色盲
视网膜变性
Erg公司
眼科
外层核层
载体(分子生物学)
视网膜
医学
视网膜电图
重组DNA
遗传增强
感光细胞
视网膜
体内分布
抗体
组织病理学
生物
病理
免疫学
基因
遗传学
体内
神经科学
作者
Guo-jie Ye,Ewa Budzynski,Peter Sonnentag,T. Michael Nork,Paul E. Miller,Leslie McPherson,James N. Ver Hoeve,Leia M. Smith,Tara Arndt,Savitri Mandapati,Paulette M. Robinson,Roberto Calcedo,David R. Knop,William W. Hauswirth,Jeffrey D. Chulay
出处
期刊:Human gene therapy. Clinical development
[Mary Ann Liebert]
日期:2016-03-01
卷期号:27 (1): 27-36
被引量:19
标识
DOI:10.1089/humc.2015.163
摘要
Applied Genetic Technologies Corporation (AGTC) is developing rAAV2tYF-PR1.7-hCNGB3, a recombinant adeno-associated virus (rAAV) vector expressing the human CNGB3 gene, for treatment of achromatopsia, an inherited retinal disorder characterized by markedly reduced visual acuity, extreme light sensitivity, and absence of color discrimination. We report here results of a study evaluating safety and biodistribution of rAAV2tYF-PR1.7-hCNGB3 in CNGB3-deficient mice. Three groups of animals (n = 35 males and 35 females per group) received a subretinal injection in one eye of 1 μl containing either vehicle or rAAV2tYF-PR1.7-hCNGB3 at one of two dose concentrations (1 × 10(12) or 4.2 × 10(12) vg/ml) and were euthanized 4 or 13 weeks later. There were no test-article-related changes in clinical observations, body weights, food consumption, ocular examinations, clinical pathology parameters, organ weights, or macroscopic observations at necropsy. Cone-mediated electroretinography (ERG) responses were detected after vector administration in the treated eyes in 90% of animals in the higher dose group and 31% of animals in the lower dose group. Rod-mediated ERG responses were reduced in the treated eye for all groups, with the greatest reduction in males given the higher dose of vector, but returned to normal by the end of the study. Microscopic pathology results demonstrated minimal mononuclear cell infiltrates in the retina and vitreous of some animals at the interim euthanasia and in the vitreous of some animals at the terminal euthanasia. Serum anti-AAV antibodies developed in most vector-injected animals. No animals developed antibodies to hCNGB3. Biodistribution studies demonstrated high levels of vector DNA in vector-injected eyes but little or no vector DNA in nonocular tissue. These results support the use of rAAV2tYF-PR1.7-hCNGB3 in clinical studies in patients with achromatopsia caused by CNGB3 mutations.
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