AAV Gene Augmentation of Truncated Complement Factor H Differentially Rescues Ocular Complement Dysregulation in a...

Area of Science:

• Ophthalmology
• Immunology
• Genetics

Background:

• Complement dysregulation in the eye is linked to age-related macular degeneration (AMD).
• Genetic variants of complement factor H (CFH) are strongly associated with AMD risk.
• Understanding the ocular roles of CFH and its splice variant, factor H-like 1 (FHL-1), is vital for AMD pathogenesis.

Purpose of the Study:

• To investigate the role of CFH and FHL-1 in ocular complement regulation from local versus circulating sources.
• To assess the therapeutic efficacy of adeno-associated viruses (AAVs) expressing FHL-1 and a truncated CFH (tCFH) in restoring complement regulation in Cfh-/- mouse eyes and plasma.

Main Methods:

• Utilized Cfh-/- mice as a model for complement dysregulation.
• Administered AAV vectors expressing tCFH or FHL-1 via subretinal or tail vein injections.
• Evaluated the efficacy of these constructs in regulating the alternative complement pathway.

Main Results:

• Subretinal injection of tCFH, but not FHL-1, rescued factor B (FB) retention in the eye.
• Both tCFH and FHL-1 restored FB detection in plasma after tail vein injections.
• While circulating tCFH and FHL-1 reached the posterior eyecup, they did not significantly regulate local ocular complement.

Conclusions:

• The C-terminus of human CFH is essential for complement regulation within the murine eye.
• Local synthesis of exogenous CFH is required for maximal complement regulation in the retina.
• These findings provide a foundation for developing CFH augmentation gene therapies for ocular diseases like AMD.