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Gene therapy approach to treating AMD with virally delivered complement Factor H shows potential in animal models.

Research, led by scientists at the Department of Ophthalmology, Tufts University School of Medicine, Boston, has shown that complement Factor H, virally delivered to the retina of AMD animal models, appears to demonstrate significant therapeutic benefit. The research used different gene constructs carried in separate adenoviral vectors to both simulate a retinal disease pathology and rescue the same pathology in a murine model of AMD. The authors of the study argue that a gene therapy approach may present a preferable and sustained option to efficiently treat geographic atrophy, especially in light of recent clinical studies, sponsored by Roche, indicating that anti-Factor D antibody injections, targeting the complement pathway, do not appear to be effective when given every second month compared to monthly injections.


A significant risk factor for developing AMD has been the presence of cellular debris – known as “drusen” – underneath the retinal pigment epithelium (RPE) in the macula. Among other components, the drusen is comprised of “complement” – serum proteins which mediate one of the more important immune system’s antibody-mediated disposal mechanisms, a process known as “complement fixation”. This observation led researchers to the suggestion that drusen is the product of a localised inflammatory response and a series of ground-breaking research publications beginning in 2005 showed convincing links between mutations in complement factor genes and the occurrence of age related macular degeneration. A major breakthrough in 2005 identified the factor H gene (known as CFH or HF1) located on human chromosome 1q32 as a major risk factor for AMD. Since then several follow up studies have confirmed the finding in addition to identifying further variants and further genes conferring risk or protection in the development of AMD. Two loci in particular account for a significant proportion of AMD cases: complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2)/HtrA serine peptidase 1 (HTRA1), on chromosome 10q26. Subsequent candidate gene studies identified risk-associated variants in or close to a further three complement genes, complement component 2 (C2)/complement factor B (CFB), complement component 3 (C3) and complement factor I (CFI).


The Boston research group used an adenoviral (Ad) mediated expression of complement component C3 (AdCMVC3) to induce a number of the pathological features found in human AMD. To test the effect of complement Factor H in such a model the team introduced a second adenovirus incorporating the genetic sequence for complement Factor H (AdCAGfH) and found that both morphological and functional deterioration could be arrested by AdCAGfH. Results showed that endothelial cell proliferation was reduced by 91% and RPE atrophy was attenuated by 69%. In addition, eyes treated with complement Factor H showed 90% to 150% greater A-wave and 120% to 180% greater B-wave amplitudes when compared to untreated controls.