Gene Therapy and Stem Cell Transplantation in Retinal Disease: The New Frontier.
Gene Therapy and Stem Cell Transplantation in Retinal Disease: The New Frontier.
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DOI：
10.1016/j.ophtha.2016.06.041
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发表时间：
2016-10
期刊：
影响因子：
13.7
通讯作者：
Schwartz SD
中科院分区：
文献类型：
--
作者：
MacLaren RE;Bennett J;Schwartz SD
基因和细胞疗法有可能预防、停止或逆转目前无法治愈的致盲患者的视网膜疾病。在过去的20年里，我们对视网膜疾病的病理生物学基础的理解取得了重大进展，再加上基因转移和细胞移植生物技术的发展，使人们乐观地认为，以前致盲的视网膜疾病可能是可以治疗的。现在可以将克隆基因安全稳定地传递到人类特定的视网膜细胞类型中。在人类隐性疾病中测试基因增强策略的初步结果表明，安全性和有效性很有希望，包括长期改善视觉功能。正在开发的其他基于基因的策略包括常染色体显性疾病（“功能获得”）的方法，尝试递送编码具有干扰特定疾病途径的经证实的作用机制的治疗性蛋白质的基因，以及可用于使视网膜细胞而不是萎缩的光感受器对光敏感的方法。在研究RPE 65突变导致视网膜变性的个体的最重要的监管安全性和有效性试验中，初步结果显示了稳健的安全性特征和视觉功能的临床显著改善，从而使该计划成为美国第一个批准的基因治疗产品的领跑者。与基因治疗类似，再生或基于干细胞的移植策略也取得了实质性进展。现在可以安全地将干细胞衍生的、终末分化的、生物学和遗传学上确定的视网膜色素上皮（RPE）递送到患病的人眼。虽然临床疗效的证明仍然远远落后于基因治疗领域，但研究RPE疾病再生策略的多个项目开始招募受试者，初步结果表明可能存在疗效迹象。能够变成其他视网膜细胞类型（如光感受器）的干细胞正处于临床试验的风口浪尖。干细胞衍生的移植物可以被递送到眼睛中的精确目标位置，并且可以评估它们改善、逆转、再生或神经保护以对抗疾病过程的能力。这些研究的结果将提供基础知识，可能导致临床上重要的治疗目前无法治疗的视网膜疾病。
Gene and cell therapies have the potential to prevent, halt, or reverse diseases of the retina in patients with currently incurable blinding conditions. Over the past 2 decades, major advances in our understanding of the pathobiologic basis of retinal diseases, coupled with growth of gene transfer and cell transplantation biotechnologies, have created optimism that previously blinding retinal conditions may be treatable. It is now possible to deliver cloned genes safely and stably to specific retinal cell types in humans. Preliminary results testing gene augmentation strategies in human recessive diseases suggest promising safety and efficacy profiles, including improved visual function outcomes over extended periods. Additional gene-based strategies under development include approaches to autosomal dominant disease (“gain of function”), attempts to deliver genes encoding therapeutic proteins with proven mechanisms of action interfering with specific disease pathways, and approaches that could be used to render retinal cells other than atrophied photoreceptors light sensitive. In the programs that are the furthest along—pivotal regulatory safety and efficacy trials studying individuals with retinal degeneration resulting from RPE65 mutations—initial results reveal a robust safety profile and clinically significant improvements in visual function, thereby making this program a frontrunner for the first approved gene therapy product in the United States. Similar to gene therapy, progress in regenerative or stem cell–based transplantation strategies has been substantial. It is now possible to deliver safely stem cell–derived, terminally differentiated, biologically and genetically defined retinal pigment epithelium (RPE) to the diseased human eye. Although demonstration of clinical efficacy is still well behind the gene therapy field, multiple programs investigating regenerative strategies in RPE disease are beginning to enroll subjects, and initial results suggest possible signs of efficacy. Stem cells capable of becoming other retinal cell types, such as photoreceptors, are on the cusp of clinical trials. Stem cell–derived transplants can be delivered to precise target locations in the eye, and their ability to ameliorate, reverse, regenerate, or neuroprotect against disease processes can be assessed. Results from these studies will provide foundational knowledge that may lead to clinically significant therapies for currently untreatable retinal disease.
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影响因子：
4.2
作者：
Radtke, Norman D.;Aramant, Robert B.;Seiler, Magdalene J.
通讯作者：
Seiler, Magdalene J.
影响因子：
--
作者：
Jacobson, Samuel G.;Cideciyan, Artur V.;Ratnakaram, Ramakrishna;Heon, Elise;Schwartz, Sharon B.;Roman, Alejandro J.;Peden, Marc C.;Aleman, Tomas S.;Boye, Sanford L.;Sumaroka, Alexander;Conlon, Thomas J.;Calcedo, Roberto;Pang, Ji-Jing;Erger, Kirsten E.;Olivares, Melani B.;Mullins, Cristina L.;Swider, Malgorzata;Kaushal, Shalesh;Feuer, William J.;Iannaccone, Alessandro;Fishman, Gerald A.;Stone, Edwin M.;Byrne, Barry J.;Hauswirth, William W.
通讯作者：
Hauswirth, William W.
影响因子：
3.4
作者：
Bok, D;Yasumura, D;Lavail, MM
通讯作者：
Lavail, MM
DOI：
10.1056/nejmoa1412965
发表时间：
2015-05-14
期刊：
The New England journal of medicine
影响因子：
--
作者：
Jacobson SG;Cideciyan AV;Roman AJ;Sumaroka A;Schwartz SB;Heon E;Hauswirth WW
通讯作者：
Hauswirth WW
影响因子：
5.3
作者：
Kwan, ASL;Wang, S;Lund, RD
通讯作者：
Lund, RD