Journal
DISEASE MODELS & MECHANISMS
Volume 11, Issue 7, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dmm.034157
Keywords
Cerebral small vessel disease; Stroke; Intracerebral hemorrhage; Collagen; COL4A1; Myopathy; Drug therapy; Chaperones
Categories
Funding
- National Institutes of Health [NS83830]
- Muscular Dystrophy Association [MDA295085]
- American Heart Association [17POST33660668]
- National Eye Institute [EY02162]
- Research to Prevent Blindness
- National Center for Advancing Translational Sciences [UL1 TR001872]
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Collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) form heterotrimers that constitute a major component of nearly all basement membranes. COL4A1 and COL4A2 mutations cause a multisystem disorder that includes variable cerebrovascular and skeletal muscle manifestations. The pathogenicity of COL4A1 and COL4A2 mutations is generally attributed to impaired secretion into basement membranes. Sodium 4-phenylbutyrate (4PBA) is a US Food and Drug Administration-approved drug that promotes mutant heterotrimer secretion in vitro and in vivo. Here, we use different 4PBA treatment paradigms to define therapeutic parameters for preventing cerebrovascular and muscular pathologies in Col4a1 mutant mice. We show the efficacy of long-term 4PBA treatment in reducing the severity of intracerebral hemorrhages (ICHs) in Col4a1 mutant mice aged up to 8 months. In addition, we demonstrate that maximal efficacy of 4PBA on ICH and myopathy was achieved when treatment was initiated prenatally, whereby even transient 4PBA administration had lasting benefits after being discontinued. Importantly, postnatal treatment with 4PBA also reduced ICH and skeletal myopathy severities in Col4a1 mutant mice, which has significant clinical implications for patients with COL4A1 and COL4A2 mutations.
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