Accumulation of these byproducts may lead to increased inflammation, which is implicated in the development of GA. In phototransduction, photoreceptors exert a high metabolic demand, which results in increased production of metabolic waste products. In this review, we examine the past and current research into a pharmaceutical treatment for atrophic AMD.Visual cycle modulators are oral medications that target enzymes in the visual cycle. Due to its complexity, many therapeutic approaches have been considered, including visual cycle modulation, neuroprotection, cell-based therapy, inflammation suppression and complement inhibition. Unfortunately, there has yet to be a similar breakthrough for GA.
Latest Treatment For Wet Degen 2015 Trial Showed ThatThe modified vitamin A forms toxic vitamin A dimers more slowly, which is postulated to slow the accumulation of toxic end products and therefore slow the development and/or progression of AMD. 5ALK-001 is a modified form of vitamin A that replaces natural vitamin A in the body. Unfortunately, the Phase IIb/III clinical trial showed that oral emixustat hydrochloride was ineffective at reducing the progression of GA. In the study, 508 people were enrolled with GA secondary to macular degeneration. 4 It was studied in the Safety and Efficacy Assessment Treatment Trials of Emixustat hydrochloride (SEATTLE) study, a large randomized clinical trial for GA by Bascom Palmer’s Philip Rosenfeld, MD, and co-workers. A drug that can be delivered orally is especially attractive however, a consequence of modulating the visual cycle is that dark adaptation and low-light vision are often adversely affected.Following are the two highest-profile visual cycle modulators that have been studied.Emixustat hydrochloride (ACU-4429) is an oral non-retinoid small molecule that inhibits the visual cycle enzyme isomerohydrolase, RPE65.However, studies in animal models with systemic administration have demonstrated that it also has neuroprotective properties, though clinical trials have yet to confirm similar efficacy in humans. So far, brimonidine tartrate (Allergan) is the only agent that has shown possible neuroprotective properties that might be beneficial in GA.Brimonidine is an alpha-2 adrenergic agonist that’s an established topical ophthalmic intraocular pressure-lowering agent. Pharmacologic agents with cyto- and neuroprotective properties may help protect at-risk neuroretinal tissue by increasing its resilience and resistance to cellular injury, thereby providing a defense against GA progression. It’s currently being studied in a Phase III clinical trial for GA.Neuroprotection has been investigated as a possible solution for the problem of progressive cellular damage and eventual cell loss that occurs in atrophic AMD.![]() ![]() Compared with the control group, the rate of GA progression was lower in the brimonidine groups, but the difference wasn’t statistically significant. Patients were randomized to study-eye treatment with brimonidine tartrate DDS 200 µg (n=49), 400 µg (n=41) or sham procedure (n=23). The study evaluated 113 patients over a two-year period the primary endpoint was the change in size of GA lesion area from baseline to month 12. It’s designed to release brimonidine over six months patients receive a second injection at month six. The DDS is a biodegradable polymer drug delivery system similar to the dexamethasone implant Ozurdex (Allergan) with a 22-gauge needle attached to a proprietary applicator system. The stem cell approach involves delivering new retinal pigment epithelium cells to help maintain the health of the remaining retinal photoreceptors, which may allow damaged or dormant light-sensitive cells to return to function. The non-stem cell approach is centered on delivering cells which can produce protective factors that are deficient within the extracellular milieu. 9The immune-privileged environment of the subretinal space makes it a unique target for cell-based therapy, which consists of two approaches: stem cell- and non-stem cell-based therapies. The Phase IIa study was eventually suspended due to the significant risk of adverse events.Although palucorcel was well-tolerated in the Phase I/IIa study, the ab externo surgical approach required to access the subretinal space with a microcatheter delivery system was associated with a high rate of retinal perforations (13/35 operated subjects) and retinal detachments (6/35 operated subjects). In the first phase of the study, 29 participants received a single, subretinal dose of palucorcel of 27 µl (3.03 X 10 5 viable cells), 50 µl (6.03 X 10 4, 1.23 X 10 5 viable cells) or 50 µl (5.63 X 10 5 viable cells) via an external approach, superior to the GA lesion. 10 The initial study was a Phase I/IIa, multicenter study of subretinal palucorcel in 35 patients with bilateral GA and exudative neovascular AMD, who had no other ophthalmic conditions, and were suitable candidates for ophthalmic surgery. ![]() A total of 16 patients with advanced dry AMD were enrolled in the Phase I/IIa study. 15 The composite implant, termed the California Project to Cure Blindness-Retinal Pigment Epithelium 1 (CPCB-RPE1), is a polarized monolayer of human embryonic stem cell-derived RPE (hESC-RPE) on an ultrathin, synthetic parylene substrate designed to mimic Bruch’s membrane. The trial was initially suspended prior to enrollment due to changes in the study design and cell line but is now enrolling.Another stem cell-based approach involving a subretinal implant is being investigated by a group led by USC’s Keck Eye Institute researchers Amir Kashani, MD, and Mark Humayun, MD, in a trial sponsored by the implant’s maker, Regenerative Patch Technologies. 14 The related, Phase II PORTRAY trial of hESC-derived RPE cells in dry AMD was aimed at assessing graft rejection strategies and secondarily at change in area of GA and in visual acuity. Optical coherence tomography showed reconstitution or thickening of the RPE layer in some subjects. Parallels for mac 12 crack18,19Tetracyclines are broad-spectrum antibiotic compounds that also exhibit non-antimicrobial anti-inflammatory properties. 15,17Another group is working on a similar RPE patch as a part of The London Project to Cure Blindness. 16 The concurrent structural and functional findings suggest that CPCB-RPE1 may improve visual function. None of the implanted eyes showed progression of vision loss and one eye improved by 17 letters. In at least three subjects, the implant covered 100 percent of the area of GA, and in the last 14 patients, the area of GA coverage was greater than half.
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