ABCA4 disease progression and a proposed strategy for gene therapy
ABCA4 disease progression and a proposed strategy for gene therapy
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DOI：
10.1093/hmg/ddn421
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发表时间：
2009-03-01
影响因子：
3.5
通讯作者：
Palczewski, Krzysztof
中科院分区：
文献类型：
--
作者：
Cideciyan, Artur V.;Swider, Malgorzata;Palczewski, Krzysztof
ABCA 4基因突变引起的常染色体隐性视网膜疾病正在考虑进行基因替代治疗。所有患有ABCA 4疾病的人都表现出黄斑变性，但只有一些人被认为会发展为全视网膜失明。目前还无法预测特定的ABCA 4基因型是否或何时会显示黄斑外疾病，以及此后进展的速度。视网膜下基因治疗的早期临床试验旨在阻止黄斑外视网膜的疾病进展。在66名已知致病ABCA 4等位基因的个体中，我们通过测量视杆细胞和视锥细胞介导的视觉来定义视网膜范围内的疾病表达。平均8.7年的连续测量与模型一致，其中可变长度的正常平台期之后是呈指数级进展的全视网膜疾病的开始。一旦开始，视杆细胞的平均疾病进展率为1.1 log/decade，视锥细胞为0.45 log/decade。疾病的时空进展可以被描述为两个分量的总和，一个具有中央到外周的梯度，另一个具有均匀的视网膜范围的模式。疾病起始年龄的估计值被用作严重性度量，并预测每个ABCA 4等位基因的贡献。三分之一的非截短等位基因被发现会导致更严重的疾病比过早截短支持的致病成分的存在超出简单的功能丧失。基于基因型的纳入/排除标准和对视网膜疾病发病年龄的预测对于选择合适的候选人进行ABCA 4疾病的临床试验将是非常宝贵的。
Autosomal recessive retinal diseases caused by mutations in the ABCA4 gene are being considered for gene replacement therapy. All individuals with ABCA4-disease show macular degeneration, but only some are thought to progress to retina-wide blindness. It is currently not predictable if or when specific ABCA4 genotypes will show extramacular disease, and how fast it will progress thereafter. Early clinical trials of focal subretinal gene therapy will aim to arrest disease progression in the extramacular retina. In 66 individuals with known disease-causing ABCA4 alleles, we defined retina-wide disease expression by measuring rod- and cone-photoreceptor-mediated vision. Serial measurements over a mean period of 8.7 years were consistent with a model wherein a normal plateau phase of variable length was followed by initiation of retina-wide disease that progressed exponentially. Once initiated, the mean rate of disease progression was 1.1 log/decade for rods and 0.45 log/decade for cones. Spatio-temporal progression of disease could be described as the sum of two components, one with a central-to-peripheral gradient and the other with a uniform retina-wide pattern. Estimates of the age of disease initiation were used as a severity metric and contributions made by each ABCA4 allele were predicted. One-third of the non-truncating alleles were found to cause more severe disease than premature truncations supporting the existence of a pathogenic component beyond simple loss of function. Genotype-based inclusion/exclusion criteria and prediction of the age of retina-wide disease initiation will be invaluable for selecting appropriate candidates for clinical trials in ABCA4 disease.