Oral administration of a synthetic vinyl-ether plasmalogen normalizes open field activity in a mouse model of rhizomelic chondrodysplasia punctata
Rhizomelic 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 i...
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2020-01-01
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| Series: | Disease Models & Mechanisms |
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| Online Access: | http://dmm.biologists.org/content/13/1/dmm042499 |
| _version_ | 1828783622833831936 |
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| author | Wedad Fallatah Tara Smith Wei Cui Dushmanthi Jayasinghe Erminia Di Pietro Shawn A. Ritchie Nancy Braverman |
| author_facet | Wedad Fallatah Tara Smith Wei Cui Dushmanthi Jayasinghe Erminia Di Pietro Shawn A. Ritchie Nancy Braverman |
| author_sort | Wedad Fallatah |
| collection | DOAJ |
| description | Rhizomelic 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. |
| first_indexed | 2024-12-11T23:16:13Z |
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| id | doaj.art-9a20bdb91c264e33bac85c9a0b50e106 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-12-11T23:16:13Z |
| publishDate | 2020-01-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-9a20bdb91c264e33bac85c9a0b50e1062022-12-22T00:46:32ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112020-01-0113110.1242/dmm.042499042499Oral administration of a synthetic vinyl-ether plasmalogen normalizes open field activity in a mouse model of rhizomelic chondrodysplasia punctataWedad Fallatah0Tara Smith1Wei Cui2Dushmanthi Jayasinghe3Erminia Di Pietro4Shawn A. Ritchie5Nancy Braverman6 Department of Human Genetics and Pediatrics, Research Institute of the McGill University Health Center and McGill University, Montreal, QC H4A3J1, Canada Med-Life Discoveries LP, Saskatoon, SK S7N2X8, Canada Department of Human Genetics and Pediatrics, Research Institute of the McGill University Health Center and McGill University, Montreal, QC H4A3J1, Canada Med-Life Discoveries LP, Saskatoon, SK S7N2X8, Canada Department of Human Genetics and Pediatrics, Research Institute of the McGill University Health Center and McGill University, Montreal, QC H4A3J1, Canada Med-Life Discoveries LP, Saskatoon, SK S7N2X8, Canada Department of Human Genetics and Pediatrics, Research Institute of the McGill University Health Center and McGill University, Montreal, QC H4A3J1, Canada Rhizomelic 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.http://dmm.biologists.org/content/13/1/dmm042499ppi-1040rhizomelic chondrodysplasia punctatarcdpperoxisomal disorderplasmalogen |
| spellingShingle | Wedad Fallatah Tara Smith Wei Cui Dushmanthi Jayasinghe Erminia Di Pietro Shawn A. Ritchie Nancy Braverman Oral administration of a synthetic vinyl-ether plasmalogen normalizes open field activity in a mouse model of rhizomelic chondrodysplasia punctata Disease Models & Mechanisms ppi-1040 rhizomelic chondrodysplasia punctata rcdp peroxisomal disorder plasmalogen |
| title | Oral administration of a synthetic vinyl-ether plasmalogen normalizes open field activity in a mouse model of rhizomelic chondrodysplasia punctata |
| title_full | Oral administration of a synthetic vinyl-ether plasmalogen normalizes open field activity in a mouse model of rhizomelic chondrodysplasia punctata |
| title_fullStr | Oral administration of a synthetic vinyl-ether plasmalogen normalizes open field activity in a mouse model of rhizomelic chondrodysplasia punctata |
| title_full_unstemmed | Oral administration of a synthetic vinyl-ether plasmalogen normalizes open field activity in a mouse model of rhizomelic chondrodysplasia punctata |
| title_short | Oral administration of a synthetic vinyl-ether plasmalogen normalizes open field activity in a mouse model of rhizomelic chondrodysplasia punctata |
| title_sort | oral administration of a synthetic vinyl ether plasmalogen normalizes open field activity in a mouse model of rhizomelic chondrodysplasia punctata |
| topic | ppi-1040 rhizomelic chondrodysplasia punctata rcdp peroxisomal disorder plasmalogen |
| url | http://dmm.biologists.org/content/13/1/dmm042499 |
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