July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018

The CFTR corrector, VX-809 (Lumacaftor) and Hsp27 rescues ABCA4 trafficking mutants: a potential treatment for Stargardt disease
Author Affiliations & Notes
  • Liudmila Cebotaru
    Medicine, Johns Hopkins U, Baltimore, Maryland, United States
  • Qiangni Liu
    Medicine, Johns Hopkins U, Baltimore, Maryland, United States
  • Inna Sabirzhanova
    Medicine, Johns Hopkins U, Baltimore, Maryland, United States
  • Emily Bergbower
    Medicine, Johns Hopkins U, Baltimore, Maryland, United States
  • Murali Yanda
    Medicine, Johns Hopkins U, Baltimore, Maryland, United States
  • William Guggino
    Physiology, Johns Hopkins U., Baltimore, Maryland, United States
  • Footnotes
    Commercial Relationships   Liudmila Cebotaru, None; Qiangni Liu, None; Inna Sabirzhanova, None; Emily Bergbower, None; Murali Yanda, None; William Guggino, None
  • Footnotes
    Support  none
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 218. doi:
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      Liudmila Cebotaru, Qiangni Liu, Inna Sabirzhanova, Emily Bergbower, Murali Yanda, William Guggino;
      The CFTR corrector, VX-809 (Lumacaftor) and Hsp27 rescues ABCA4 trafficking mutants: a potential treatment for Stargardt disease. Invest. Ophthalmol. Vis. Sci. 2018;59(9):218.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Mutations in abca4 cause Stargardt macular degeneration, which results from failure to recycle all-trans retinal ending in legal blindness. There is no known cure. We tested the hypothesis, that correctors designed to rescue ΔF508-CFTR (ABCC7) can also rescue the common disease causing mutants, A1038V in NBD1 (nucleotide binding domain 1), and G1961E in NBD2 of ABCA4 because of the high degree of homology between their NBDs.

Methods : VX-809 (obtained from Selleck Chem.) which is currently approved for the treatment of CF was applied (10 & 20 μM) for 16h in HEK293 stably expressing the mutants. We explored how these mutants interact with the cell’s quality control mechanism and how they can be rescued.

Results : We found that G1961E is very sensitive to inhibitors of the aggresome such as tubacin and lysosome, such as bafilomycin A. Both mutants cause a profound reduction in heat shock protein, Hsp27. Incubation of HEK293 cells stably expressing the mutants with VX-809, increased the steady-state levels of A1038V and G1961E by 2- to 3-fold. Importantly, VX-809 increased the steady-state levels of both mutants at the plasma membrane, suggesting that trafficking to the plasma membrane had been restored. Transfecting additional Hsp27 to the cells also increased the steady state levels of both mutants. However, in combination with VX-809 the addition of Hsp27 caused a dramatic increase in the protein expression particularly in the G1961 mutant which increased approximately 5-fold.

Conclusions : Correctors to rescue trafficking mutants of CFTR will also rescue ABCA4 mutants selected within regions of greatest similarity. Our results suggest that VX809 may work directly on the ABCA4 rather than affecting a component of the ER quality control pathway. Interestingly VX-809 may even be more effective in increasing the trafficking of the ABCA4 mutants in NBD2, such as G1961E than it is for ΔF508-CFTR. Because VX-809 is already in clinical trials for CF, our results provide a potential pathway toward a treatment for Stargardt disease.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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