Treatment of Dry Age-Related Macular Degeneration

Querques, Giuseppe; Rosenfeld, Philip J.; Cavallero, Edoardo; Borrelli, Enrico; Corvi, Federico; Querques, Lea; Bandello, Francesco; Zarbin, Marco A.

doi:10.1159/000363187

Cited by 39 publications

(34 citation statements)

References 92 publications

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“…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. Because of the lack of effective therapeutic options available to the patients with dry AMD, there is a pressing need to develop additional treatments.…”

Section: Discussionmentioning

confidence: 99%

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

Lyzogubov

Bora

et al. 2016

The American Journal of Pathology

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In the mouse, membrane cofactor protein (CD46), a key regulator of the alternative pathway of the complement system, is only expressed in the eye and on the inner acrosomal membrane of spermatozoa. We noted that although Cd46 À/À mice have normal systemic alternative pathway activating ability, lack of CD46 leads to dysregulated complement activation in the eye, as evidenced by increased deposition of C5b-9 in the retinal pigment epithelium (RPE) and choroid. A knockout of CD46 induced the following cardinal features of human dry age-related macular degeneration (AMD) in 12-month-old male and female mice: accumulation of autofluorescent material in and hypertrophy of the RPE, dense deposits in and thickening of Bruch's membrane, loss of photoreceptors, cells in subretinal space, and a reduction of choroidal vessels. Collectively, our results demonstrate spontaneous age-related degenerative changes in the retina, RPE, and choroid of Cd46 À/À mice that are consistent with human dry AMD. These findings provide the exciting possibility of using Cd46 À/À mice as a convenient and reliable animal model for dry AMD. Having such a relatively straight-forward model for dry AMD should provide valuable insights into pathogenesis and a test model system for novel drug targets. More important, tissue-specific expression of CD46 gives the Cd46 À/À mouse model of dry AMD a unique advantage over other mouse models using knockout strains. Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in individuals >50 years of age in the United States and around the world. 1e5 This disease causes a progressive destruction of the macula, leading to the loss of central vision. AMD is a chronic degenerative process with multiple risk factors. 2,3,6e17 Nearly two million individuals in the United States alone are currently afflicted with AMD. This number is expected to grow in part because of increasing life expectancy. 5 Clinically, AMD is usually classified into two formsdnonexudative (dry type) and exudative (wet type). Although the dry form of AMD is more prevalent (approximately 85% of the cases) and a precursor to wet AMD, the fundamental processes underlying dry AMD are particularly not well understood. 2e4,6e10 Several agents to treat dry AMD are currently in the developmental stage. However, no effective treatment option is currently available. 11,12 Novel therapeutic targets for dry AMD need to be discovered.

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Section: Discussionmentioning

confidence: 99%

“…However, no effective treatment option is currently available. 11,12 Novel therapeutic targets for dry AMD need to be discovered.…”

mentioning

confidence: 99%

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

Lyzogubov

Bora

et al. 2016

The American Journal of Pathology

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“…The median FD plasma level was shown to be approximately 30% higher in AMD patients than in age-matched controls [69]. In view of the central role of FD in the C3 feedback loop and its raised levels in AMD, it has been suggested that it is one of the complement proteins that could be therapeutically targeted in AMD patients [76]. We have recently shown that lutein supplementation was able to markedly decrease the levels of plasma FD and the activation products C3d, C5a and sC5b-9 in patients with early AMD [77,78].…”

Section: Complement Factor Dmentioning

confidence: 99%

“…Once the damage has been done, one would tend to think that the role of complement in further damage could be limited. The fact that clinical trials show that FD blockade still has an effect in late AMD [76] indicates that the damaging effect of complement is ongoing.…”

Section: Amd: a Disease Caused By A Hyperactive Complement Systemmentioning

confidence: 99%

Age-Related Macular Degeneration: A Complementopathy?

Kijlstra¹,

Berendschot²

2015

Ophthalmic Res

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Age-related macular degeneration (AMD) is a progressive eye disease affecting many elderly individuals. It has a multifactorial pathogenesis and is associated with numerous environmental (e.g. smoking, light and nutrition) and genetic risk factors. A breakthrough in the mechanisms causing AMD is emerging; the involvement of the alternative pathway of the complement system appears to play a pivotal role. This has led to the statement that AMD is a disease caused by a hyperactive complement system, allowing the term ‘complementopathy' to define it more precisely. Abundant evidence includes: the identification of drusen components as activators of complement, immunohistochemical data showing the presence of many species of the complement system in the retinal pigment epithelium-Bruch's membrane-choroidocapillary region of AMD eyes, a strong association of AMD with certain genetic complement protein variants, raised complement levels in blood from AMD patients and the preliminary successful treatments of geographic atrophy with complement factor D (FD) inhibitors. FD is the rate-limiting enzyme of the alternative complement pathway, and is produced by adipose tissue. Recent findings suggest that nutrition may play a role in controlling the level of FD in the circulation. Addressing modifiable risk factors such as smoking and nutrition may thus offer opportunities for the prevention of AMD.

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“…As in many other diseases with an inflammatory component, the alternative complement pathway has been implicated in the development of AMD [5]; this mechanism of action is now well known and described [6]. …”

Section: Inhibitors Of Complement Factorsmentioning

confidence: 99%

Emerging Therapeutic Options in Age-Related Macular Degeneration

et al. 2015

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Intravitreal injection of anti-VEGF drugs currently represents the standard of treatment for exudative age-related macular degeneration. Several therapeutic options including steroids, inhibitors of complement factors, anti-platelet-derived growth factor agents, new anti-VEGF drugs, designed ankyrin repeat proteins, sustained drug delivery devices as an alternative to intravitreal injections and encapsulated cell technology are the objects of several studies and trials worldwide in association with anti-VEGF therapy or not. Expectations are that such efforts will help overcome limitations of current therapy with anti-VEGF, extending the duration of effects and hopefully contributing to the regression of neovascular lesions.

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Treatment of Dry Age-Related Macular Degeneration

Cited by 39 publications

References 92 publications

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

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

Age-Related Macular Degeneration: A Complementopathy?

Emerging Therapeutic Options in Age-Related Macular Degeneration

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