ArticleLipids in health and disease2011
In vitro and in vivo plasmalogen replacement evaluations in rhizomelic chrondrodysplasia punctata and Pelizaeus-Merzbacher disease using PPI-1011, an ether lipid plasmalogen precursor.
Article in Lipids in health and disease, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 38 citations in OpenAlex.
- First-In-Human Safety, Tolerability, and Pharmacokinetics of PPI-1011, a Synthetic Plasmalogen Precursor.Clinical and translational science · 2025Trial
- Review
- Plasmalogen as a Bioactive Lipid Drug: From Preclinical Research Challenges to Opportunities in Nanomedicine.FASEB bioAdvances · 2025Article
- Development and evaluation of RhizoQOL, a quality-of-life caregiver-reported survey for rhizomelic chondrodysplasia punctata, a rare peroxisomal disorder.Orphanet journal of rare diseases · 2025Article
- Marine Plasmalogens: A Gift from the Sea with Benefits for Age-Associated Diseases.Molecules (Basel, Switzerland) · 2023Review
- Using Machine Learning to Identify Metabolomic Signatures of Pediatric Chronic Kidney Disease Etiology.Journal of the American Society of Nephrology : JASN · 2022Article
- Pharmacokinetics, Mass Balance, Excretion, and Tissue Distribution of Plasmalogen Precursor PPI-1011.Frontiers in cell and developmental biology · 2022Article
- Ether Lipids in Obesity: From Cells to Population Studies.Frontiers in physiology · 2022Review
- Rhizomelic chondrodysplasia punctata: Role of EEG as a biomarker of impending epilepsy.eNeurologicalSci · 2020Article
- Oral administration of a synthetic vinyl-ether plasmalogen normalizes open field activity in a mouse model of rhizomelic chondrodysplasia punctata.Disease models & mechanisms · 2020Article
- Plasmalogen deficiency and neuropathology in Alzheimer's disease: Causation or coincidence?Alzheimer's & dementia (New York, N. Y.) · 2019Review
- From peroxisomal disorders to common neurodegenerative diseases - the role of ether phospholipids in the nervous system.FEBS letters · 2017Review
- Peroxisome biogenesis disorders.Translational science of rare diseases · 2016Article
- Article
- Homeostasis of phospholipids - The level of phosphatidylethanolamine tightly adapts to changes in ethanolamine plasmalogens.Biochimica et biophysica acta · 2015Article
- Mass spectrometry strategies for clinical metabolomics and lipidomics in psychiatry, neurology, and neuro-oncology.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2014Review
- Choline plasmalogens isolated from swine liver inhibit hepatoma cell proliferation associated with caveolin-1/Akt signaling.PloS one · 2013Article
- The ether lipid precursor hexadecylglycerol causes major changes in the lipidome of HEp-2 cells.PloS one · 2013Article
- Dietary plasmalogen increases erythrocyte membrane plasmalogen in rats.Lipids in health and disease · 2012Article
- Anti-inflammatory/anti-amyloidogenic effects of plasmalogens in lipopolysaccharide-induced neuroinflammation in adult mice.Journal of neuroinflammation · 2012Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundChildhood peroxisomal disorders and leukodystrophies are devastating diseases characterized by dysfunctional lipid metabolism. Plasmalogens (ether glycerophosphoethanolamine lipids) are decreased in these genetic disorders. The biosynthesis of plasmalogens is initiated in peroxisomes but completed in the endoplasmic reticulum. We therefore undertook a study to evaluate the ability of a 3-substituted, 1-alkyl, 2-acyl glyceryl ether lipid (PPI-1011) to replace plasmalogens in rhizomelic chrondrodysplasia punctata type 1 (RCDP1) and rhizomelic chrondrodysplasia punctata type 2 (RCDP2) lymphocytes which possess peroxisomal mutations culminating in deficient plasmalogen synthesis. We also examined plasmalogen synthesis in Pelizaeus-Merzbacher disease (PMD) lymphocytes which possess a proteolipid protein-1 (PLP1) missense mutation that results in abnormal PLP1 folding and it's accumulation in the endoplasmic reticulum (ER), the cellular site of the last steps in plasmalogen synthesis. In vivo incorporation of plasmalogen precursor into tissue plasmalogens was also evaluated in the Pex7 mouse model of plasmalogen deficiency.
resultsIn both RCDP1 and RCDP2 lymphocytes, PPI-1011 repleted the target ethanolamine plasmalogen (PlsEtn16:0/22:6) in a concentration dependent manner. In addition, deacylation/reacylation reactions resulted in repletion of PlsEtn 16:0/20:4 in both RCDP1 and RCDP2 lymphocytes, repletion of PlsEtn 16:0/18:1 and PlsEtn 16:0/18:2 in RCDP2 lymphocytes, and partial repletion of PlsEtn 16:0/18:1 and PlsEtn 16:0/18:2 in RCDP1 lymphocytes. In the Pex7 mouse, oral dosing of labeled PPI-1011 demonstrated repletion of tissue levels of the target plasmalogen PlsEtn 16:0/22:6 with phospholipid remodeling also resulting in significant repletion of PlsEtn 16:0/20:4 and PlsEtn 16:0/18:1. Metabolic conversion of PPI-1011 to the target plasmalogen was most active in the liver.
conclusionsOur data demonstrate that PPI-1011 is activated (removal of 3-substitution) and converted to PlsEtn in vitro in both RCDP1 and RCDP2 lymphocytes and in vivo in the Pex7 mouse model of RCPD1 effectively bypassing the peroxisomal dysfunction present in these disorders. While PPI-1011 was shown to replete PlsEtns 16:0/x, ether lipid precursors of PlsEtn 18:0/x and PlsEtn 18:1/x may also be needed to achieve optimal clinical benefits of plasmalogen replacement in these complex patient populations. In contrast, only limited plasmalogen replacement was observed in PMD lymphocytes suggesting that the effects of protein misfolding and accumulation in the ER negatively affect processing of plasmalogen precursors in this cellular compartment.
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