Nicotinamide, iRPE-in-a dish, and age-related macular degeneration therapy development.

Age related macular degeneration (AMD) is a complex retinal disorder, which progressively affects central vision in 4% of the population over 60 (1,2). AMD is caused by multiple environmental and genetic risk factors. Most importantly, smoking as well as genetic variants in the CFH gene (chrom. 1) and the ARMS2/HTRA1 locus (chrom. 10) contribute to the disease pathogenesis. Molecular modeling and functional annotation implicated oxidative stress, the innate immune response, lipid metabolism and neovascularisation in the pathobiology of AMD (1,3). A common, dry form of AMD exist, and a, more rare, wet form (affecting 10% of patients). The dry form is characterized by the appearance of drusen underneath the retinal pigment epithelium (RPE), pigment atrophy and slow progressive loss of vision. There is no cure for this type of AMD, although dietary antioxidant, zinc or fishoil supplements may postpone or even slow down the progression of the disease. The wet form of AMD usually appears even later in the life and consist of new fragile and leaky choroidal blood vessels growing through the bloodretina barrier, into the retina, which causes local fibrosis, scar tissue and vision loss. There is no effective cure for this type of AMD either, although bimonthly intra-ocular injections with anti-VEGF drugs (Lucentis, Avastin) may prevent further neo-vascularization (1,3). Finding a cure and therapeutic research into AMD has been hampered so far by the lack of suitable experimental models: Only a few immortalised RPE cell lines, such as “ARPE-19 (ATCC)”, have been available for in vitro studies, while there is no single animal model yet that captures all the complex AMD features at once. However, this is about to change: The recent introduction of stem cell and Crisprcas9 technology will provide a wealth of new opportunities to model and study genetic disorders, including AMD. A sneak preview of these new developments was published recently. In the May issue of Cell Stem Cell, Saini and coworkers published pioneering work and showed the extra-ordinary potential of human IPSCs and RPE modeling for therapeutic investigations in AMD (4). In summary, the authors selected patients, diagnosed with AMD and controls on the basis of their phenotype and ARMS2/HTRA1 risk genotypes (mostly homozygote risk vs. homozygote protective alleles). From these selected patients and controls, they constructed iPSCs and subsequently induced RPE (iRPE) cell lines. Next, they treated these in vitro models with Nicotinamide (NAM), shown to be effective against cognitive loss in Alzheimer’s disease. Using RT-PCR, immunohistochemistry, RNA-seq and ELISA, the authors measured an increased expression of complement and inflammatory factors in the highrisk allele AMD samples compared to low-risk controls. Moreover, the authors observe that NAM treatment inhibits drusen-, complement factor and inflammatory protein formation. The authors conclude: “NAM ameliorates the disease phenotype and may be an effective agent in developing therapies for AMD” (4). Editorial