ArticleCellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology2019
The CFTR Corrector, VX-809 (Lumacaftor), Rescues ABCA4 Trafficking Mutants: a Potential Treatment for Stargardt Disease.
Article in Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 23 citations in OpenAlex.
- Update on the Management of ABCA4 Retinopathy (Stargardt Disease).Ophthalmology and therapy · 2026Review
- A Proximity Complementation Assay to Identify Small Molecules That Enhance the Traffic of ABCA4 Misfolding Variants.International journal of molecular sciences · 2024Article
- Cell-cell interaction in the pathogenesis of inherited retinal diseases.Frontiers in cell and developmental biology · 2024Review
- Antisense oligonucleotide therapy corrects splicing in the common Stargardt disease type 1-causing variantMolecular therapy. Nucleic acids · 2023Article
- C20D3-Vitamin A Prevents Retinal Pigment Epithelium Atrophic Changes in a Mouse Model.Translational vision science & technology · 2021Article
- SARS-CoV-2 spike protein and RNA dependent RNA polymerase as targets for drug and vaccine development: A review.Biosafety and health · 2021Review
- An Overview of the Genetics ofGenes · 2021Review
- Medically Important Alterations in Transport Function and Trafficking of ABCG2.International journal of molecular sciences · 2021Review
- Binding mode analysis of ABCA7 for the prediction of novel Alzheimer's disease therapeutics.Computational and structural biotechnology journal · 2021Article
- Strategies to gain novel Alzheimer's disease diagnostics and therapeutics using modulators of ABCA transporters.Free neuropathology · 2021Article
- Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations.Progress in retinal and eye research · 2020Review
- Assistance for Folding of Disease-Causing Plasma Membrane Proteins.Biomolecules · 2020Review
- Combined Use of CFTR Correctors in LGMD2D Myotubes Improves Sarcoglycan Complex Recovery.International journal of molecular sciences · 2020Article
- CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine.Frontiers in pharmacology · 2019Review
- The role of multimodal imaging and vision function testing inTherapeutic advances in ophthalmologyReview
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
BACKGROUND/
aimsMutations in ABCA4 cause Stargardt macular degeneration, which invariably ends in legal blindness. We studied two common mutants, A1038V (in NBD1) and G1961E (in NBD2), with the purpose of exploring how they interact with the cell's quality control mechanism. The study was designed to determine how these mutants can be rescued.
methodsWe expressed wt and mutant ABCA4 in HEK293 cells and studied the effect of the mutations on trafficking and processing and the ability of correctors to rescue them. We used a combination of western blotting, confocal microscopy and surface biotinylation coupled with pulldown of plasma membrane proteins.
resultsG1961E is sensitive to inhibitors of the aggresome, tubacin and the lysosome, bafilomycin A. Both mutants cause a reduction in heat shock protein, Hsp27. Incubation of HEK293 cells expressing the mutants with VX-809, an FDA approved drug for the treatment of cystic fibrosis, increased the levels of A1038V and G1961E by 2- to 3-fold. Importantly, VX-809 increased the levels of both mutants at the plasma membrane suggesting that trafficking 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.
conclusionOur results provide a new mechanism for the rescue of ABCA4 trafficking mutants based on the restoration of Hsp27. Our results provide a pathway for the treatment of Stargardt disease.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.