Age‐related macular degeneration—emerging pathogenetic and therapeutic concepts

Abstract

Today, the average life expectancy in developed nations is over 80 years and climbing. And yet, the quality of life during those additional years is often significantly diminished by the effects of age-related, degenerative diseases, including age-related macular degeneration (AMD), the leading cause of blindness in the elderly worldwide. AMD is characterized by a progressive loss of central vision attributable to degenerative and neovascular changes in the macula, a highly specialized region of the ocular retina responsible for fine visual acuity. Estimates gathered from the most recent World Health Organization (WHO) global eye disease survey conservatively indicate that 14 million persons are blind or severely visually impaired because of AMD. The disease has a tremendous impact on the physical and mental health of the geriatric population and their families and is becoming a major public health burden.Currently, there is neither a cure nor a means to prevent AMD. Palliative treatment options for the less prevalent, late-stage 'wet' form of the disease include anti-neovascular agents, photodynamic therapy and thermal laser. There are no current therapies for the more common 'dry' AMD, except for the use of antioxidants that delay progression in 20%-25% of eyes. New discoveries, however, are beginning to provide a much clearer picture of the relevant cellular events, genetic factors, and biochemical processes associated with early AMD. Recently, compelling evidence has emerged that the innate immune system and, more specifically, uncontrolled regulation of the complement alternative pathway plays a central role in the pathobiology of AMD. The complement Factor H gene-which encodes the major inhibitor of the complement alternative pathway-is the first gene identified in multiple independent studies that confers a significant genetic risk for the development of AMD. The emergence of this new paradigm of AMD pathogenesis should hasten the development of novel diagnostic and therapeutic approaches for this disease that will dramatically improve the quality of our prolonged lifespan.

The Complement Regulatory Protein CD46 Deficient Mouse Spontaneously Develops Dry-Type Age-Related Macular Degeneration–Like Phenotype

“…2,3,6 The management of patients with dry AMD remains a significant challenge because dry AMD is managed using non-specific therapies. 11,12 Unfortunately, these therapeutic modalities do not address the underlying primary mechanisms of disease development.…”

“…2,3,6 To detect RPE autofluorescence, thick (3 mm thick) optical slices of paraffin sections from 2-and 12-month-old Cd46 À/À and WT mice were used using confocal microscopy to obtain a strong signal for analysis. Granules of autofluorescent material were occasionally detected in RPE of 2-month-old male and female Cd46 À/À and WT mice (Figure 2, AeD).…”

Exacerbation of retinal degeneration in the absence of alpha crystallins in an in vivo model of chemically induced hypoxia

“…The primary manifestations of age-related macular degeneration (AMD) are seen in the retinal pigment epithelium (RPE) layer, and dysfunction or loss of RPE will induce metabolic changes in the rest of the retina, especially the photoreceptors (Gehrs et al, 2006). Animal models of retinal degeneration have provided a better understanding of disease pathogenesis and have led to the development of novel therapeutic strategies (Delyfer et al, 2004).…”

The marine n-3 PUFA DHA evokes cytoprotection against oxidative stress and protein misfolding by inducing autophagy and NFE2L2 in human retinal pigment epithelial cells

“…7,8 Currently, for 80% to 85% of the 30 to 50 million AMD patients worldwide there are no effective treatment alternatives. 9 Therefore, one major public health challenge is to devise an effective primary prevention of AMD and to improve current treatments.…”