Science of Lipidomics

Fatty acids are an integral part of nature's extensive set of basic biological building blocks. Also, as a fatty substance, fatty acids are an excellent energy source or storage form of energy. As phospholipids, fatty acids serve as structural tissue components and are part of cell membranes and cell organelles, which are sub-cellular functional units. As eicosanoids or docosanoids, they have been converted into important signaling molecules in inflammatory processes (prostaglandins, leukotriens, and resolvins), coagulatory pathways (thromboxanes), and as regulators of many other biological pathways. Fatty acids and related forms are often grouped together under the term "lipids."

Over the last few years, the scientific knowledge base around lipids and their biological roles has expanded rapidly. Recent discoveries have demonstrated that fatty acids are not only functional agents as described above, but are also directly involved in gene regulation. Many of these genes support key metabolic pathways, and it appears that many poly-unsaturated long chain fatty acids may have therapeutic applications. Building on these novel discoveries, the field of lipidomics is developing into a key medical research area.

Whereas most short chain fatty acids serve as a form of energy storage, much broader functional roles are associated with longer chain poly-unsaturated fatty acids. These include the omega-6 and omega-3 fatty acids. Most of these fatty acids are essential fatty acids, and are a key component of nutrition, usually in relatively low daily intake together with many other fatty acids in essentially crude mixtures. The focus of Matinas BioPharma, however, is to establish therapeutic applications and develop lipids comprising these fatty acids as value-added prescription therapeutics.

Omega-3 fatty acids have been shown to exhibit a range of therapeutic benefits. Omega-3 fatty acid-based prescription medications have been approved in most countries for the treatment of dyslipidemia, and in many countries for the reduction in the risk of cardiovascular events (e.g. heart attacks). Although most of today's omega-3 medications are based on EPA and DHA, it is clear from the table below that nature has created many more omega-3 fatty acids.

Common Name for
Omega-3 Fatty Acid (+abbreviation)
Codified Lipid Name Chemical Name
Hexadecatrienoic acid (HTA) 16:3 (n-3) all-cis-7,10,13-hexadecatrienoic acid
α-Linolenic acid (ALA) 18:3 (n-3) all-cis-9,12,15-octadecatetraenoic acid
Stearidonic acid (SDA) 18:4 (n-3) all-cis-6,9,12,15-octadecatetraenoic acid
Eicosatrienoic acid (ETE) 20:3 (n-3) all-cis-11,14,17-eicosatrienoic acid
Eicosatetraenoic acid (ETA) 20:4 (n-3) all-cis-8,11,14,17-eicosatetraenoic acid
Eicosapentaenoic acid (EPA) 20:5 (n-3) all-cis-5,8,11,14,17-eicosapentaenoic acid
Heneicosapentaenoic acid (HPA) 21:5 (n-3) all-cis-6,9,12,15,18-heneicosapentaenoic acid
Docosapentaenoic acid (DPA) or Clupanodonic acid 22:5 (n-3) all-cis-7,10,13,16,19-docosapentaenoic acid
Docosahexaenoic acid (DHA) 22:6 (n-3) all-cis-4,7,10,13,16,19-docosahexaenoic acid
Tetracosapentaenoic acid (TPA) 24:5 (n-3) all-cis-9,12,15,18,21-tetracosahexaenoic acid
Tetracosahexaenoic acid (THA) or Nisinic acid 24:6 (n-3) all-cis-6,9,12,15,18,21-tetracosahexaenoic acid

Omega-3 fatty acids other than EPA and DHA are significantly less prevalent in nature. We have found that these rare omega-3 fatty acids are often very potent as compared to EPA and DHA, and have unique biological properties in the metabolism of humans and other mammals. From our research, we have specifically observed very impressive characteristics of omega-3 Docosapentaenoic acid (DPA).

To date, it has been very difficult to isolate the rare omega-3 fatty acids in a highly pure form. Matinas BioPharma has developed the technology for isolating rare omega-3 fatty acids, and with our unique processes we can produce highly pure single omega-3 fatty acid concentrates.

A Novel Therapeutic Approach With Omega-3 Docosapentaenoic Acid

DPA is a key component of MAT9001, and we believe that this rare omega-3 will be a driver of significant differentiation for MAT9001. Below we outline several of the characteristics associated with DPA.

Although relatively rare in natural lipid sources as compared to EPA and DHA, the relevance of DPA in biological processes becomes very clear once we appreciate its relative potency. Japanese researchers studying the motility of endothelial cells (the cells lining the inner side of our blood vessels), have demonstrated that omega-3 fatty acids stimulate the motility of these types of cells. This mechanism may have biological significance as endothelial cell migration appears to play an important role in the repair of damaged/inflamed walls of arteries and blood vessels. Such blood vessel wall damage is the hallmark of atherosclerosis. It was found that while both EPA and DPA stimulate the mobility of endothelial cells, DPA appears about 10x more potent that EPA in this respect.

Our research has shown that DPA also has a very potent effect in reducing fasting triglyceride levels. In studies of omega-3 fatty acids in the "Fatty Zucker" rat model, we have found that a dose of 50 mg DPA/kg was at least as effective as 400 mg EPA/kg (the equivalent dose to about 4 grams EPA/day in humans).

How this efficacy of DPA in the "Fatty Zucker" model translates into DPA's ability in reduce fasting triglyceride levels in humans has not yet been established. However, work by Australian researchers in a related field suggests that DPA may have significant effects in humans. In a 3-way cross-over study of 10 healthy women, they established that DPA stabilizes post-meal (post-prandial) triglycerides levels, to a greater extent than EPA. Most of this effect seems to originate from a reduction in the production of chylomicrons (lipid particles produced by the intestines to capture and transport fats from nutrition).

For many years it was believed that the efficacy of omega-3 fatty acids in the reduction of triglycerides was mostly due to an inhibitory effect on enzymes such as DGAT. Recent work has established that omega-3 fatty acids have a direct effect on the regulation of many genes involved in lipogenesis. Based on research such as this, we believe that DPA may have profound therapeutically useful effects.

The gene regulatory effects of DPA in rat liver cells do not only include the down regulation of the genes for SREBP-1c, Acetyl Coenzyme-A Carboxylase, ChREBP, and fatty acid synthetase, but also the reduction in expression of the mRNA for HMG-CoA reductase (the same enzyme that is targeted by a class of medications known as "statins"), and PCSK9, a protein that increases LDL, or "bad cholesterol.

Our own in vivo research in the "Fatty Zucker" rats has confirmed many of the gene regulatory effects described above. Besides demonstrating such direct regulatory effects on genes, our work is also exploring how DPA may work together with other medications such as statins. Our research indicates that statin therapy may induce an up-regulation of certain lipogenic genes to compensate for the presence of statin therapy, thereby potentially "undoing" some of the statin effect. Our work suggests that DPA may mitigate some of these compensatory effects.

In addition to the effects described above, DPA has several other types of activity. These include an aspirin-like platelet inhibitory effect [Akiba et al.; Biol.Pharm.Bull. (2000), 1293-1297] and an anti-angiogenic effect through the suppression of the expression of the gene for the VEGF-2 receptor [Tsuji et al.; PLEFA (2003) 68; 337-342].

Based on the data above, we believe that there is significant potential for extensive therapeutic use of DPA in a range of medical conditions. It is our goal to further develop well defined therapeutic applications and regimens of DPA, and advance lipidomics-based-medicine.