Age-related macular degeneration: how could gene and cell therapy help?

‘Dry’ AMD is more common, accounting for about 85-90% of AMD cases. It involves the gradual loss of cells in the macula, resulting in a slow decline in vision. Small yellowish deposits of proteins and lipids, called drusen accumulate in the macula. These drusen can interfere with the normal function of retinal cells. In advanced stages of ‘dry’ AMD (also known as geographic atrophy), the retinal cells have died. This leads to significant central vision impairment.

‘Wet’ AMD, although less common, is typically more severe.  It involves the growth of abnormal blood vessels beneath the macula, in a tissue called the choroid. This process is called choroidal neovascularisation. These new blood vessels can leak fluid and thus cause rapid vision loss. This type of AMD often manifests as sudden and noticeable changes in the central vision. These changes can include the appearance of dark spots or distorted and wavy lines. Importantly, ‘dry’ AMD can sometimes develop into ‘wet’ AMD upon the presence of these abnormal blood vessels.

‘Wet’ AMD is treated by blocking the growth of new, abnormal blood vessels. This is achieved by repeated injections into the eye of a protein called anti-VEGF (vascular endothelial growth factor). This protein reduces choroidal neovascularisation within the macula. As a result, vision loss slows down or completely stops. In some cases, when treated early enough, these injections can even lead to improved vision. Researchers continue to investigate new anti-VEGF drugs and treatment strategies. The goals are to improve their effectiveness, reduce treatment frequency, and minimise side effects.  

Until recently, there was no treatment for ‘dry’ AMD. Based on extensive genetic evidence that the complement pathway is important in disease development and progression, several therapies have been developed to block complement pathway activity in the retina. Recently, two anti-complement therapeutics - Syfovre (pegcetacopla) and Iverzay (avacincaptad pegol) have been approved by the FDA (not the EMA) to treat geographic atrophy. Continuous monthly injections reduce inflammation which slows the rate at which the damaged region spreads, without improving vision. 

However, these therapies are not without complications.  Some patients have reported cases of occlusive retinal vasculitis, a serious eye condition involving inflammation and blockage of the retinal blood vessels, have been reported. The EMA has repeatedly refused authorisation for Syfovre in Europe as of 2024, citing concerns around low efficacy and significant risk of adverse events. As of 2024, Izervay has withdrawn its EMA application. While this treatment approach requires further research, it could pave the way for future therapies focussing on ‘dry’ AMD. 

Outside of the gene-, cell-, and pharmacologic treatments, some researchers are exploring the use of electronic implants or visual prostheses to bypass the damaged macula. These would stimulate the remaining healthy retinal cells, allowing individuals with advanced AMD to perceive light and shapes. 

Scientists are investigating whether AMD can be treated using gene transfer methods. Theoretically, a successful gene therapy would be a one-off treatment. This would reduce patients’ treatment burden of receiving repeated injections. For example, viral vectors containing genes for anti-VEGF could be injected into the eye. These modified cells would then be able to produce higher levels of a protein that blocks VEGF, avoiding the need for continuous injections, and still reduce choroid neovascularisation.[ 

Modifier gene therapy is also being investigated for treatment of dry AMD, for example, with the Phase 1/2 ArMaDa clinical trial testing safety and efficacy in a dose-escalation study for AAV-delivery of the RORA (retinoid-related orphan receptor alpha) gene to the retina following sub-retinal injection. RORA has been shown to improve lipid metabolism, reduce oxidative stress and inhibit complement pathway activity in studies both in retinal cells in the lab and in animal models. Targeting these pathways may improve retinal cell health and slow progression of dry AMD. 

One hallmark of AMD is the disruption and loss of a specific cell layer called the retinal pigment epithelium, which is important for maintaining a healthy retina. When this layer is working suboptimal, the light-sensing photoreceptors of the eye stop functioning correctly resulting in significant vision loss. Stem cells hold promise for treating or slowing down the progression of this by replacing the damaged retinal cells or by providing protective factors. In the past two decades, extensive effort has been put into working on developing techniques to generate specialised retinal cells from stem cells for the purpose of transplanting them into the macula to restore lost vision.