James Davis

 Introduction. Age-related Macular Degeneration (AMD) is one of the leading causes of severe, irreversible vision impairment, affecting an estimated 200 million people globally^2,4. It is a late-onset disease that causes loss of central vision by damaging the macular region of the retina². Though the etiology of AMD is not fully understood, studies have described many risk factors and biomarkers for AMD, leading to further investigation of oxidation and complement activation as mechanisms involved in the pathogenesis of the disease^1,3,4. Researchers have found HOHA Lactone to be an important molecule involved in AMD^5,6,7. Researchers have also made promising advancements toward stem-cell therapy as a potential treatment for AMD. Methods. Researchers used DHA-enriched erythrocyte ghost cells and measured levels of CEP-PC-dipeptide vs CEP-dipeptide produced upon exposure to oxidizing agents⁶. Another study measured levels of HOHA Lactone production when DHA-enriched RPE cell cultures were exposed to UV, blue light, and white light radiation⁵. The same study also used MitoClick and JC-10 assays to measure changes in mitochondrial membrane potentials in RPE cells exposed to HOHA Lactone⁵. Another study measured levels of complement protein expression in RPE cells exposed to varying levels of HOHA Lactone⁷. In another study, researchers used CD34+ peripheral blood cells and generated RPE cells from IPSCs⁸. They used a biodegradable scaffold to transplant their iRPE cell patch into a pig AMD model and took observations via OCT⁸. Results. In DHA-PC oxidation, HOHA-PC primarily deacylates to form HOHA Lactone as a stable intermediate⁶. Light radiation was found to increase DHA oxidation to form HOHA Lactone products (UV light > blue light > white light > dark)⁵. RPE cells exposed to HOHA Lactone showed measurable changes in mitochondrial membrane potential⁵. RPE cells exposed to HOHA Lactone also showed increased complement protein expression⁷. The iRPE cell patch with a biodegradable scaffold showed better grafting into a pig AMD model⁸. Conclusions. Studies have found light radiation may be an early step in AMD pathogenesis⁵. Lipid oxidation in AMD produces HOHA Lactone as a stable intermediate with toxic effects on RPE cells^5,6,7. HOHA Lactone causes damage to mitochondrial membranes and induces complement activation/MAC formation on RPE cells, both leading to cell death^6,7. Improved manufacturing techniques for RPE cell lines, better graft scaffolds, and evidence of RPE cell rescue with iRPE grafts in AMD models show promising steps forward in stem cell therapy as a potentially effective treatment for AMD patients⁸.

1. Zajac-Pytrus, H. M., et al. (2015). “The Dry Form of Age-Related Macular Degeneration (AMD): The Current Concepts of Pathogenesis and Prospects for Treatment.” Adv Clin Exp Med 24(6): 1099-1104.
2. Mitchell, P., et al. (2018). “Age-related macular degeneration.” Lancet 392(10153): 1147-1159.
3. Lambert, N. G., et al. (2016). “Risk factors and biomarkers of age-related macular degeneration.” Prog Retin Eye Res 54: 64-102.
4. Oner, A., et al. (2018). “Suprachoroidal Adipose Tissue-Derived Mesenchymal Stem Cell Implantation in Patients with Dry-Type Age-Related Macular Degeneration and Stargardt’s Macular Dystrophy: 6-Month Follow-Up Results of a Phase 2 Study.” Cell Reprogram 20(6): 329-336.
5. Cheng, Y. S., et al. (2019). “Light-induced generation and toxicity of docosahexaenoate-derived oxidation products in retinal pigmented epithelial cells.” Exp Eye Res 181: 325-345.
6. Wang, H., et al. (2015). “4-Hydroxy-7-oxo-5-heptenoic Acid (HOHA) Lactone is a Biologically Active Precursor for the Generation of 2-(omega-Carboxyethyl)pyrrole (CEP) Derivatives of Proteins and Ethanolamine Phospholipids.” Chem Res Toxicol 28(5): 967-977.
7. Linetsky, M., et al. (2018). “4-Hydroxy-7-oxo-5-heptenoic Acid Lactone Is a Potent Inducer of the Complement Pathway in Human Retinal Pigmented Epithelial Cells.” Chem Res Toxicol 31(8): 666-679.
8. Sharma, R., et al. (2019). “Clinical-grade stem cell-derived retinal pigment epithelium patch rescues retinal degeneration in rodents and pigs.” Sci Transl Med 11(475).