Age-related macular degeneration (AMD) is an acquired eye condition that causes vision loss in the elderly. It is the commonest cause of blindness in developed countries affecting people above 60 years. AMD is a disease that causes progressive destruction of the macular leading to loss of central vision. It might not present with symptoms at first, but over time, people begin to experience gradual bilateral vision loss. The most important risk factors are age, smoking, family history, and race.
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Age-related Macular Degeneration
It is also the most common cause of irreversible loss of central vision in adults and causes difficulty in reading, driving, walking, etc. In 2019, reports had it that AMD affected 19.8 million Americans and about 1.49 million of them were living with threats of vision loss. The prevalence increased with age from 2% to 46.6% among people aged 40 to 44 and >85 years respectively.
AMD involves three groups; early stage, intermediate, and late stage. The late stage involves central geographic atrophy (GA) or neovascular AMD. In the US, it has been estimated that 18 million individuals aged 40 and above have early-stage AMD, and 1.5 million have late-stage AMD, which includes GA and/or neovascular AMD.
Geographical Atrophy
GA is characterized by the progressive loss of photoreceptors, retinal pigment epithelium (RPE), and underlying choriocapillaris, resulting in a central scotoma or vision loss. It enlarges over time and occurs bilaterally. People with the unilateral version are prone to developing it in the contralateral eye.
Treatment options for this include laser photocoagulation, photodynamic therapy, and various antiangiogenic therapies. Surgery may be required if patients present with submacular hemorrhage.
PPY998
PPY998 is an antiangiogenic subretinal gene therapy used to increase the concentration of factor I (FI) in areas of macular atrophy. Certain complements like C3 and its breakdown products play a key role in the pathogenesis of GA. They are involved in the alternate pathway that mops up antigens from the eye. If not regulated, they go ahead to cause inflammation and self-damage. Regulatory proteins like factor H and factor I stop this from happening.
Researchers believe that stimulating the CFI gene using PPY998 can increase the production of FI and significantly reduce inflammation, self-damage, and macular destruction. Studies have also shown that those who have an abnormal CFI gene have low serum FI or may have normal levels with a non-functional CFI gene. They are more at risk of developing AMD.
Thomas Hallam et al carried out the FOCUS study to find out if 3 doses of PPY998 subretinal gene therapy are safe and effective. Later on, they also compared the efficacy of PPY998, pegcetacoplan (C3 inhibitor), and FH.
They analyzed the vitreous humor of the participants before and after the delivery of the therapy. They observed a consistent rise in FI levels post-administration over 2 years, however, the levels of C3 breakdown products did not significantly reduce.
When they compared the efficacy of PPY998, pegcetacoplan (C3 inhibitor), and FH, they discovered that pegcetacoplan completely blocks the production of C3a at concentrations much lower than the estimated dosage needed for FI. Also, FH administered produced similar potency to pegcetacoplan
Clinical significance
This study shows the subvitreal therapy with PPY998 is effective in increasing the concentrations of FI in the vitreous and it also reveals the therapeutic benefit of inducing the CFI gene for the treatment of AMD, even though the other therapies were more efficacious.
Perhaps, future studies will analyze the potency of various medications for AMD to maximize patient satisfaction and good clinical outcomes.
References
Hallam, T. M., Gardenal, E., McBlane, F., Cho, G., Ferraro, L. L., Pekle, E., Lu, D., Carney, K., Wenden, C., Beadsmoore, H., Kaiser, S., Drage, L., Haye, T., Kassem, I., Rangaswamy, N., Obeidat, M., Grosskreutz, C., Saint-Geniez, M., Steel, D. H., MacLaren, R. E., Ellis, S., Harris, C. L., Poor, S., Jones, A. V., & FOCUS Principal Investigators. (2024). Ocular biomarker profiling after complement factor I gene therapy in geographic atrophy secondary to age-related macular degeneration. medRxiv. https://doi.org/10.1101/2024.06.12.24308796
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