scholarly journals Functional expression of complement factor I following AAV-mediated gene delivery in the retina of mice and human cells

Gene Therapy ◽  
2021 ◽  
Author(s):  
Anna K. Dreismann ◽  
Michelle E. McClements ◽  
Alun R. Barnard ◽  
Elise Orhan ◽  
Jane P. Hughes ◽  
...  
Keyword(s):  
Complement System ◽  
Functional Expression ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Complement Factor ◽  
Factor I ◽  
Complement Factor I ◽  
Age Related ◽  
The Complement System

AbstractDry age-related macular degeneration (AMD) is characterised by loss of central vision and currently has no approved medical treatment. 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. 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. Four codon optimised constructs were compared to the most common human CFI sequence. All constructs expressed CFI protein; however, most codon optimised sequences resulted in significantly reduced CFI secretion compared to the non-optimised CFI sequence. In vivo expression analysis showed that CFI was predominantly expressed in the RPE and photoreceptors. Secreted protein in vitreous humour was demonstrated to be functionally active. 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).

scholarly journals Support for the involvement of complement factor I in age-related macular degeneration

2009 ◽  
Vol 18 (1) ◽  
pp. 15-16 ◽  
Author(s):  
Sarah Ennis ◽  
Jane Gibson ◽  
Angela J Cree ◽  
Andrew Collins ◽  
Andrew J Lotery
Keyword(s):  
Macular Degeneration ◽  
Age Related Macular Degeneration ◽  
Complement Factor ◽  
Factor I ◽  
Complement Factor I ◽  
Age Related

scholarly journals Complement System and Potential Therapeutics in Age-Related Macular Degeneration

2021 ◽  
Vol 22 (13) ◽  
pp. 6851
Author(s):  
Young-Gun Park ◽  
Yong-Soo Park ◽  
In-Beom Kim
Keyword(s):  
Macular Degeneration ◽  
Complement System ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Pigment Epithelium Cell ◽  
Immune Surveillance ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
The Complement System

Age-related macular degeneration (AMD) is a complex multifactorial disease characterized in its late form by neovascularization (wet type) or geographic atrophy of the retinal pigment epithelium cell layer (dry type). The complement system is an intrinsic component of innate immunity. There has been growing evidence that the complement system plays an integral role in maintaining immune surveillance and homeostasis in AMD. Based on the association between the genotypes of complement variants and AMD occurrence and the presence of complement in drusen from AMD patients, the complement system has become a therapeutic target for AMD. However, the mechanism of complement disease propagation in AMD has not been fully understood. This concise review focuses on an overall understanding of the role of the complement system in AMD and its ongoing clinical trials. It provides further insights into a strategy for the treatment of AMD targeting the complement system.

Association of polymorphisms of complement factor I rs141853578 (G119R) with age-related macular degeneration in Iranian population

2018 ◽  
Vol 39 (3) ◽  
pp. 551-556 ◽  
Author(s):  
Mortaza Bonyadi ◽  
Neda Norouzi ◽  
Esmaeil Babaei ◽  
Mohammad Hossein Jabbarpoor Bonyadi ◽  
Alireza Javadzadeh ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Iranian Population ◽  
Age Related Macular Degeneration ◽  
Complement Factor ◽  
Factor I ◽  
Complement Factor I ◽  
Age Related

Systemic activation of the complement system in patients with advanced age-related macular degeneration

2019 ◽  
Vol 30 (5) ◽  
pp. 1061-1068 ◽  
Author(s):  
Anne M Lynch ◽  
Naresh Mandava ◽  
Jennifer L Patnaik ◽  
Ashley A Frazer-Abel ◽  
Brandie D Wagner ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Macular Degeneration ◽  
Complement System ◽  
Odds Ratio ◽  
Adjusted Odds Ratio ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Advanced Age ◽  
Age Related ◽  
The Complement System

Purpose: To examine the role of systemic activation of the complement system (assessed by levels of circulating C3a, Ba, and sC5b-9) in patients (n = 122) with advanced age-related macular degeneration, geographic atrophy, and neovascular age-related macular degeneration, compared with cataract controls (n = 27). Methods: Plasma complement factors were measured using enzyme-linked immunosorbent assays. Statistical analysis included univariate and multivariate logistic regression (p < 0.05). Results: Adjusted for age, the odds ratios of C3a and sC5b-9 for any advanced age-related macular degeneration were 1.78 (95% confidence interval = 1.16–2.73, p < 0.01) and 1.20 (95% confidence interval = 1.04–1.39, p = 0.01), respectively. We found a significantly elevated adjusted odds ratio of C3a (adjusted odds ratio = 1.71, 95% confidence interval = 1.12–2.60, p = 0.01) and sC5b-9 (adjusted odds ratio = 1.22, 95% confidence interval = 1.04–1.43, p = 0.01) for neovascular age-related macular degeneration. Adjusted for age, neither C3a, sC5b-9, nor Ba were associated with geographic atrophy. Conclusion: We suggest a role for elevated plasma levels of C3a and sC5b-9 in patients with neovascular age-related macular degeneration. The study’s results reinforce the need for more investigation to assess the impact of therapeutic interventions targeted at the complement signaling pathways in age-related macular degeneration.

A novel complement factor I involving in the complement system immune response from Lampetra morii

2020 ◽  
Vol 98 ◽  
pp. 988-994 ◽  
Author(s):  
Wanrong Lv ◽  
Anqi Ma ◽  
Xiaoyuan Chi ◽  
Qingwei Li ◽  
Yue Pang ◽  
...  
Keyword(s):  
Immune Response ◽  
Complement System ◽  
Complement Factor ◽  
Factor I ◽  
Complement Factor I ◽  
The Complement System

scholarly journals Associations of the intestinal microbiome with the complement system in age-related macular degeneration

2019 ◽  
Author(s):  
Denise Corinne Zysset-Burri ◽  
Irene Keller ◽  
Lieselotte E. Berger ◽  
Carlo R. Largiadèr ◽  
Matthias Wittwer ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Complement System ◽  
Age Related Macular Degeneration ◽  
Classification Model ◽  
Intestinal Microbiome ◽  
Complement Factor ◽  
Age Related ◽  
Potential Biomarker ◽  
The Complement System ◽  
Deficient Mice

Abstract Background: Age-related macular degeneration (AMD) is a leading cause of severe vision loss in the aged population. The etiology of AMD is multifactorial and includes nutritional factors, genetic variants mainly in the complement pathway, environmental risk factors and alterations in the intestinal microbiome. However, it remains largely unexplored whether there is an interdependency of these factors leading to the development of AMD. To investigate this issue, a comprehensive shotgun metagenomics analysis of 57 AMD and 58 healthy controls as well as of 16 complement C3 deficient mice and 16 wildtypes was performed. Single nucleotide polymorphisms (SNPs) in the complement factors were assessed with pre-designed TaqMan® SNP genotyping assays. Results: The composition of the intestinal microbiome differed significantly between AMD patients and controls. Whereas the class Negativicutes was more abundant in patients, the genus Oscillibacter and Bacteroides species had a significantly higher prevalence in persons without AMD. While SNPs within the complement factor B gene were more abundant in controls, SNPs within the high temperature requirement A serine peptidase 1 and complement factor H (CFH) genes were associated with AMD. Using a classification model, Negativicutes was identified as a potential biomarker for AMD and furthermore, it positively correlated with CFH. In addition, similar taxonomic features were identified that distinguished wildtype mice from C3 deficient mice. Conclusion: The composition of the intestinal microbiome differs between AMD patients and controls as well as between C3 deficient mice and wildtype mice. Moreover, since the phylum Firmicutes has been identified as potential biomarker for AMD and positively correlates with the genetic risk factor CFH, the study suggests an association between the intestinal microbiome and the complement system in AMD.

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