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Gene therapy for inherited retinal diseases: exploiting new tools in genome editing and nanotechnology 遗传性视网膜疾病的基因治疗:利用基因组编辑和纳米技术的新工具
Pub Date : 2023-09-19 DOI: 10.3389/fopht.2023.1270561
Cláudia Carvalho, Luísa Lemos, Pedro Antas, Miguel C. Seabra
Inherited retinal diseases (IRDs) encompass a diverse group of genetic disorders that lead to progressive visual impairment and blindness. Over the years, considerable strides have been made in understanding the underlying molecular mechanisms of IRDs, laying the foundation for novel therapeutic interventions. Gene therapy has emerged as a compelling approach for treating IRDs, with notable advancements achieved through targeted gene augmentation. However, several setbacks and limitations persist, hindering the widespread clinical success of gene therapy for IRDs. One promising avenue of research is the development of new genome editing tools. Cutting-edge technologies such as CRISPR-Cas9 nucleases, base editing and prime editing provide unprecedented precision and efficiency in targeted gene manipulation, offering the potential to overcome existing challenges in gene therapy for IRDs. Furthermore, traditional gene therapy encounters a significant challenge due to immune responses to viral vectors, which remain crucial obstacles in achieving long-lasting therapeutic effects. Nanotechnology has emerged as a valuable ally in the quest to optimize gene therapy outcomes for ocular diseases. Nanoparticles engineered with nanoscale precision offer improved gene delivery to specific retinal cells, allowing for enhanced targeting and reduced immunogenicity. In this review, we discuss recent advancements in gene therapy for IRDs and explore the setbacks that have been encountered in clinical trials. We highlight the technological advances in genome editing for the treatment of IRDs and how integrating nanotechnology into gene delivery strategies could enhance the safety and efficacy of gene therapy, ultimately offering hope for patients with IRDs and potentially paving the way for similar advancements in other ocular disorders.
遗传性视网膜疾病(IRDs)包括导致进行性视力损害和失明的多种遗传性疾病。多年来,在了解IRDs的潜在分子机制方面取得了长足的进步,为新的治疗干预奠定了基础。基因治疗已成为治疗ird的一种引人注目的方法,通过靶向基因增强取得了显着进展。然而,一些挫折和限制仍然存在,阻碍了基因治疗ird的广泛临床成功。一个有前途的研究途径是开发新的基因组编辑工具。CRISPR-Cas9核酸酶、碱基编辑和引物编辑等尖端技术为靶向基因操作提供了前所未有的精度和效率,为克服ird基因治疗中的现有挑战提供了潜力。此外,由于对病毒载体的免疫反应,传统的基因治疗遇到了重大挑战,这仍然是实现持久治疗效果的关键障碍。纳米技术已经成为寻求优化眼部疾病基因治疗结果的宝贵盟友。纳米级精密工程纳米颗粒提供了改善的基因传递到特定的视网膜细胞,允许增强靶向性和降低免疫原性。在这篇综述中,我们讨论了ird基因治疗的最新进展,并探讨了在临床试验中遇到的挫折。我们强调了用于治疗ird的基因组编辑技术的进步,以及如何将纳米技术整合到基因传递策略中可以提高基因治疗的安全性和有效性,最终为ird患者带来希望,并可能为其他眼部疾病的类似进展铺平道路。
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引用次数: 0
Endothelial to mesenchymal cell transition in diabetic retinopathy: targets and therapeutics. 糖尿病视网膜病变中的内皮细胞向间质细胞转化:靶点和疗法。
Pub Date : 2023-09-07 eCollection Date: 2023-01-01 DOI: 10.3389/fopht.2023.1230581
Wasef Nijim, Mohamed Moustafa, Julia Humble, Mohamed Al-Shabrawey

Diabetic retinopathy (DR) is a result of neurovacular insults from hyperglycemia in diabetes mellitus (DM), and it is one of the top causes of vision loss throughout the modern world. This review article explores the role endothelial to mesenchymal transition (EndMT) has on the pathogenesis of DR. EndMT contributes to the disruption of the blood-retinal barrier, vascular leakage, neovascularization, and fibrosis observed in DR. Risk factors and biomarkers associated with DR severity are discussed, highlighting the importance of early detection and targeted therapies. Current treatments primarily focus on anti-vascular endothelial growth factor (anti-VEGF) agents, corticosteroids, and laser photocoagulation. However, emerging therapeutic strategies aimed at inhibiting EndMT and its downstream effects show promise in preventing the development and progression of DR. Understanding the molecular and cellular mechanisms underlying EndMT in DR provides valuable insights into the disease process and offers potential options for the development of potential treatments.

糖尿病视网膜病变(DR)是糖尿病(DM)患者高血糖引起的神经视网膜损伤的结果,是现代世界视力丧失的主要原因之一。这篇综述文章探讨了内皮细胞向间充质转化(EndMT)在糖尿病视网膜病变发病机制中的作用。内皮细胞向间质转化(EndMT)是导致DR的血液-视网膜屏障破坏、血管渗漏、新生血管形成和纤维化的原因之一。本文讨论了与 DR 严重程度相关的风险因素和生物标志物,强调了早期检测和靶向治疗的重要性。目前的治疗方法主要集中在抗血管内皮生长因子(anti-VEGF)药物、皮质类固醇和激光光凝上。然而,旨在抑制内膜生长因子及其下游效应的新兴治疗策略有望预防 DR 的发生和发展。了解 DR 中内膜种植的分子和细胞机制可为了解疾病过程提供宝贵的信息,并为开发潜在的治疗方法提供潜在的选择。
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引用次数: 0
The spaceflight contrast sensitivity hypothesis and its role to investigate the pathophysiology of spaceflight-associated neuro-ocular syndrome. 太空飞行对比敏感性假说及其在研究太空飞行相关神经眼综合征病理生理学方面的作用。
Pub Date : 2023-09-05 eCollection Date: 2023-01-01 DOI: 10.3389/fopht.2023.1229748
Ethan Waisberg, Joshua Ong, Nasif Zaman, Phani Paladugu, Sharif Amit Kamran, Alireza Tavakkoli, Andrew G Lee
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引用次数: 0
Advancements in high-resolution imaging of the iridocorneal angle. 虹膜角膜高分辨率成像的进展。
Pub Date : 2023-08-21 eCollection Date: 2023-01-01 DOI: 10.3389/fopht.2023.1229670
Matthew J Keller, Thomas J Gast, Brett J King

High-resolution imaging methods of the iridocorneal angle (ICA) will lead to enhanced understanding of aqueous humor outflow mechanisms and a characterization of the trabecular meshwork (TM) morphology at the cellular level will help to better understand glaucoma mechanics (e.g., cellular level biomechanics of the particulate glaucomas). This information will translate into immense clinical value, leading to more informed and customized treatment selection, and improved monitoring of procedural interventions that lower intraocular pressure (IOP). Given ICA anatomy, imaging modalities that yield intrinsic optical sectioning or 3D imaging capability will be useful to aid in the visualization of TM layers. This minireview examines advancements in imaging the ICA in high-resolution.

虹膜角膜(ICA)的高分辨率成像方法将有助于加深对房水外流机制的了解,而小梁网(TM)在细胞水平上的形态特征将有助于更好地了解青光眼的力学原理(如颗粒状青光眼的细胞水平生物力学)。这些信息将转化为巨大的临床价值,使治疗选择更加明智和个性化,并改善对降低眼内压(IOP)的手术干预的监测。鉴于 ICA 的解剖结构,能产生固有光学切片或三维成像功能的成像模式将有助于 TM 层的可视化。本微型视图将探讨 ICA 高分辨率成像的进展。
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引用次数: 0
Congenital optic disc pits and optic disc pit maculopathy: a review. 先天性视盘凹陷和视盘凹陷黄斑病变:综述。
Pub Date : 2023-08-16 eCollection Date: 2023-01-01 DOI: 10.3389/fopht.2023.1222979
Ali Esmaeil, Ali Ali, Salman Almutairi, Khaled Alkandari, Raed Behbehani, Alaa Alali

Optic disc pits are a rare but significant anomaly of the optic nerve head that can lead to visual impairment and associated complications. These pits are characterized by a small, oval-shaped depression in the disc, which can cause fluid accumulation and subsequent damage to the adjacent retina. Although the etiology and pathogenesis of optic disc pits are not fully understood, several theories have been proposed, including abnormal embryonic development and degenerative changes. Diagnosis is typically made through a comprehensive eye examination, including a dilated fundus exam and optical coherence tomography. Management options vary depending on the severity of the condition and associated complications, ranging from observation to surgical intervention.

视盘凹陷是视神经头的一种罕见但严重的异常,可导致视力损伤和相关并发症。视盘凹陷的特征是视盘上有一个椭圆形的小凹陷,它会导致液体积聚,进而损害邻近的视网膜。虽然视盘凹陷的病因和发病机制尚未完全明了,但已提出了几种理论,包括胚胎发育异常和退行性病变。诊断通常需要进行全面的眼部检查,包括散瞳眼底检查和光学相干断层扫描。根据病情严重程度和相关并发症的不同,治疗方案也各不相同,从观察到手术干预,不一而足。
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引用次数: 0
Adult-onset foveomacular vitelliform dystrophy: epidemiology, pathophysiology, imaging, and prognosis. 成人发病的眼窝黄斑玻璃体营养不良症:流行病学、病理生理学、影像学和预后。
Pub Date : 2023-08-10 eCollection Date: 2023-01-01 DOI: 10.3389/fopht.2023.1237788
Grace E Nipp, Terry Lee, Kubra Sarici, Goldis Malek, Majda Hadziahmetovic

Adult-onset foveomacular dystrophy (AOFVD) is a retinal pattern dystrophy that may affect up to 1 in 7,400 individuals. There is much that is unknown regarding this disease's epidemiology, risk factors for development, and rate of progression through its four stages. Advancements in retinal imaging over the past 15 years have enabled improved characterization of the different stages of AOFVD. These imaging advancements also offer new ways of differentiating AOFVD from phenotypically similar retinal diseases like age-related macular degeneration and Best disease. This review synthesizes the most recent discoveries regarding imaging correlates within AOFVD as well as risk factors for the development of AOFVD, complications of AOFVD, and treatment options. Our aim is to provide ophthalmologists a succinct resource so that they may offer clarity, guidance, and appropriate monitoring and treatments for their patients with suspected AOFVD.

成人发病型眼窝视网膜营养不良症(AOFVD)是一种视网膜形态营养不良症,每 7,400 人中就可能有 1 人患病。关于这种疾病的流行病学、发病风险因素和四个阶段的进展速度,还有很多未知数。在过去的 15 年中,视网膜成像技术不断进步,从而改进了对 AOFVD 不同阶段的特征描述。这些成像技术的进步还提供了新的方法,将 AOFVD 与表型相似的视网膜疾病(如老年性黄斑变性和贝斯特病)区分开来。本综述综合了有关 AOFVD 影像相关性、AOFVD 发病风险因素、AOFVD 并发症和治疗方案的最新发现。我们的目的是为眼科医生提供一份简明扼要的资料,使他们能够为疑似 AOFVD 患者提供清晰的指导、适当的监测和治疗。
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引用次数: 0
Rod-cone signal interference in the retina shapes perception in primates 视网膜中的视锥杆信号干扰影响了灵长类动物的感知能力
Pub Date : 2023-07-31 DOI: 10.3389/fopht.2023.1230084
Adree Songco-Aguas, William N. Grimes, Fred Rieke
Linking the activity of neurons, circuits and synapses to human behavior is a fundamental goal of neuroscience. Meeting this goal is challenging, in part because behavior, particularly perception, often masks the complexity of the underlying neural circuits, and in part because of the significant behavioral differences between primates and animals like mice and flies in which genetic manipulations are relatively common. Here we relate circuit-level processing of rod and cone signals in the non-human primate retina to a known break in the normal seamlessness of human vision – a surprising inability to see high contrast flickering lights under specific conditions. We use electrophysiological recordings and perceptual experiments to identify key mechanisms that shape the retinal integration of rod- and cone-generated retinal signals. We then incorporate these mechanistic insights into a predictive model that accurately captures the cancellation of rod- and cone-mediated responses and can explain the perceptual insensitivity to flicker.
将神经元、电路和突触的活动与人类行为联系起来是神经科学的一个基本目标。实现这一目标具有挑战性,部分原因是行为,尤其是感知,往往掩盖了潜在神经回路的复杂性,部分原因是灵长类动物与老鼠和苍蝇等动物之间的显著行为差异,在这些动物中,基因操作相对常见。在这里,我们将非人类灵长类动物视网膜中杆状和锥体信号的电路级处理与人类视觉正常无缝性的已知中断联系起来——在特定条件下无法看到高对比度闪烁的灯光。我们使用电生理记录和感知实验来确定形成视杆和视锥产生的视网膜信号的视网膜整合的关键机制。然后,我们将这些机制见解整合到一个预测模型中,该模型准确地捕获了杆状和锥体介导的反应的取消,并可以解释对闪烁的感知不敏感。
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引用次数: 0
Efficacy and safety of 'dropless vitrectomy surgery' and comparison of outcomes to standard of care topical therapy. 无滴眼液玻璃体切除手术 "的有效性和安全性,以及与标准局部疗法的结果比较。
Pub Date : 2023-07-28 eCollection Date: 2023-01-01 DOI: 10.3389/fopht.2023.1215968
K V Chalam, Harris Ahmed

Objective/background: To compare the effectiveness of intravitreal injection of triamcinolone acetonide/moxifloxacin (Tri-Moxi) with the standard eye drop regimen for controlling postoperative inflammation, intraocular pressure, infections, macular thickness, and visual acuity (VA) in patients undergoing pars plana vitrectomy for various retinal disorders.

Subject/methods: In this retrospective longitudinal study, patients who underwent vitrectomy using intravitreal Tri-Moxi at the end of surgery (Group 1) were compared with those who received standard topical steroid antibiotics (Group 2) in terms of intraocular inflammation, intraocular pressure, macular thickness based on optical coherence tomography, and visual acuity.

Results: In total, 162 consecutive eyes (group 1 [81 eyes]; group 2 [82 eyes]) were included. VA improved by two lines in both groups at 90 days. In Group 1, preoperative VA (logMAR) was 0.92 (0.66) compared to 0.92 (0.75) in Group 2 (p = 1), while at 3 months, it was 0.61 (0.3) and 0.57 (0.3), respectively (p = 0.46). Group 1 showed superior outcomes concerning central foveal thickness. The average central foveal thickness CFT (µm) in group 2 preoperatively was 423 (95) and 348 (63) at 3 months compared to group 1 526 (109) and 306 (108) preoperatively and 3 months, respectively (p = 0.042). There was no statistically significant difference in the rate of elevated intraocular pressure between the two groups or anterior chamber cell reaction severity, and no cases of endophthalmitis were observed in either group.

Conclusions: Tri-Moxi is effective after vitrectomy and is not inferior to standard postoperative topical therapy.

目的/背景:比较玻璃体内注射曲安奈德/氧氟沙星(Tri-Moxi)与标准滴眼液方案在控制因各种视网膜疾病接受玻璃体旁切除术的患者术后炎症、眼压、感染、黄斑厚度和视力(VA)方面的有效性:在这项回顾性纵向研究中,将在手术结束时使用玻璃体内Tri-Moxi的玻璃体切除术患者(第1组)与接受标准局部类固醇抗生素治疗的患者(第2组)在眼内炎症、眼压、基于光学相干断层扫描的黄斑厚度和视力方面进行了比较:共纳入了 162 只连续眼(第 1 组[81 只眼];第 2 组[82 只眼])。90 天后,两组患者的视力均提高了两行。第一组的术前视力(logMAR)为 0.92 (0.66),第二组为 0.92 (0.75)(p = 1),3 个月后分别为 0.61 (0.3) 和 0.57 (0.3)(p = 0.46)。第 1 组在中心眼窝厚度方面的疗效更佳。第 2 组术前的平均中心眼窝厚度 CFT(微米)为 423(95),3 个月时为 348(63),而第 1 组术前和 3 个月时的平均中心眼窝厚度分别为 526(109)和 306(108)(p = 0.042)。两组患者的眼压升高率或前房细胞反应严重程度无统计学差异,两组患者均未观察到眼内炎病例:结论:Tri-Moxi 在玻璃体切割术后效果显著,并不比标准的术后局部疗法差。
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引用次数: 0
Scleral flaps, pars plana vitrectomy and gore-tex sutured posterior chamber intraocular lens placement: a case series and review of literature. 巩膜瓣、玻璃体旁切除术和 Gore-tex 缝合后房型眼内透镜置入术:病例系列和文献综述。
Pub Date : 2023-07-26 eCollection Date: 2023-01-01 DOI: 10.3389/fopht.2023.1147881
Pasquale Napolitano, Mariaelena Filippelli, Marianna Carosielli, Ciro Costagliola, Roberto Dell'Omo

Introduction: Cataract surgery is one of the most common surgical procedures performed worldwide. Intraocular lens (IOL) implants are placed routinely in the capsular bag after successful cataract extraction. However, in the absence of adequate capsular support, IOL may be placed in the anterior chamber, fixated to the iris or fixated to the sclera. The purpose of this study is to report the clinical outcomes and safety profile of a trans-scleral sutured intraocular lens (IOL) technique using scleral flaps, vitrectomy, and Gore-Tex suture to place posterior chamber IOL.

Methods: Retrospective, interventional case series of eyes undergoing scleral fixation of an IOL using Gore-Tex suture with concurrent vitrectomy. Ocular examination with the logarithm of the minimum angle of resolution visual acuity (logMAR BCVA), tonometry, and slit-lamp biomicroscopy was performed on all patients at 1, 3, 6, and 12 months after the operation. All post-operative complications were recorded.

Results: Twenty-five eyes of 25 patients were included. Mean logMAR BCVA improved from 0.43 ± 0.36 (2040 Snellen equivalent) preoperatively to 0.13 ± 0.18 (2025 Snellen equivalent) postoperatively at 12 months (p<0.01). Indications included surgical aphakia (16) and dislocated lens implant (9). No cases of IOL opacification, suprachoroidal haemorrhage, post-operative endophthalmitis, IOL dislocation, Gore-Tex exposure, or retinal detachment were observed during the follow-up period.

Conclusion: Ab externo scleral fixation of IOLs with Gore-Tex suture plus scleral flap is well tolerated and associated with a very low rate of suture exposition. Moreover, our study confirms excellent refractive outcomes after surgery.

简介白内障手术是全球最常见的外科手术之一。成功摘除白内障后,眼内人工晶体(IOL)植入物通常会被放置在囊袋内。但是,如果没有足够的囊袋支撑,人工晶体可能会被放置在前房、固定在虹膜上或固定在巩膜上。本研究旨在报告使用巩膜瓣、玻璃体切除术和 Gore-Tex 缝合线放置后房型人工晶体(IOL)的经巩膜缝合技术的临床效果和安全性:使用 Gore-Tex 缝合线固定人工晶体并同时进行玻璃体切除术的回顾性、介入性病例系列。所有患者均在术后 1、3、6 和 12 个月接受了最小解像角视力对数(logMAR BCVA)、眼压测量和裂隙灯生物显微镜检查。所有术后并发症均被记录在案:结果:共纳入 25 名患者的 25 只眼睛。术后12个月时,BCVA的平均logMAR值从术前的0.43 ± 0.36(2040 Snellen等值)提高到0.13 ± 0.18(2025 Snellen等值)(p结论:巩膜外巩膜内固定术对患者的视力和视力都有显著的改善:使用 Gore-Tex 缝合线加巩膜瓣进行人工晶体巩膜外固定的耐受性良好,缝线外露率极低。此外,我们的研究证实术后屈光效果极佳。
{"title":"Scleral flaps, pars plana vitrectomy and gore-tex sutured posterior chamber intraocular lens placement: a case series and review of literature.","authors":"Pasquale Napolitano, Mariaelena Filippelli, Marianna Carosielli, Ciro Costagliola, Roberto Dell'Omo","doi":"10.3389/fopht.2023.1147881","DOIUrl":"10.3389/fopht.2023.1147881","url":null,"abstract":"<p><strong>Introduction: </strong>Cataract surgery is one of the most common surgical procedures performed worldwide. Intraocular lens (IOL) implants are placed routinely in the capsular bag after successful cataract extraction. However, in the absence of adequate capsular support, IOL may be placed in the anterior chamber, fixated to the iris or fixated to the sclera. The purpose of this study is to report the clinical outcomes and safety profile of a trans-scleral sutured intraocular lens (IOL) technique using scleral flaps, vitrectomy, and Gore-Tex suture to place posterior chamber IOL.</p><p><strong>Methods: </strong>Retrospective, interventional case series of eyes undergoing scleral fixation of an IOL using Gore-Tex suture with concurrent vitrectomy. Ocular examination with the logarithm of the minimum angle of resolution visual acuity (logMAR BCVA), tonometry, and slit-lamp biomicroscopy was performed on all patients at 1, 3, 6, and 12 months after the operation. All post-operative complications were recorded.</p><p><strong>Results: </strong>Twenty-five eyes of 25 patients were included. Mean logMAR BCVA improved from 0.43 ± 0.36 (2040 Snellen equivalent) preoperatively to 0.13 ± 0.18 (2025 Snellen equivalent) postoperatively at 12 months (p<0.01). Indications included surgical aphakia (16) and dislocated lens implant (9). No cases of IOL opacification, suprachoroidal haemorrhage, post-operative endophthalmitis, IOL dislocation, Gore-Tex exposure, or retinal detachment were observed during the follow-up period.</p><p><strong>Conclusion: </strong>Ab externo scleral fixation of IOLs with Gore-Tex suture plus scleral flap is well tolerated and associated with a very low rate of suture exposition. Moreover, our study confirms excellent refractive outcomes after surgery.</p>","PeriodicalId":73096,"journal":{"name":"Frontiers in ophthalmology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11182314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88516509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Target identification and validation of the alpha7 nicotinic acetylcholine receptor as a potential therapeutic target in retinal disease. 作为视网膜疾病潜在治疗靶点的 alpha7 尼古丁乙酰胆碱受体的靶点识别和验证。
Pub Date : 2023-07-24 eCollection Date: 2023-01-01 DOI: 10.3389/fopht.2023.1190439
David M Linn

The role of acetylcholine (ACh) in visual processing in the mammalian retina has been the focus of research for many decades. Pioneering work on the localization of ACh discovered that the neurotransmitter is synthesized and stored in a distinct subpopulation of amacrine (starburst) cells. It has been shown that ACh release is regulated to a low resting "tonic" level, much like what is observed at the neuromuscular junction (NMJ). If there were a dysfunction in the tonic release of ACh, might post-synaptic changes render the targets of ACh [i.e., retinal ganglion cells (RGCs)] vulnerable to disease? During my time at Pharmacia & Upjohn (PNU), selective nicotinic ACh receptor (nAChR) agonists (e.g., PNU-282987) were developed as a possible therapy for central nervous system (CNS) diseases. As RGCs are the main targets of neurodegeneration in glaucoma, could the activation of this target provide neuroprotection? In response to this question, experiments to identify alpha7 nAChRs in the retina (i.e., target ID studies) followed by "proof-of-concept" experiments were conducted. Target ID studies included binding studies with retinal homogenates, [125I]-alpha-bungarotoxin (α-BTX) autoradiography, and fluorescently tagged α-BTX binding in retinal slices. Imaging studies of intracellular calcium dynamics in the retinal slice were conducted. Reverse transcription-polymerase chain reaction (RT-PCR) analysis with alpha7 nAChR knockout mice using the "laser-capture microdissection" technique, in situ hybridization studies, and RT-PCR analysis of the human retina were conducted. Collectively, these experiments confirmed the presence of alpha7 nAChRs on specific cells in the retina. "Proof-of-concept" neuroprotection studies demonstrated that PNU-282987 provided significant protection for RGCs. This protection was dose dependent and was blocked with selective antagonists. More recently, evidence for the generation of new RGCs has been reported with PNU-282987 in rodents. Interestingly, the appearance of new RGCs is more pronounced with eye-drop application than with intravitreal injection. One could postulate that this reflects the neurogenic activation of alpha7 receptors on the retinal pigment epithelium (RPE) (eye drops) vs. a neuroprotective effect on RGCs (injections). In conclusion, there does appear to be a cholinergic retinal "tone" associated with RGCs that could be utilized as a neuroprotective therapy. However, a distinct cholinergic neurogenic mechanism also appears to exist in the outer retina that could possibly be exploited to generate new RGCs lost through various disease processes.

几十年来,乙酰胆碱(ACh)在哺乳动物视网膜视觉处理过程中的作用一直是研究的重点。关于乙酰胆碱定位的开创性研究发现,这种神经递质是在杏仁核(星状突起)细胞的一个独特亚群中合成和储存的。研究表明,ACh 的释放被调节到一个较低的静息 "强直 "水平,这与在神经肌肉接头(NMJ)观察到的情况非常相似。如果乙酰胆碱的强直性释放功能失调,突触后的变化是否会使乙酰胆碱的靶点(即视网膜神经节细胞(RGC))容易患病?我在 Pharmacia & Upjohn (PNU) 工作期间,开发了选择性烟碱 ACh 受体(nAChR)激动剂(如 PNU-282987),作为治疗中枢神经系统(CNS)疾病的一种可能疗法。由于 RGC 是青光眼神经变性的主要靶点,激活这一靶点能否提供神经保护?针对这一问题,我们进行了视网膜中 alpha7 nAChRs 的鉴定实验(即靶点 ID 研究)和 "概念验证 "实验。目标 ID 研究包括视网膜匀浆的结合研究、[125I]-α-银杏毒素(α-BTX)自显影和视网膜切片中荧光标记的 α-BTX 结合。对视网膜切片的细胞内钙动力学进行了成像研究。利用 "激光捕获显微切割 "技术对α7 nAChR基因敲除小鼠进行了反转录聚合酶链反应(RT-PCR)分析,进行了原位杂交研究,并对人类视网膜进行了RT-PCR分析。这些实验共同证实了视网膜特定细胞上存在 alpha7 nAChR。"概念验证 "神经保护研究表明,PNU-282987 能显著保护 RGC。这种保护作用与剂量有关,并被选择性拮抗剂阻断。最近,有证据表明,PNU-282987 能在啮齿动物体内生成新的 RGC。有趣的是,与玻璃体内注射相比,滴眼应用时新 RGC 的出现更为明显。可以推测,这反映了视网膜色素上皮(RPE)上的α7受体的神经源性激活(滴眼液)与对RGCs的神经保护作用(注射)。总之,似乎确实存在一种与 RGC 相关的胆碱能视网膜 "基调",可用作神经保护疗法。不过,视网膜外层似乎还存在一种独特的胆碱能神经源机制,可用于生成因各种疾病过程而丧失的新 RGC。
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引用次数: 0
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Frontiers in ophthalmology
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