An iPSC patient specific model of CFH (Y402H) polymorphism displays characteristic features of AMD and indicates a beneficial role for UV light exposure

  1. Lookup NU author(s)
  2. Dr Dean Hallam
  3. Dr Joseph Collin
  4. Dr Sanja Bojic
  5. Dr Valeria Chichagova
  6. Adriana Buskin
  7. Dr Yaobo Xu
  8. Lucia Lafage
  9. Dr Christian Otten
  10. Dr George Anyfantis
  11. Dr Carla Mellough
  12. Dr Viktor Korolchuk
  13. Dr Gabriele Saretzki
  14. Professor Lyle Armstrong
  15. David Steel
  16. Professor David Kavanagh
  17. Professor Majlinda Lako
Author(s)Hallam D, Collin j, Bojic S, Chichagova V, Buskin A, Xu Y, Lafage L, Otten EG, Anyfantis G, Mellough C, Przyboski S, Alhart S, Korolchuk V, Lotery A, Saretzki G, McKibbin M, Armstrong L, Steel D, Kavanagh D, Lako M
Publication type Article
JournalStem Cells
PagesAccepted article
ISSN (print)1066-5099
ISSN (electronic)1549-4918
Full text is available for this publication:
Age related macular degeneration (AMD) is the most common cause of blindness, accounting for 8.7% of all blindness globally. Vision loss is caused ultimately by apoptosis of the retinal pigment epithelium (RPE) and overlying photoreceptors. Treatments are evolving for the wet form of the disease, however these do not exist for the dry form. Complement factor H (CFH) polymorphism in exon 9 (Y402H) has shown a strong association with susceptibility to AMD resulting in complement activation, recruitment of phagocytes, retinal pigment epithelium (RPE) damage and visual decline. We have derived and characterised induced pluripotent stem cell (iPSCs) lines from two patients without AMD and low risk genotype and two patients with advanced AMD and high risk genotype and generated RPE cells that show local secretion of several proteins involved in the complement pathway including factor H (FH), factor I (FI) and factor H like 1 (FHL-1). The iPSC RPE cells derived from high risk patients mimic several key features of AMD including increased inflammation and cellular stress, accumulation of lipid droplets, impaired autophagy and deposition of “drüsen” like deposits. The low and high risk RPE cells respond differently to intermittent exposure to UV light which leads to an improvement in cellular and functional phenotype only in the high risk AMD-RPE cells. Taken together our data indicate that the patient specific iPSC model provides a robust platform for understanding the role of complement activation in AMD, evaluating new therapies based on complement modulation and drug testing.
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