Revisiting the role of factor H in age-related macular degeneration: Insights from complement-mediated renal disease and rare genetic variants

Tzoumas, Nikolaos; Hallam, Dean; Harris, Claire L.; Lako, Majlinda; Kavanagh, David; Steel, David

doi:10.1016/j.survophthal.2020.10.008

Cited by 22 publications

(22 citation statements)

References 250 publications

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“…Aggregates of lipids and proteins ("drusen") associated with AMD are similar in molecular composition to amyloid beta (Ab) plaques [55]. Treatment for AMD currently involves the use of repurposed anti-angiogenic compounds [56]. Once again, in the context of these other diseases, the new approach described here to repurpose anti-cancer drugs for modulating cerebral neoangiogenesis in AD shows considerable promise in a preclinical model and may prove efficacious in treating AD patients.…”

Section: Discussionmentioning

confidence: 99%

Reversing pathology in a preclinical model of Alzheimer's disease by hacking cerebrovascular neoangiogenesis with advanced cancer therapeutics

et al. 2021

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Background: Cognitive decline leading to dementia, accompanied by the accumulation of amyloid-beta (Ab) in neuritic plaques together with the appearance of neurofibrillary tangles (NFT) composed of hyperphosphorylated tau protein (tau), are previously noted hallmarks of Alzheimer's disease (AD). We previously discovered hypervascularity in brain specimens from AD patients and consistent with this observation, we demonstrated that overexpression of Ab drives cerebrovascular neoangiogenesis leading to hypervascularity and coincident tightjunction disruption and blood-brain barrier (BBB) leakiness in animal models of AD. We subsequently demonstrated that amyloid plaque burden and cerebrovascular pathogenesis subside when pro-angiogenic Ab levels are reduced. Based on these data, we propose a paradigm of AD etiology where, as a compensatory response to impaired cerebral blood flow (CBF), Ab triggers pathogenic cerebrovascular neoangiogenesis that underlies the conventional hallmarks of AD. Consequently, here we present evidence that repurposing anti-cancer drugs to modulate cerebrovascular neoangiogenesis, rather than directly targeting the amyloid cascade, may provide an effective treatment for AD and related vascular diseases of the brain. Methods: We explored whether the anti-cancer drug, Axitinib, a small molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors (VEGFR) can inhibit aberrant cerebrovascular neoangiogenic changes, reduce Ab deposits and reverse cognitive decline in an animal model of AD. One month posttreatment with Axitinib, we employed a battery of tests to assess cognition and memory in aged Tg2576 AD mice and used molecular analysis to demonstrate reduction of amyloid plaques, BBB leakage, hypervascularity and associated disease pathology. Findings: Targeting the pro-angiogenic pathway in AD using the cancer drug, Axitinib, dramatically reduced cerebrovascular neoangiogenesis, restored BBB integrity, resolved tight-junction pathogenesis, diminishes Ab depositions in plaques and effectively restores memory and cognitive performance in a preclinical mouse model of AD. Interpretation: Modulation of neoangiogenesis, in an analogous approach to those used to treat aberrant vascularization in cancer and also in the wet form of age-related macular degeneration (AMD), provides an alternative therapeutic strategy for intervention in AD that warrants clinical investigation.

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Section: Discussionmentioning

confidence: 99%

Reversing pathology in a preclinical model of Alzheimer's disease by hacking cerebrovascular neoangiogenesis with advanced cancer therapeutics

et al. 2021

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“…Specifically, although CP commonly responds to antigen-antibody complexes and LP is started by mannosebinding lectin (MBL) and identification of the polysaccharide or glycoprotein motif on the damaged cell surface [14], both of them will produce a common membrane-bound C4b2a (classical C3 convertase) afterwards. Furthermore, AP can be activated in two ways: by spontaneous hydrolysis of C3 into C3(H 2 O) in the fluid phase, also known as "tick-over," and by C4b2a (C3 convertase) to cleave C3 into C3a and C3b in the solid phase [6,15]. Subsequently, both C3(H 2 O) and C3b can be bonded by factor B (FB) and factor D (FD) to form C3(H 2 O)Bb and C3bBb, respectively.…”

Section: Complement System and Amdmentioning

confidence: 99%

“…It is worth mentioning that 42% Europeans are heterozygous for the Y402H variant, which is regarded to be consistently associated with the occurrence and progression of AMD. It is reported that homozygous individuals have about 7-fold greater odds of relationship with AMD, while heterozygotes own 2-to 3-fold greater odds of relationship with the disease [15]. The inhibitory effect of FH on the complement system is assumed to be reduced owing to the decreased binding affinity of many complement components of the damaged retina led by the Y402H variant, which further results in excessive chronic local inflammation to occur [49,60,61].…”

Section: Genetic Studies Of Complement System In Amdmentioning

confidence: 99%

Complement Inhibitors in Age-Related Macular Degeneration: A Potential Therapeutic Option

Qin

Dong

Yang

et al. 2021

Journal of Immunology Research

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Age-related macular degeneration (AMD) is a multifactorial disease, which can culminate in irreversible vision loss and blindness in elderly. Nowadays, there is a big gap between dry AMD and wet AMD on treatment. Accounting for nearly 90% of AMD, dry AMD still lacks effective treatment. Numerous genetic and molecular researches have confirmed the significant role of the complement system in the pathogenesis of AMD, leading to a deeper exploration of complement inhibitors in the treatment of AMD. To date, at least 14 different complement inhibitors have been or are being explored in AMD in almost 40 clinical trials. While most complement inhibitors fail to treat AMD successfully, two of them are effective in inhibiting the rate of GA progression in phase II clinical trials, and both of them successfully entered phase III trials. Furthermore, recently emerging complement gene therapy and combination therapy also offer new opportunities to treat AMD in the future. In this review, we aim to introduce genetic and molecular associations between the complement system and AMD, provide the updated progress in complement inhibitors in AMD on clinical trials, and discuss the challenges and prospects of complement therapeutic strategies in AMD.

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“…Atypical haemolytic uraemic syndrome (aHUS) ( 1 ), membranoproliferative glomerulonephritis (MPGN), C3 glomerulopathy (C3G) ( 2 ) and age-related macular degeneration (AMD) ( 3 ) are all diseases that have been associated with dysregulation of the alternative pathway (AP) of complement.…”

Section: Introductionmentioning

confidence: 99%

Functional Characterization of Rare Genetic Variants in the N-Terminus of Complement Factor H in aHUS, C3G, and AMD

et al. 2021

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Membranoproliferative glomerulonephritis (MPGN), C3 glomerulopathy (C3G), atypical haemolytic uraemic syndrome (aHUS) and age-related macular degeneration (AMD) have all been strongly linked with dysfunction of the alternative pathway (AP) of complement. A significant proportion of individuals with MPGN, C3G, aHUS and AMD carry rare genetic variants in the CFH gene that cause functional or quantitative deficiencies in the factor H (FH) protein, an important regulator of the AP. In silico analysis of the deleteriousness of rare genetic variants in CFH is not reliable and careful biochemical assessment remains the gold standard. Six N-terminal variants of uncertain significance in CFH were identified in patients with these diseases of the AP and selected for analysis. The variants were produced in Pichia Pastoris in the setting of FH CCPs 1–4, purified by nickel affinity chromatography and size exclusion and characterized by surface plasmon resonance and haemolytic assays as well as by cofactor assays in the fluid phase. A single variant, Q81P demonstrated a profound loss of binding to C3b with consequent loss of cofactor and decay accelerating activity. A further 2 variants, G69E and D130N, demonstrated only subtle defects which could conceivably over time lead to disease progression of more chronic AP diseases such as C3G and AMD. In the variants S159N, A161S, and M162V any functional defect was below the capacity of the experimental assays to reliably detect. This study further underlines the importance of careful biochemical assessment when assigning functional consequences to rare genetic variants that may alter clinical decisions for patients.

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Revisiting the role of factor H in age-related macular degeneration: Insights from complement-mediated renal disease and rare genetic variants

Cited by 22 publications

References 250 publications

Reversing pathology in a preclinical model of Alzheimer's disease by hacking cerebrovascular neoangiogenesis with advanced cancer therapeutics

Reversing pathology in a preclinical model of Alzheimer's disease by hacking cerebrovascular neoangiogenesis with advanced cancer therapeutics

Complement Inhibitors in Age-Related Macular Degeneration: A Potential Therapeutic Option

Functional Characterization of Rare Genetic Variants in the N-Terminus of Complement Factor H in aHUS, C3G, and AMD

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