8/11/2023 0 Comments Function of retina in human eye![]() The initial C3b is generated by classical or lectin pathway activation or by activated factors of the coagulation, contact activation and fibrinolysis systems (reviewed in ). The resulting C3b can form another C3 convertase with CFB and thereby creates a positive feedback amplification mechanism that leads to rapid multiplication of C3b molecules and complement effector proteins. It depends on the so-called ‘tick-over’ mechanism (more recently described in ) and is initiated by binding of CFB to C3b which forms the AP C3 convertase, C3bBb, that cleaves C3 into C3b. The alternative pathway (AP) can be activated on protected surfaces but mainly acts as a powerful amplification mechanism of the other two pathways. ![]() The first two pathways are activated by binding of their recognition molecules to IgG or IgM immune complexes, C-reactive protein, pentraxin 3, RNA, DNA, extracellular matrix proteins, altered self-structures such as beta-amyloid, apoptotic or necrotic cells, microorganism derived ligands, like LPS or carbohydrate structures on microorganisms or altered self-cells. The complement system is a critical component of the immune system and can be activated via the classical, lectin, or alternative pathway. Together, these findings implicate loss of complement regulatory control in AMD pathogenesis. These findings have since been confirmed in further independent studies and low serum CFI levels associated with the presence of rare CFI variants were found to be associated with a much higher risk of developing advanced AMD (P = 5.6E-05). Mutations in Complement C3, Complement Factor I (CFI), Complement Factor H (CFH) and Complement Factor B (CFB) genes strongly correlate with the likelihood of developing AMD, with CFI highlighted as particularly significant. The accumulation of complement proteins may act as a depot of continual complement stimulation by triggering local production of inflammatory mediators and attracting leukocytes that further augment the local inflammatory state, driving AMD pathology. Moreover, oxidative stress was linked to AMD through formation of neoepitopes that bind to autoantibodies capable of activating complement. Genome wide association studies (GWAS) further revealed an association of disease with key regulatory proteins of the complement system. Complement proteins are accumulated in drusen, one of the main hallmarks of early AMD, and Bruch’s membrane plasma, aqueous or vitreous humour levels of complement activation fragments C3a, C3dg, Bb and C5a are increased in AMD patients. The complement system, a major effector arm of innate and adaptive immunity, is thought be involved in disease pathology. The exact molecular pathways leading to disease are not yet identified however, it is established that AMD is a complex disease and that genetic predisposition together with environmental and demographic factors play a significant role. ![]() Late stage AMD is divided into wet AMD and geographic atrophy (GA), the former currently being treated with anti-VEGF therapeutics, while for the latter there is currently no approved medical treatment. ![]() While the early stages of the disease are characterised by slight disturbances in vision, such as blurred or distorted vision, late stage forms can be associated with severe sight loss that has a dramatic impact on the lives of affected individuals. The findings presented here have led to the formulation of an AAV-vectored gene therapy product currently being tested in a first-in-human clinical trial in subjects with geographic atrophy secondary to dry AMD (NCT03846193).Īge-related macular degeneration (AMD) is the most common cause of blindness amongst the elderly in the industrialised world, affecting approximately 36 to 40 million people globally. Secreted protein in vitreous humour was demonstrated to be functionally active. In vivo expression analysis showed that CFI was predominantly expressed in the RPE and photoreceptors. All constructs expressed CFI protein however, most codon optimised sequences resulted in significantly reduced CFI secretion compared to the non-optimised CFI sequence. Four codon optimised constructs were compared to the most common human CFI sequence. In this study, we demonstrate the generation of AAV constructs carrying the human CFI sequence and expression of CFI in cell lines and in the retina of C57BL/6 J mice. Dysregulation of the complement system is thought to play an important role in disease pathology and supplementation of Complement Factor I (CFI), a key regulator of the complement system, has the potential to provide a treatment option for AMD. Dry age-related macular degeneration (AMD) is characterised by loss of central vision and currently has no approved medical treatment.
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