Herein partially summarizes one scientist-clinician's wanderings through the jungles of primate aqueous humor outflow over the past ~45 years. Totally removing the iris has no effect on outflow facility or its response to pilocarpine, whereas disinserting the ciliary muscle (CM) from the scleral spur/trabecular meshwork (TM) completely abolishes pilocarpine's effect. Epinephrine increases facility in CM disinserted eyes. Cytochalasins and latrunculins increase outflow facility, subthreshold doses of cytochalasins and epinephrine given together increase facility, and phalloidin, which has no effect on facility, partially blocks the effect of both cytochalasins and epinephrine. H-7, ML7, Y27632 and nitric oxide – donating compounds all increase facility, consistent with a mechanosensitive TM/SC. Adenosine A1 agonists increase and angiotensin II decrease facility. OCT and optical imaging techniques now permit visualization and digital recording of the distal outflow pathways in real time. Prostaglandin (PG) F2α analogues increase the synthesis and release of matrix metalloproteinases by the CM cells, causing remodeling and thinning of the interbundle extracellular matrix (ECM), thereby increasing uveoscleral outflow and reducing IOP. Combination molecules (one molecule, two or more effects) and fixed combination products (two molecules in one bottle) simplify drug regimens for patients. Gene and stem cell therapies to enhance aqueous outflow have been successful in laboratory models and may fill an unmet need in terms of patient compliance, taking the patient out of the delivery system. Functional transfer of genes inhibiting the rho cascade or decoupling actin from myosin increase facility, while genes preferentially expressed in the glaucomatous TM decrease facility. In live NHP, reporter genes are expressed for 2+ years in the TM after a single intracameral injection, with no adverse reaction. However, except for one recent report, injection of facility-effective genes in monkey organ cultured anterior segments (MOCAS) have no effect in live NHP. While intracameral injection of an FIV. BOVPGFS-myc.GFP PGF synthase vector construct reproducibly induces an ~2 mmHg reduction in IOP, the effect is much less than that of topical PGF_2⍺ analogue eyedrops, and dissipates after 5 months. The turnoff mechanism has yet to be defeated, although proteasome inhibition enhances reporter gene expression in MOCAS. Intracanalicular injection might minimize off-target effects that activate turn-off mechanisms. An AD-P21 vector injected sub-tenon is effective in ‘right-timing’ wound healing after trabeculectomy in live laser-induced glaucomatous monkeys. In human (H)OCAS, depletion of TM cells by saponification eliminates the aqueous flow response to pressure elevation, which can be restored by either cultured TM cells or by IPSC-derived TM cells.

There were many other steps along the way, but much was accomplished, biologically and therapeutically over the past half century of research and development focused on one very small but complex ocular apparatus. I am deeply grateful for this award, named for a giant in our field that none of us can live up to.

本文部分总结了一位科学家兼临床医生在过去约 45 年里在灵长类动物房水流出丛林中的徘徊。完全去除虹膜对流出设施或其对毛果芸香碱的反应没有影响，而从巩膜刺/小梁网（TM）中去除睫状肌（CM）则完全消除了毛果芸香碱的作用。肾上腺素可增加 CM 脱离眼睛的便利性。细胞松弛素和latrunculins增加流出能力，阈下剂量的细胞松弛素和肾上腺素一起给予增加能力，而鬼笔环肽对能力没有影响，部分阻断细胞松弛素和肾上腺素的作用。 H-7、ML7、Y27632 和一氧化氮 - 捐赠化合物均增加设施，与机械敏感 TM/SC 一致。腺苷 A1 激动剂增加而血管紧张素 II 减少。 OCT 和光学成像技术现在可以实时可视化和数字记录远端流出路径。前列腺素 (PG) F2α 类似物增加 CM 细胞基质金属蛋白酶的合成和释放，导致束间细胞外基质 (ECM) 重塑和变薄，从而增加葡萄膜巩膜流出并降低 IOP。组合分子（一种分子，两种或更多种作用）和固定组合产品（一瓶中两种分子）简化了患者的药物治疗方案。增强房水流出的基因和干细胞疗法已在实验室模型中取得成功，并且可能填补患者依从性方面未满足的需求，使患者脱离输送系统。抑制 rho 级联或将肌动蛋白与肌球蛋白解偶联的基因的功能转移会增加功能，而在青光眼 TM 中优先表达的基因会减少功能。 在活体 NHP 中，单次前房注射后，报告基因在 TM 中表达 2 年以上，且无不良反应。然而，除了最近的一份报告外，在猴器官培养前段（MOCAS）中注射设施有效基因对活体 NHP 没有影响。同时前房内注射 FIV。 BOVPGFS-myc.GFP PGF 合酶载体构建体可重复地诱导 IOP 降低约 2 mmHg，其效果远低于局部 PGF _2⍺类似滴眼液的效果，并在 5 个月后消失。尽管蛋白酶体抑制增强了 MOCAS 中报告基因的表达，但关闭机制尚未被克服。管内注射可能会最大限度地减少激活关闭机制的脱靶效应。在活体激光诱导青光眼猴中进行小梁切除术后，在眼球筋膜下注射 AD-P21 载体可有效促进“适时”伤口愈合。在人类 (H)OCAS 中，皂化作用耗尽 TM 细胞消除了水流对压力升高的反应，这可以通过培养的 TM 细胞或 IPSC 衍生的 TM 细胞来恢复。

一路上还有许多其他步骤，但在过去半个世纪的研究和开发中，在生物学和治疗学上都取得了很大的成就，重点是一种非常小但复杂的眼部装置。我非常感谢这个奖项，它以我们领域中无人能及的巨人的名字命名。