Plasmalogens, a subclass of glycerophospholipids containing a vinyl-ether bond, are one of the major components of biological membranes. Changes in plasmalogen content and molecular species have been reported in a variety of pathological conditions ranging from inherited to metabolic and degenerative diseases. Most of these diseases have no treatment, and attempts to develop a therapy have been focusing primarily on protein/nucleic acid molecular targets. However, recent studies have shifted attention to lipids as the basis of a therapeutic strategy. In these pathological conditions, the use of plasmalogen replacement therapy (PRT) has been shown to be a successful way to restore plasmalogen levels as well as to ameliorate the disease phenotype in different clinical settings.
Plasmalogens are one of the major constituents of biological membranes . They differ from other major lipid components of membranes by containing a vinyl-ether linkage. The unique chemical structure of plasmalogens endows them with altered chemical and physical properties. The level of plasmalogens in membranes of human cells decreases with age as well as with many pathological conditions, particularly with several neurodegenerative diseases . Conditions leading to disease accompanied by a loss of plasmalogens have no known treatment; the only therapy is through the amelioration of symptoms. However, there is accumulating evidence that diseases accompanied by a loss of a lipid component can be treated by reversing that loss through the administration of the missing lipid component or a biochemical precursor of that lipid . There are several examples of conditions leading to the loss of plasmalogens being treated with plasmalogens themselves, with monoacylglycerols that are known to be metabolized to plasmalogens or with synthetic compounds resembling natural plasmalogens. These findings have been recently reviewed by us in more detail .
Different biological membranes contain different amounts and different molecular species of lipids . This lipid chemical heterogeneity is tightly controlled to ensure suitable membrane physical properties and optimal membrane functioning. Plasmalogens are a vinyl-ether subclass of glycerophospholipids. They are one of the major lipid components of biological membranes that are found in a variety of organisms ranging from bacteria to mammals . In mammals, plasmalogen levels are tissue-specific, and their content comprises up to 20% of the total membrane lipid . Because of their high abundance, it is not unexpected that loss of plasmalogens is associated with several pathologies.
The chemical structure of plasmalogens is like their diacyl glycerophospholipids counterparts . The major forms of plasmalogens in mammals are plasmenylcholine and plasmenylethanolamine. Plasmalogens differ from their diacyl counterparts by having an alkyl (instead of an acyl) chain attached via a vinyl-ether (instead of an ester) bond to the sn-1 position of the glycerol moiety (see Figure 1 of ). The presence of a vinyl-ether bond makes plasmalogen different from other ether glycerophospholipids (e.g., plasmanyl phospholipids that are generally in lower abundance). In comparison to the ester bond, the vinyl-ether bond is more hydrophobic and acid/oxidation labile as well as less involved in hydrogen bonding .
Plasmalogens impart different physical properties to membranes in comparison to their diacyl counterparts. For instance, plasmalogens tend to increase lipid packing and membrane thickness, decrease membrane fluidity, and contribute to the formation and stabilization of membrane domains and curved membrane surfaces . Plasmalogens also have distinct biological functions. One of the main biological functions ascribed to plasmalogens is their ability to function as scavengers of radical species such as reactive oxygen and nitrogen species (ROS/RNS) . In addition, plasmalogens have been suggested to play key roles in signal transduction . Plasmalogens have also been suggested to play a role in membrane trafficking and viral infection .
A replacement therapy is a pharmacological intervention aimed at restoring the levels of a biological molecule that is deficient. Lately, this strategy has attracted increased interest as potentially useful in several pathological conditions. There is increasing evidence that many diseases are caused by the loss of a lipid component. These diseases can be treated by administering the lipid that is lacking so as to achieve its normal level . Plasmalogen replacement therapy (PRT) is a lipid replacement therapy that uses small molecules to increase plasmalogen levels with the final goal of improving health outcomes. PRT can be administered orally using compounds that are non-toxic. There are three approaches to PRT: administration of metabolic precursors of plasmalogens, administration of plasmalogens from natural sources, and finally administration of synthetic analogs of plasmalogens.
One plasmalogen precursor that has received some attention is alkylglycerol (AG) (see Figure 3 in ). AGs are lipid intermediates of the plasmalogen biosynthesis pathway that readily cross the cellular plasma membrane and can enter the plasmalogen biosynthesis pathway in the ER, after being phosphorylated in the cytosol. AGs containing different acyl chains have been used, the most common ones being 1-O-hexadecyl-sn-glycerol (HG, 16:0-AG), 1-O-octadecyl-sn-glycerol (OG, 18:0-AG), and 1-O-octadecenyl-sn-glycerol (OeG, 18:1-AG). In mammals, oral administration of purified plasmalogens shows extensive breakdown in the intestinal mucosal cells, while administration of AG leads to complete absorption through the intestine. In the intestinal mucosal cells, the majority of AG is metabolized into plasmalogens (specifically PE-Pls).
PRT can be implemented by dietary intervention using natural plasmalogens. Sources with high levels of natural plasmalogens include marine animals (such as shark liver, krill, mussels, sea squirt/urchin/cucumber, and scallops) as well as land animals’ meat (e.g., pork, beef, and chicken). Plasmalogens from fish and mollusk have a lower ω-6/ω-3 fatty acid ratio than livestock ones, suggesting the former provide an advantage because of the proposed health benefits of ω-3 fatty acids. While natural sources of plasmalogens have the potential to provide dietary plasmalogen supplementation, the decreased bioavailability, particularly in the gastro-intestinal tract, if taken orally, requires ingestion of an enormous amount of raw material to attain significant plasmalogen levels in tissues. To circumvent this purified plasmalogen extracts are often used. These plasmalogen extracts tend to be enriched in PE-Pls, and they are often prepared from marine animals (e.g., scallop and sea squirt) or from chicken. Plasmalogens are transported from the intestine and liver to other organs, but it seems that they do not cross the blood-brain barrier and are not transported across the placenta (from mother to fetus) .
The use of synthetic analogs of plasmalogens in PRT has also been described to achieve more favorable pharmacokinetic properties (see Figure 4 in ). One such analog is PPI-1011 (an alkyl-diacyl plasmalogen precursor with DHA at the sn-2 position) . Another synthetic analog, PPI-1025, has been designed specifically for the treatment of multiple sclerosis. PPI-1025 is an alkyl-diacyl plasmalogen precursor with oleoyl at the sn-2 position. It has been shown to increase plasmalogen levels in the brain and to protect against demyelination in animal studies (http://med-life.ca/multiple sclerosis). PPI-1040 is a PE-Pls analog with a proprietary cyclic PE headgroup. It is unique among these analogs in that it contains a vinyl-ether headgroup. It is currently undergoing clinical trials for the treatment of rhizomelic chondrodysplasia punctata (RCDP) (http://rhrizotrial.org/pp1-1040).
PRT provides a new, modern, and innovative pharmacological and nutritional approach aiming at improving health outcomes in clinically unmet needs of local, national, and global importance. PRT has been employed in different clinical settings (see Table 1 in ). In humans, PRT has been investigated as a therapy for several different conditions where it has been established that the condition is accompanied by a loss of plasmalogen in the whole body or in an affected organ. Clinical trials have been reported for the use of PRT in peroxisomal disorders and in neurodegenerative and metabolic disorders. In these trials PRT results were encouraging showing the ability of PRT to restore plasmalogen levels in some organs as well as improving to some extent the phenotype. While PRT is in its infancy, the findings so far are encouraging. In the future, more systematic investigations will allow the design of better, more potent strategies for PRT.