a Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences , University of Oxford , Oxford , UK.
b National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) , Oxford , UK.
Expert Opin Biol Ther. 2018 Jul;18(7):807-820. doi: 10.1080/14712598.2018.1484448. Epub 2018 Jun 22.
Choroideremia is an X-linked inherited retinal degeneration that causes blindness in afflicted males by middle age. The causative gene, CHM, plays a key role in intracellular trafficking pathways, and its disruption impairs cell homeostasis.
The mechanism by which mutations in CHM cause choroideremia is still under debate. Here we describe the molecular defects in choroideremia cells regarding both the deficiency of prenylation and the involvement of Rab GTPases. Important in vivo and in vitro studies that contributed to the current knowledge are also discussed. Finally, the rationale for the development of a treatment strategy using AAV for gene replacement is presented, together with other treatment strategies under consideration.
Despite ubiquitous expression of the CHM gene, the primary defect in choroideremia is driven by retinal pigment epithelium (RPE) and photoreceptors degeneration. Here we discuss how impairment of vesicular trafficking pathways in the RPE plays a major role in the molecular pathogenesis of choroideremia. Moreover, this defect is likely restored by subretinal delivery of a functional copy of CHM using AAV, as evidenced by clinical trial results. The surgical complexity of delivering the AAV vector to the target area remains as the main challenge to this therapy.
AAV: adeno-associated virus; BCD: Bietti's crystalline dystrophy; CHM: choroideremia; CHML: choroideremia-like; Dfp: days post-fertilization; EMA: European Medicines Agency; ERG: electroretinogram; ETDRS: Early Treatment Diabetic Retinopathy Study; FDA: Food and Drug Administration; FTase: farnesyl transferase; GFP: green fluorescent protein; GGPP: geranylgeranyl-diphosphate; GGTase-I: geranylgeranyl transferase type-I; GGTase-II: geranylgeranyl transferase type-II; HMG-CoA: 3-hydroxy-3-methylglutayl-CoA; HMGCR: HMG-CoA reductase; iPSC: induced pluripotent stem cells; IRDs: inherited retinal diseases; KO: knockout; LCA: Leber congenital amaurosis; NMD: nonsense-mediated mRNA decay; OCT: optical coherence tomography; PMBCs: peripheral blood mononuclear cells; POS: photoreceptor outer segments; PTCs: premature termination codons; Rab GGTase: Rab geranylgeranyl transferase; REP: Rab escort protein; RPE: retinal pigment epithelium; TRIDs: translational read-through inducing drugs; WPRE: woodchuck post-transcriptional regulatory element.
脉络膜视网膜变性是一种 X 连锁遗传性视网膜退行性疾病，导致受影响的男性在中年失明。致病基因 CHM 在细胞内运输途径中发挥关键作用，其功能障碍会损害细胞内稳态。
CHM 基因突变导致脉络膜视网膜变性的机制仍存在争议。在这里，我们描述了脉络膜视网膜变性细胞中关于prenylation 缺乏和 Rab GTPases 参与的分子缺陷。还讨论了对当前知识有贡献的重要体内和体外研究。最后，提出了使用 AAV 进行基因替代治疗策略的基本原理，以及正在考虑的其他治疗策略。
尽管 CHM 基因广泛表达，但脉络膜视网膜变性的主要缺陷是由视网膜色素上皮 (RPE) 和光感受器变性驱动的。在这里，我们讨论了 RPE 中囊泡运输途径的损伤如何在脉络膜视网膜变性的分子发病机制中发挥主要作用。此外，正如临床试验结果所示，使用 AAV 将功能性 CHM 拷贝递送至靶区可恢复这种缺陷。将 AAV 载体递送至靶区的手术复杂性仍然是该疗法的主要挑战。
AAV：腺相关病毒；BCD：Bietti 结晶性营养不良；CHM：脉络膜视网膜变性；CHML：脉络膜视网膜变性样；Dfp：受精后天数；EMA：欧洲药品管理局；ERG：视网膜电图；ETDRS：早期糖尿病性视网膜病变治疗研究；FDA：美国食品和药物管理局；FTase：法尼基转移酶；GFP：绿色荧光蛋白；GGPP：香叶基香叶基二磷酸；GGTase-I：法尼基转移酶 I 型；GGTase-II：法尼基转移酶 II 型；HMG-CoA：3-羟-3-甲基戊二酰辅酶 A；HMGCR：3-羟-3-甲基戊二酰辅酶 A 还原酶；iPSC：诱导多能干细胞；IRDs：遗传性视网膜疾病；KO：敲除；LCA：Leber 先天性黑蒙；NMD：无义介导的 mRNA 降解；OCT：光学相干断层扫描；PMBCs：外周血单核细胞；POS：光感受器外段；PTCs：过早终止密码子；Rab GGTase：Rab 异戊二烯转移酶；REP：Rab 护送蛋白；RPE：视网膜色素上皮；TRIDs：翻译通读诱导药物；WPRE：土拨鼠转录后调节元件。
