential for a complicating immune response after the first injection. Here, we evaluated the immunological and functional consequences of readministration of rAAV2-hRPE65v2 to the contralateral eye using large animal models. Neither RPE65-mutant (affected; RPE65?/?) nor unaffected animals developed antibodies against the transgene product, but all developed neutralizing antibodies against the AAV2 capsid in sera and intraocular fluid after subretinal injection. Cell-mediated immune responses were benign, with only 1 of 10 animals in the study developing a persistent T cell immune response to AAV2, a response that was mediated by CD4+ T cells. Sequential bilateral injection caused minimal inflammation and improved visual function in affected animals. Thus, subretinal readministration of rAAV2 in animals is safe and effective, even in the setting of preexisting immunity to the vector, a parameter that has been used to exclude patients from gene therapy trials.
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