Abstract
ABSTRACTRhizomelic chondrodysplasia punctata (RCDP) is a rare genetic disorder caused by mutations in peroxisomal genes essential for plasmalogen biosynthesis. Plasmalogens are a class of membrane glycerophospholipids containing a vinyl-ether-linked fatty alcohol at the sn-1 position that affect functions including vesicular transport, membrane protein function and free radical scavenging. A logical rationale for the treatment of RCDP is therefore the therapeutic augmentation of plasmalogens. The objective of this work was to provide a preliminary characterization of a novel vinyl-ether synthetic plasmalogen, PPI-1040, in support of its potential utility as an oral therapeutic option for RCDP. First, wild-type mice were treated with 13C6-labeled PPI-1040, which showed that the sn-1 vinyl-ether and the sn-3 phosphoethanolamine groups remained intact during digestion and absorption. Next, a 4-week treatment of adult plasmalogen-deficient Pex7hypo/null mice with PPI-1040 showed normalization of plasmalogen levels in plasma, and variable increases in plasmalogen levels in erythrocytes and peripheral tissues (liver, small intestine, skeletal muscle and heart). Augmentation was not observed in brain, lung and kidney. Functionally, PPI-1040 treatment normalized the hyperactive behavior observed in the Pex7hypo/null mice as determined by open field test, with a significant inverse correlation between activity and plasma plasmalogen levels. Parallel treatment with an equal amount of ether plasmalogen precursor, PPI-1011, did not effectively augment plasmalogen levels or reduce hyperactivity. Our findings show, for the first time, that a synthetic vinyl-ether plasmalogen is orally bioavailable and can improve plasmalogen levels in an RCDP mouse model. Further exploration of its clinical utility is warranted.This article has an associated First Person interview with the joint first authors of the paper.
Highlights
Rhizomelic chondrodysplasia punctata (RCDP) is a heterogeneous group of genetic disorders with a prevalence estimated at less than 1 per 100,000 (Stoll et al, 1989)
Rhizomelic chondrodysplasia punctata (RCDP) is a rare genetic disorder caused by mutations in peroxisomal genes essential for plasmalogen biosynthesis
The objective of this work was to provide a preliminary characterization of a novel vinyl-ether synthetic plasmalogen, PPI-1040, in support of its potential utility as an oral therapeutic option for RCDP
Summary
Rhizomelic chondrodysplasia punctata (RCDP) is a heterogeneous group of genetic disorders with a prevalence estimated at less than 1 per 100,000 (Stoll et al, 1989). RCDP results from mutations in peroxisomal genes involved in plasmalogen phospholipid production and is clinically characterized by skeletal dysplasia (rhizomelia and chondrodysplasia punctata), congenital cataracts, and profound growth, motor and cognitive delays. Reduced life expectancy is common to RCDP patients; survival varies widely with severity of the symptoms. Severe phenotype only 50% will survive beyond 6 years of age and most succumb to the disease prior to adolescence (White et al, 2003). Patients with milder phenotypes have variable rhizomelia and have better survival, growth and developmental outcomes
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