Combined Complement Inhibitors and Anti-VEGF Therapy for the Treatment of Dry Age-Related Macular Degeneration (AMD)

Abstract

Purpose : Age-related macular degeneration (AMD) is a multifactorial disease that significantly contributes to visual impairment and vision loss in individuals aged 50 and older worldwide.. AMD is categorized into wet AMD and dry AMD. Treatment outcomes for dry AMD remain unsatisfactory.
Clinical evidence indicates the role of complement pathway dysregulation in the pathophysiology of dry AMD. In recent clinical trials, intravitreal injection of biologics inhibiting complement pathway activation significantly slowed the progression of geographic atrophy (GA), a late-stage manifestation of dry AMD. The necessity for frequent ocular injections imposes treatment burden. Gene therapy offers the potential for sustained, long-term expression of target proteins in vivo. Our goal is to develop a long-acting gene therapy medication for alleviating the progression of dry AMD.

Methods : We developed various adeno-associated virus (AAV) vectors expressing a dual framework of anti-C3 antibodies and anti-VEGF fusion proteins, including improved codon-optimized anti-human C3 antibodies and anti-VEGF fusion proteins, named AAV.CB.anti-C3-anti-VEGF. The expression and potential efficacy were evaluated.

Results : Expression levels in HEK293 cells demonstrated the vector expressing anti-C3 and anti-VEGF effectively expressed both anti-C3 and anti-VEGF proteins. Subsequent subretinal administration with dosage of 8E9 vg/eye in mice revealed 27% suppression of serum C3 complement levels after 15 days, reducing from a baseline of 0.89 mg/mL to 0.65 mg/mL.

Conclusions : The results present a novel therapeutic approach for dry AMD through combination of anti-C3 and anti-VEGF, offering the potential for dual treatment objectives. Early intervention in the onset of AMD holds promise for achieving delay and possible halt of progression from early and intermediate AMD to advanced AMD, thereby preventing vision loss caused by advanced AMD.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.