Emerging Treatment Options for Geographic Atrophy (GA) Secondary to Age-Related Macular Degeneration

Abstract

Age-related macular degeneration (AMD) is characterized as a chronic, multifactorial disease and is the leading cause of irreversible blindness. Advanced AMD is classified as neovascular (wet) AMD and non-neovascular (dry) AMD. Dry AMD can progress to a more advanced form that manifests as geographic atrophy (GA), which significantly threatens vision, leading to progressive and irreversible loss of visual function. There are currently no approved therapeutics commercially available for GA patients. However, data from various clinical trials have demonstrated favorable results with significant reduction in GA lesion growth. This review furthers the understanding of the pathophysiology of GA, as well as current clinical trial data on investigational therapeutics.

Review of Gene Therapy Clinical Trials for Retinal Diseases

“…Nonexudative age-related macular degeneration GT005 GT005 (Gyroscope Therapeutics) is an AAV2 vector gene therapy agent that increases complement factor I (CFI) in an effort to downregulate an overactive complement cascade as a means of slowing the progression of geographic atrophy (GA) secondary to nonexudative age-related macular degeneration (neAMD). 22 Atrophy of the retinal pigment epithelium (RPE), photoreceptors, and choriocapillaris results from advanced AMD manifesting as GA and can cause irreversible vision loss. Over 50% of patients suffering from GA have been found to have mutations in complement cascade regulatory proteins, leading to upregulation of the humoral immune response in retinal cells.…”

“…GT005 (Gyroscope Therapeutics) is an AAV2 vector gene therapy agent that increases complement factor I (CFI) in an effort to downregulate an overactive complement cascade as a means of slowing the progression of geographic atrophy (GA) secondary to nonexudative age-related macular degeneration (neAMD) 22 . Atrophy of the retinal pigment epithelium (RPE), photoreceptors, and choriocapillaris results from advanced AMD manifesting as GA and can cause irreversible vision loss.…”

Replenishing Age-Related Decline of IRAK-M Expression in Retinal Pigment Epithelium Attenuates Outer Retinal Degeneration

“…Specifically, rare coding variants in regulatory genes of complement such as CFH and CFI have been associated with AMD risk. This knowledge has led to developing therapeutics, including complement inhibitors and gene therapies for augmenting regulators of complement pathway ( 8, 9 ). Notwithstanding there remain a number of pathological pathways implicated in the pathogenesis of AMD, including oxidative stress and innate immune responses ( 10, 11 ).…”

Small-Molecule Drug Repurposing for Counteracting Phototoxic A2E Aggregation

“…Age-related macular degeneration (AMD) is the leading worldwide cause of irreversible blindness in the elderly . The dry (atrophic) form of the disease is the most prevalent form of AMD. , Current treatment options are limited to the recently approved C3 convertase inhibitor pegcetacoplan, , which provides a mild reduction in lesion growth. The yellow-brown “wear and tear” pigment lipofuscin is implicated in the etiology and progression of dry AMD. , The best-known component of lipofuscin is the pyridinium bis-retinoid N -retinylidene- N -retinylethanolamine (A2E), a fluorescent byproduct of the visual cycle derived from two molecules of vitamin A aldehyde and one ethanolamine .…”

“…1 The dry (atrophic) form of the disease is the most prevalent form of AMD. 2,3 Current treatment options are limited to the recently approved C3 convertase inhibitor pegcetacoplan, 4,5 which provides a mild reduction in lesion growth. The yellowbrown "wear and tear" pigment lipofuscin is implicated in the etiology and progression of dry AMD.…”