# Complement Factor H-based Therapeutic Strategies in Macular Degeneration

> **NIH VA I01** · RALPH H JOHNSON VA MEDICAL CENTER · 2024 · —

## Abstract

Age-related macular degeneration (AMD) is a slowly progressing disease involving genetic abnormalities
and environmental insults. It is the leading cause of blindness for older Americans; and as the population
ages, the prevalence of AMD continues to grow. Since smoking increases AMD risk and there is a higher
incidence of smoking in veterans, disproportionally more veterans will be affected. Treatments are available
for choroidal neovascularization (CNV); but those come with risks and only target a subpopulation of AMD
patients. No treatment is available for early AMD and geographic atrophy (GA; >85% of all cases), making it
paramount to develop a treatment for early disease intervention. While mechanistic studies have shown that
inflammation and smoking are fundamental components of AMD, genetic studies have demonstrated that
polymorphisms in complement proteins each increase the risk for developing AMD. One of the most detri-
mental mutation occurs in factor H (fH) an essential inhibitor in the complement alternative pathway (AP),
suggesting that inadequate control of complement-driven inflammation is a major AMD risk factor. To date,
complement therapeutics in GA have not been FDA approved. Approaches included blocking complement
factor C3 and C5 (activators in the terminal pathway) or factor D (fD; AP activator). What these strategies
had in common was that most of the drug was wasted on non-pathophysiologically important target mole-
cules; i.e., most complement components in fluids or tissue are not engaged in complement activation and
hence to reduce complement activation at the ocular target sites [basal RPE, Bruch’s membrane (BrM) or
choriocapillaris (CC)], the majority of a given complement component has to be permanently inhibited to
achieve the desired effect. In addition, complement components are made in the eye and systemically, and
many complement components can penetrate BrM; hence an almost unlimited reservoir of complement pro-
teins exists that needs to be controlled. Given these complications, we propose to build on our data utilizing
an “addressable” inhibitor that target to sites of complement activation regardless of the location (CR2-fH)
delivered via gene therapy, as well as antibody to monitor complement activation. First, we will utilize hu-
man iPSC-RPE cells to examine efficacy of AAV-CR2-fH in complement-mediated RPE pathology, focusing
on control and cells with AMD genetic risk factors, assaying complement activation and deposit formation.
Second, both diagnosis and monitoring of efficacy of treatment would benefit from in vivo tools to monitor
complement activation. We have developed tools (antibodies and nanobodies) as well as fluorescence
quenched C3 convertase-specific substrate for monitoring of complement activation in tissues and ocular
fluids, which will be tested in animals and iPSC-RPE cultures. Overall, this work is designed to move anti-
complement therapy towards clinical application, with the long-te...

## Key facts

- **NIH application ID:** 10855098
- **Project number:** 2I01RX000444-14A1
- **Recipient organization:** RALPH H JOHNSON VA MEDICAL CENTER
- **Principal Investigator:** Baerbel Rohrer
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2010-07-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10855098

## Citation

> US National Institutes of Health, RePORTER application 10855098, Complement Factor H-based Therapeutic Strategies in Macular Degeneration (2I01RX000444-14A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10855098. Licensed CC0.

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