Age-related macular degeneration (AMD) is a multifactorial progressive degeneration of macula and it is the major cause of irreversible blindness in senile population in developed world. According to World Health Organization (WHO), about 10% of blindness is due to AMD. About 196 million individuals are affected by AMD worldwide.1
Several genetic and environmental risk factors are associated with AMD. Aging is the strongest non-modifiable risk factor whereas smoking, obesity, atherosclerosis, hypertension, hyperlipidemia are moderate and modifiable risk factors. Oxidative stress, altered hemodynamics, immune inflammatory responses play important role in pathogenesis of AMD.2 AMD is usually classified into dry (non-exudative) and wet (exudative) forms. The dry form is more common comprising around 80 -90% of cases.
A positive family history increases the risk of AMD.3 Klaver CC et al. reported one in four cases of advanced AMD is genetically determined.4 Important genes implicated in AMD are: CFH (Compliment factor H), HTRA-1 (Htra Serine Peptidase-1) and ApoE (apolipoprotein- E) etc.2 CFH inhibits multiple steps of the alternate pathway of inflammation. It binds with C-reactive protein (CRP) and inhibits the CRP-mediated response to photoreceptor damage. The Y402h mutation in the CHF gene may lead to complement dysregulation in AMD.5, 6, 7 Single-nucleotide polymorphisms (SNPs) in chromosome 10q26 are associated with high risk of wet AMD.8
Ischemia-induced neovascularization of photoreceptor involves release of HIF-1 (Hypoxia inducible factor-1) and vascular endothelial growth factor (VEGF) that can be modulated by gene therapy.
rAAV2-sFLT1 treatment is used for prolonged management of neovascular AMD. Adeno-associated virus type 2 (AAV2)-sFLT1 combines a viral factor with plasmid which transduce retinal cells to produce highly potent naturally occurring anti VEGF (sFLT1=fms-like tyrosine kinase). Phase I/ IIa trial established safety and efficacy of rAAVs FLT1.9 It improves central macular thickness and regain vision.
ADVM-022 / ADVM-032 - utilize a modified AAV2 vector which is specified for intravitreal infections, ADVM-022 expressing an aflibercept-like protein while ADVM-032 producing a ranibizumab like protein.2
Retinostat utilizes a recombinant equine infectious anemia virus (EIAV) vector which encodes two protein - endostatin and angiostatin through a subretinal injection. The phase-1 trial has been done for neovascular AMD without any adverse effects.10
AKST4290- is an oral treatment that targets against CCR3 which is receptor for eotaxin. Eotaxin is associated with membrane permeability in pathogenesis of AMD. Phase II trial showed improvement in BCVA of 2-83Y of wet AMD.11
