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. 2020 Jan 24;13(1):dmm042499.
doi: 10.1242/dmm.042499.

Oral administration of a synthetic vinyl-ether plasmalogen normalizes open field activity in a mouse model of rhizomelic chondrodysplasia punctata

Wedad Fallatah  1   2 , Tara Smith  3 , Wei Cui  1 , Dushmanthi Jayasinghe  4 , Erminia Di Pietro  1 , Shawn A Ritchie  4 , Nancy Braverman  5
Affiliations

Oral administration of a synthetic vinyl-ether plasmalogen normalizes open field activity in a mouse model of rhizomelic chondrodysplasia punctata

Wedad Fallatah et al. Dis Model Mech. .

Abstract

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.

Keywords: PPI-1040; Peroxisomal disorder; Plasmalogen; RCDP; Rhizomelic chondrodysplasia punctata.

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Conflict of interest statement

Competing interestsT.S., D.J. and S.A.R. are paid employees of Med-Life Discoveries LP, and were directly involved in the study design, data collection and analysis.

Figures

Fig. 1.
Fig. 1.
Chemical structures of synthetic plasmalogens. (A-C) The closed-ring version of PPI-1040 (A) is the form orally dosed to animals, which then undergo a spontaneous hydrolysis reaction upon exposure to an aqueous or acidic environment, resulting in the open-ring version (B), which is identical to endogenously occurring plasmalogen. PPI-1011 (C) is an ether analog to PPI-1040 that contains DHA at sn-2 and lipoic acid at sn-3 position of a palmitic ether glycerol.
Fig. 2.
Fig. 2.
Stability of PPI-1040 under increasingly acidic conditions as detected by HPLC FI-MS/MS. (A) The closed-ring fully intact isoform of PPI-1040 was present at high levels in the formulated control sample, but was dramatically reduced upon exposure to water or acid. (B) Hydrolysis of the cyclic phosphoethanolamine group on PPI-1040 results in the open-ring isoform, which was the prominent form molecule in formulations exposed to water or acids of pH 3-5. (C) The vinyl-ether group at sn-1 is susceptible to cleavage under acidic conditions. Loss of the sn-1 group from open-ring PPI-1040 was monitored to detect vinyl cleavage, which was prominent at pH 2. Mean±s.d., n=3.
Fig. 3.
Fig. 3.
Outline of the possible metabolic conversions of 13C6-PPI-1050, including the number of 13C labels (*) and the mass shift expected for each product. (A) Following ingestion, the closed-ring version of PPI-1050 was not detectable in plasma. (B) PPI-1050 converts to the open-ring version following hydrolysis of the phosphoethanolamine ring, resulting in 13C6 -16:0/22:6 plasmalogen (PlsEtn). The graph denotes the fold change in the metabolite level relative to the vehicle group at each time point, illustrating a time-dependent increase. (C) Cleavage and remodeling of sn-2 would result in 13C6 -PlsEtn with differing sn-2 fatty acids, which were detected and mirrored the time-dependent increase seen in the target. (D) Cleavage and remodeling of the sn-1 group of PPI-1040 would result in 13C3-PlsEtn, which was not detected. (E) Cleavage of the sn-3 would result in 13C6 vinyl-acyl glycerols, which were not detected. Mean±s.d., n=3.
Fig. 4.
Fig. 4.
Plasma PlsEtn levels in wild-type and Pex7hypo/null mice treated with vehicle, PPI-1011 or PPI-1040 for 4 weeks at 50 mg/kg. (A) Levels of the most abundant 16:0 (sn-1) plasmalogen species. (B) PlsEtn pools of the three major sn-1 fatty alcohols, as well as the total PlsEtn plasmalogen pool. All groups were significantly decreased in the vehicle relative to wild-type control. For the two treatment groups relative to the vehicle, PPI-1011 showed no significant augmentation of plasmalogens, whereas PPI-1040 significantly increased all 16:0 plasmalogen species measured except for 16:0/22:4. Levels are presented as the mean percentage of wild-type levels±s.d., n=4-6. Statistical analysis was performed using one-way ANOVA with Tukey's Honest Significant Differences post-hoc test, ***P<0.001.
Fig. 5.
Fig. 5.
Tissue plasmalogen levels in wild-type and Pex7hypo/null mice treated with vehicle, PPI-1011 or PPI-1040. (A-E) PPI-1011 treatment did not increase plasmalogen levels in any tissues analyzed. PPI-1040 treatment resulted in increased plasmalogen levels in the liver (A), skeletal muscle (B), small intestine (C), heart (D) and erythrocytes (E). Levels are presented as the mean percentage of wild-type levels±s.d. Statistical analysis was performed using one-way ANOVA with Tukey's Honest Significant Differences post-hoc test, n=4-6, *P<0.05, **P<0.01. ***P<0.001.
Fig. 6.
Fig. 6.
Results of the open field tests from Pex7 controls and Pex7hypo/null at baseline and following treatment with vehicle, PPI-1011 or PPI-1040. (A) Increased activity level of Pex7hypo/null mice at baseline as measured by distance traveled (meters) and time active (seconds). (B) Representative tracking data of treated animals in the open field. (C) Open field test at the end of treatment showed significant hyperactivity in Pex7hypo/null vehicle and PPI-1011 treated groups compared to controls. Normalization of the hyperactivity behavior to the level of the control mice was observed only in PPI-1040-treated Pex7hypo/null mice. Statistical analysis was performed using one-way ANOVA with Tukey's Honest Significant Differences post-hoc test. *P<0.05, **P<0.01, ***P<0.001. ns, not significant.
Fig. 7.
Fig. 7.
Correlation between plasma PlsEtn levels and behavior. Plasma PlsEtn 16:0/22:6 levels strongly correlated with distance traveled (R=0.50, F=6.67, P=0.015) and time active (R=0.51, F=7.08, P=0.015) (left column). Total 16:0 PlsEtn pool levels also correlated with distance traveled (R=0.51, F=6.92, P=0.016) and time active (R=0.51, F=7.10, P=0.014) (right column). n=10 controls, n=6 Pex7hypo/null mice per group. Statistical analysis was performed by basic linear regression analysis. WT, wild type.
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