McGrady Nolan R, Pasini Silvia, Baratta Robert O, Del Buono Brian J, Schlumpf Eric, Calkins David J
Department of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN, United States.
Stuart Therapeutics, Inc., Stuart, FL, United States.
Front Pharmacol. 2021 Nov 2;12:764709. doi: 10.3389/fphar.2021.764709. eCollection 2021.
Optic neuropathies are a major cause of visual disabilities worldwide, causing irreversible vision loss through the degeneration of retinal ganglion cell (RGC) axons, which comprise the optic nerve. Chief among these is glaucoma, in which sensitivity to intraocular pressure (IOP) leads to RGC axon dysfunction followed by outright degeneration of the optic projection. Current treatments focus entirely on lowering IOP through topical hypotensive drugs, surgery to facilitate aqueous fluid outflow, or both. Despite this investment in time and resources, many patients continue to lose vision, underscoring the need for new therapeutics that target neurodegeneration directly. One element of progression in glaucoma involves matrix metalloproteinase (MMP) remodeling of the collagen-rich extracellular milieu of RGC axons as they exit the retina through the optic nerve head. Thus, we investigated the ability of collagen mimetic peptides (CMPs) representing various single strand fractions of triple helix human type I collagen to protect RGC axons in an inducible model of glaucoma. First, using dorsal root ganglia maintained on human type I collagen, we found that multiple CMPs significantly promote neurite outgrowth (+35%) compared to vehicle following MMP-induced fragmentation of the 1(I) and 2(I) chains. We then applied CMP to adult mouse eyes following microbead occlusion to elevate IOP and determined its influence on anterograde axon transport to the superior colliculus, the primary RGC projection target in rodents. In glaucoma models, sensitivity to IOP causes early degradation in axon function, including anterograde transport from retina to central brain targets. We found that CMP treatment rescued anterograde transport following a 3-week +50% elevation in IOP. These results suggest that CMPs generally may represent a novel therapeutic to supplement existing treatments or as a neuroprotective option for patients who do not respond to IOP-lowering regimens.
视神经病变是全球视力残疾的主要原因，通过构成视神经的视网膜神经节细胞（RGC）轴突的退化导致不可逆转的视力丧失。其中最主要的是青光眼，对眼内压（IOP）的敏感性导致RGC轴突功能障碍，随后视神经投射完全退化。目前的治疗完全集中在通过局部降压药物、促进房水流出的手术或两者结合来降低IOP。尽管在时间和资源上投入巨大，但许多患者仍继续丧失视力，这凸显了直接针对神经退行性变的新疗法的必要性。青光眼进展的一个因素涉及RGC轴突通过视神经乳头离开视网膜时，富含胶原蛋白的细胞外环境的基质金属蛋白酶（MMP）重塑。因此，我们研究了代表三螺旋人I型胶原蛋白各种单链片段的胶原模拟肽（CMP）在青光眼诱导模型中保护RGC轴突的能力。首先，使用在人I型胶原蛋白上培养的背根神经节，我们发现与载体相比，在MMP诱导的1（I）和2（I）链断裂后，多种CMP显著促进神经突生长（+35%）。然后，我们在微珠阻塞后将CMP应用于成年小鼠眼睛以升高IOP，并确定其对向啮齿动物主要RGC投射目标上丘的顺行轴突运输的影响。在青光眼模型中，对IOP的敏感性导致轴突功能早期退化，包括从视网膜到中枢脑目标的顺行运输。我们发现，在IOP升高50%持续3周后，CMP治疗挽救了顺行运输。这些结果表明，CMPs一般可能代表一种新的治疗方法，以补充现有治疗，或作为对降低IOP方案无反应的患者的神经保护选择。
