期刊
HUMAN GENE THERAPY
卷 30, 期 5, 页码 590-600出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/hum.2018.156
关键词
adeno-associated virus; gene therapy; dual vector; ABCA4; Stargardt disease
资金
- MRC [MR/K007629/1] Funding Source: UKRI
- Medical Research Council [MR/K007629/1] Funding Source: Medline
- NEI NIH HHS [P30 EY000331, R01 EY025002] Funding Source: Medline
The recent approval in the United States of the first adeno-associated viral (AAV) vector for the treatment of an inherited retinal degeneration validates this approach for the treatment of many other diseases. A major limiting factor continues to be the size restriction of the AAV transgene at under 5 kb. Stargardt disease is the most prevalent form of recessively inherited blindness and is caused by mutations in ABCA4, the gene that codes for ATP-binding cassette transporter protein family member 4, which has a coding sequence length of 6.8 kb. Dual vector approaches increase the capacity of AAV gene therapy, but at the cost of substantially reduced levels of target protein, which may be insufficient to achieve a therapeutic effect. Here we show that the efficacy of recombination of dual vectors is dependent on the length of DNA overlap between two transgenes. With optimized recombination, full-length ABCA4 protein is expressed in the photoreceptor outer segments of Abca4(-/-) mice at levels sufficient to reduce bisretinoid formation and correct the autofluorescent phenotype. These observations support a dual vector approach in future clinical trials using AAV gene therapy to treat Stargardt disease.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据