Rare Dysfunctional Complement Factor I Genetic Variants and Progression to Advanced Age-Related Macular Degeneration

Seddon, Johanna M.; Rosner, Bernard; De, Dikha; Huan, Tianxiao; Java, Anuja; Atkinson, John P.

doi:10.1016/j.xops.2022.100265

Cited by 3 publications

(3 citation statements)

References 30 publications

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“…Despite convincing and robust genetic links to AMD reported for Type I CFI variants 19–22 , this study observed no difference in biomarker response when comparing CFI RV carriers to the broad population. Interestingly, emerging data have revealed more modest ORs for CFI RVs in progression from early to late AMD 23 and macular thinning was observed in UK Biobank eyes of carriers <60 years old 38 . Moreover, the long-term effects of complement therapy on the progression of GA are still uncertain.…”

Section: Discussionmentioning

confidence: 99%

“…FI, expressed from the CFI gene, cleaves C3b by forming a trimolecular complex with cofactors FH for C3b, and MCP and CR1 for C3b and C4b 12–18 . Studies have shown that carriers of rare variants (RV) in CFI have increased risk of developing advanced AMD and more rapid disease progression 19–23 . CFI RV can result in low levels of serum FI (Type I variants) or normal levels with functional impairment (Type II variants) 24,25 .…”

Section: Introductionmentioning

confidence: 99%

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Ocular biomarker profiling after complement factor I gene therapy in geographic atrophy secondary to age-related macular degeneration

Hallam,

Gardenal,

McBlane

et al. 2024

Preprint

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ObjectiveComplement biomarker analysis in ocular fluid samples from subjects with geographic atrophy (GA) in a Phase I/II clinical trial of subretinal AAV2 complement factor I (CFI; FI) gene therapy, PPY988 (formerly GT005), to understand target pharmacokinetics/pharmacodynamics. Clinical findings were subsequently utilized to investigate the therapeutic dose in anin vitrocomplement activation assay.Design, setting and participantsBiomarker data were evaluated from 28 subjects in FOCUS, a Phase I/II clinical trial evaluating the safety and efficacy of three ascending doses of PPY988.Main outcomes and measuresVitreous humor (VH), and aqueous humor (AH) from subjects before surgery and at serial timepoints (week 5 or 12, 36, 96) were evaluated for changes in levels of intact complement factors I, B and H (FI, FB, FH) components C3, C4, and C1q and breakdown products (Ba, C3a, C3b/iC3b, C4b) using validated assays and OLINK®proteomics.A modifiedin vitroassay of complement activation modelling VH complement concentrations was used to compare PPY988 potency to the approved intravitreal C3 inhibitor pegcetacoplan (Apellis) and complement Factor H (FH).ResultsAn average 2-fold increase in VH FI was observed post-treatment at week 36 and week 96. This correlated with a marked post-treatment reduction in VH concentration of the FB breakdown product Ba and Ba:FB ratio, but minimal changes in C3a and C3b/iC3b levels. Variable concordance in complement biomarker levels in VH versus AH suggest AH is not a reliable proxy for VH for complement activation. During the experimental comparison of doses, a 2-fold increase of FI achieved in the vitreous had only a minor effect on the complement amplification loopin vitro, indicating limited impact [IC50: 1229nM]. Pegcetacoplan completely blocks C3a generation at concentrations much lower than the estimated trough level for monthly intravitreal injections [IC50: 2nM]. Supplementation with FH in the assay revealed similar potency to pegcetacoplan [IC50: 6nM].Conclusions and relevancePPY988 subretinal gene therapy may not have provided sufficient FI protein to meaningfully modulate complement activation to slow GA growth. Reviewing VH biomarkers is important for understanding target expression, pathway engagement, and determining optimal dose, thereby informing future clinical development.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ocular biomarker profiling after complement factor I gene therapy in geographic atrophy secondary to age-related macular degeneration

Hallam,

Gardenal,

McBlane

et al. 2024

Preprint

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“…The Age-Related Maculopathy targeted sequencing study (ARTS) included 2,576 participants, 1,757 cases and 819 controls from the Seddon Longitudinal Cohort Study ( Seddon et al, 2013 ; Ferrara and Seddon, 2015 ; Seddon, 2017 ; Seddon and Rosner, 2019 ; Seddon et al, 2023 ). Board-certified ophthalmologists evaluated cases and control subjects.…”

Section: Methodsmentioning

confidence: 99%

Risk and protection of different rare protein-coding variants of complement component C4A in age-related macular degeneration

Seddon,

De,

Casazza

et al. 2024

Front. Genet.

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Introduction: Age-related macular degeneration (AMD) is the leading cause of central vision loss in the elderly. One-third of the genetic contribution to this disease remains unexplained.Methods: We analyzed targeted sequencing data from two independent cohorts (4,245 cases, 1,668 controls) which included genomic regions of known AMD loci in 49 genes.Results: At a false discovery rate of <0.01, we identified 11 low-frequency AMD variants (minor allele frequency <0.05). Two of those variants were present in the complement C4A gene, including the replacement of the residues that contribute to the Rodgers-1/Chido-1 blood group antigens: [VDLL1207-1210ADLR (V1207A)] with discovery odds ratio (OR) = 1.7 (p = 3.2 × 10−5) which was replicated in the UK Biobank dataset (3,294 cases, 200,086 controls, OR = 1.52, p = 0.037). A novel variant associated with reduced risk for AMD in our discovery cohort was P1120T, one of the four C4A-isotypic residues. Gene-based tests yielded aggregate effects of nonsynonymous variants in 10 genes including C4A, which were associated with increased risk of AMD. In human eye tissues, immunostaining demonstrated C4A protein accumulation in and around endothelial cells of retinal and choroidal vasculature, and total C4 in soft drusen.Conclusion: Our results indicate that C4A protein in the complement activation pathways may play a role in the pathogenesis of AMD.

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Comprehensive functional characterization of complement factor I rare variant genotypes identified in the SCOPE geographic atrophy cohort

Hallam,

Andreadi,

Sharp

et al. 2024

Journal of Biological Chemistry

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Rare Dysfunctional Complement Factor I Genetic Variants and Progression to Advanced Age-Related Macular Degeneration

Cited by 3 publications

References 30 publications

Ocular biomarker profiling after complement factor I gene therapy in geographic atrophy secondary to age-related macular degeneration

Ocular biomarker profiling after complement factor I gene therapy in geographic atrophy secondary to age-related macular degeneration

Risk and protection of different rare protein-coding variants of complement component C4A in age-related macular degeneration

Comprehensive functional characterization of complement factor I rare variant genotypes identified in the SCOPE geographic atrophy cohort

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