Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy: follow-up of two open-label phase 1/2 studies
Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy: follow-up of two open-label phase 1/2 studies
复制标题
DOI：
10.1016/s0140-6736(14)61376-3
复制
发表时间：
2015-02-07
期刊：
影响因子：
168.9
通讯作者：
Lanza, Robert
中科院分区：
文献类型：
--
作者：
Schwartz, Steven D.;Regillo, Carl D.;Lanza, Robert
背景胚胎干细胞自三十多年前首次被发现以来，一直被认为是再生医学中替代细胞的来源，但其可塑性和无限的自我更新能力引起了人们对其安全性的担忧，包括肿瘤形成能力、潜在的免疫排斥反应以及分化为不想要的细胞类型的风险。我们报道了从人类胚胎干细胞(HESC)来源的细胞移植到患者体内的中长期安全性。方法在美国，两项前瞻性的1/2期研究评估了9例Stargardt黄斑营养不良(年龄18岁)和9例萎缩性老年性黄斑变性(年龄55岁)患者hESC来源的视网膜色素上皮视网膜下移植的安全性和耐受性。针对每种眼病治疗三个剂量队列(50,000,100,000和150,000个细胞)。移植患者通过一系列的系统、眼科和影像检查进行了中位时间22个月的随访。这些研究在ClinicalTrials.gov上注册，编号为NCT01345006(Stargardt黄斑营养不良)和NCT01344993(年龄相关性黄斑变性)。没有发现与移植组织有关的不良增殖、排斥反应或严重的眼部或全身安全问题的证据。不良事件与玻璃体视网膜手术和免疫抑制有关。18例患者中13例(72%)有与移植视网膜色素上皮一致的视网膜下色素沉着斑块。作为安全规程的一部分，最佳矫正视力提高了10只眼，提高或保持不变的有7只眼，下降了10个字母以上的1只眼，而未治疗的对侧眼睛没有表现出类似的视力改善。视力相关的生活质量测量增加了一般视力和周边视力以及近距离和远距离活动，在萎缩性老年性黄斑变性患者移植后3-12个月提高了16-25分，在Stargardt黄斑营养不良患者提高了8-20分。这项研究的结果提供了第一个证据，证明了患有任何疾病的多能干细胞后代的中长期安全性、移植物存活率和可能的生物学活性。我们的结果表明，hESC来源的细胞可能为治疗各种需要组织修复或替换的未满足的内科疾病提供潜在的安全的新细胞来源。
Background Since they were first derived more than three decades ago, embryonic stem cells have been proposed as a source of replacement cells in regenerative medicine, but their plasticity and unlimited capacity for self-renewal raises concerns about their safety, including tumour formation ability, potential immune rejection, and the risk of differentiating into unwanted cell types. We report the medium-term to long-term safety of cells derived from human embryonic stem cells (hESC) transplanted into patients.Methods In the USA, two prospective phase 1/2 studies were done to assess the primary endpoints safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium in nine patients with Stargardt's macular dystrophy (age > 18 years) and nine with atrophic age-related macular degeneration (age > 55 years). Three dose cohorts (50 000, 100 000, and 150 000 cells) were treated for each eye disorder. Transplanted patients were followed up for a median of 22 months by use of serial systemic, ophthalmic, and imaging examinations. The studies are registered with ClinicalTrials.gov, numbers NCT01345006 (Stargardt's macular dystrophy) and NCT01344993 (age-related macular degeneration).Findings There was no evidence of adverse proliferation, rejection, or serious ocular or systemic safety issues related to the transplanted tissue. Adverse events were associated with vitreoretinal surgery and immunosuppression. 13 (72%) of 18 patients had patches of increasing subretinal pigmentation consistent with transplanted retinal pigment epithelium. Best-corrected visual acuity, monitored as part of the safety protocol, improved in ten eyes, improved or remained the same in seven eyes, and decreased by more than ten letters in one eye, whereas the untreated fellow eyes did not show similar improvements in visual acuity. Vision-related quality-of-life measures increased for general and peripheral vision, and near and distance activities, improving by 16-25 points 3-12 months after transplantation in patients with atrophic age-related macular degeneration and 8-20 points in patients with Stargardt's macular dystrophy.Interpretation The results of this study provide the first evidence of the medium-term to long-term safety, graft survival, and possible biological activity of pluripotent stem cell progeny in individuals with any disease. Our results suggest that hESC-derived cells could provide a potentially safe new source of cells for the treatment of various unmet medical disorders requiring tissue repair or replacement.