4-Sodium phenyl butyric acid has both efficacy and counter-indicative effects in the treatment of Col4a1 disease

Jones, F. E. et al. (2019) 4-Sodium phenyl butyric acid has both efficacy and counter-indicative effects in the treatment of Col4a1 disease. Human Molecular Genetics, 28(4), pp. 628-638. (doi: 10.1093/hmg/ddy369) (PMID:30351356) (PMCID:PMC6360271)

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Mutations in the collagen genes COL4A1 and COL4A2 cause Mendelian eye, kidney and cerebrovascular disease including intracerebral haemorrhage, and common collagen IV variants are a risk factor for sporadic intracerebral haemorrhage. COL4A1 and COL4A2 mutations cause endoplasmic reticulum (ER) stress and basement membrane (BM) defects, and recent data suggest an association of ER stress with intracerebral haemorrhage due to a COL4A2 mutation. However, the potential of ER-stress as a therapeutic target for the multi-systemic COL4A1 pathologies remains unclear. We performed a preventative oral treatment of Col4a1 mutant mice with the chemical chaperone phenyl butyric acid (PBA), which reduced adult intracerebral haemorrhage. Importantly, treatment of adult mice with established disease also reduced intracerebral haemorrhage. However, PBA treatment did not alter eye and kidney defects, establishing tissue specific outcomes of targeting Col4a1-derived ER stress, and therefore this treatment may not be applicable for patients with eye and renal disease. While PBA treatment reduced ER-stress and increased collagen IV incorporation into BMs, the persistence of defects in BM structure and reduced ability of the BM to withstand mechanical stress indicate PBA may be counter-indicative for pathologies caused by matrix defects. These data establish that treatment for COL4A1 disease requires a multi-pronged treatment approach that restores both ER homeostasis and matrix defects. Alleviating ER-stress is a valid therapeutic target for preventing and treating established adult intracerebral haemorrhage, but collagen IV patients will require stratification based on their clinical presentation and mechanism of their mutations.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Jones, Dr Frances and Van Agtmael, Professor Tom and Aman, Ms Alisha and Holmes, Dr William and Malomgre, Mr Ruben and Dean, Dr Afshan and MCNEILLY, Sarah
Authors: Jones, F. E., Murray, L. S., McNeilly, S., Dean, A., Aman, A., Lu, Y., Nikolova, N., Malomgre, R., Horsburgh, K., Holmes, W. M., Kadler, K. E., and Van Agtmael, T.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
Journal Name:Human Molecular Genetics
Publisher:Oxford University Press
ISSN (Online):1460-2083
Published Online:22 October 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Human Molecular Genetics 28(4): 628-638
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
544461MRC Doctoral Training Grant 2010-2014Mary GoodmanMedical Research Council (MRC)G1000389-1/1VPO VICE PRINCIPAL RESEARCH & ENTERPRISE
602621Elucidation of molecular pathways underlying renal disease caused by Co/4a 1 mutations using mouse models.Tom Van AgtmaelKidney Research UK (KIDNEYRE)RP19/2012RI CARDIOVASCULAR & MEDICAL SCIENCES
691851Targeting intracellular pathways to dissect mechanisms of cerebrovascular disease.Tom Van AgtmaelBritish Heart Foundation (BHF)PG/15/92/31813RI CARDIOVASCULAR & MEDICAL SCIENCES