Potential CRISPR Base Editing Therapeutic Options in a Sorsby Fundus Dystrophy Patient.
Potential CRISPR Base Editing Therapeutic Options in a Sorsby Fundus Dystrophy Patient.
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作者：
TIMP3突变与早发性黄斑脉络膜新生血管有关，目前尚无治疗方法。CRISPR碱基编辑能够通过在DNA水平上对核碱基进行化学修饰来不可逆地纠正点突变，可能是一种治疗选择。我们报告一个生物信息学分析潜在的治疗方案，在病人提出索斯比眼底营养不良。对一名患有双侧黄斑脉络膜新生血管的35岁男士的基因检测显示，该患者是TIMP3变异c.610A>T, p.（Ser204Cys）的杂合型。使用糖基酶碱基编辑器（GBE），可以引入另一个dna编辑器，将变体在氨基酸水平上恢复到野生型。或者，突变的残基可以改变为另一种耐受性更好的氨基酸，为此，发现一个可用的' NG ' -PAM位点可用于基于spcas9的腺嘌呤碱基编辑器（ABE），该编辑器将引入p.（Ser204Arg）。计算机分析预测这种变异是非致病性的；然而，一个旁观者编辑，p.Ile205Thr，将被引入。本病例报告强调了考虑对脉络膜新生血管的年轻患者进行基因检测的重要性，特别是在假定有湿性年龄相关性黄斑变性的强烈家族史的背景下，并描述了潜在的治疗选择。
TIMP3 mutations are associated with early-onset macular choroidal neovascularisation for which no treatment currently exists. CRISPR base editing, with its ability to irreversibly correct point mutations by chemical modification of nucleobases at DNA level, may be a therapeutic option. We report a bioinformatic analysis of potential therapeutic options in a patient presenting with Sorsby fundus dystrophy. Genetic testing in a 35-year-old gentleman with bilateral macular choroidal neovascularisation revealed the patient to be heterozygous for a TIMP3 variant c.610A>T, p.(Ser204Cys). Using a glycosylase base editor (GBE), another DNA-edit could be introduced that would revert the variant back to wild-type on amino acid level. Alternatively, the mutated residue could be changed to another amino acid that would be better tolerated, and for that, an available ‘NG’-PAM site was found to be available for the SpCas9-based adenine base editor (ABE) that would introduce p.(Ser204Arg). In silico analyses predicted this variant to be non-pathogenic; however, a bystander edit, p.Ile205Thr, would be introduced. This case report highlights the importance of considering genetic testing in young patients with choroidal neovascularisation, particularly within the context of a strong family history of presumed wet age-related macular degeneration, and describes potential therapeutic options.
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