Kieran and Brennan O'Dea
Edasalonexent: Understanding DHA in DMD
Catabasis's understanding of Duchenne Muscular Dystrophy (DMD) and Edasalonexent's role in treating the disease is fundamentally flawed.
DMD is primarily a disease of the mitochondria not a dysfunctional dystrophin disease.
DHA which plays an incredibly important role in cell signaling slowly is cannibalized by DMD patients over time due to a number of factors.
Edasalonexent's primary MoA in treating DMD is actually the injection of DHA into the cells and not the inhibition of NF-kB.
When it comes to Edasalonexent’s potential as a therapy for Duchenne Muscular Dystrophy (DMD) and other rare diseases, the company, Catabasis, is overly focused on the inhibition NF-kB. While NF-kB is an important and relevant component that Edasalonexent can effectively inhibit, it only represents a small component of DMD progression and Edasalonexent’s role in halting it.
If the inhibition of NF-kB was the whole story, the patients would not see improvements in well-being, and merely a slowed progression of this disease. Phase 2 trial results, however, show us that patients continue to improve the longer they are on Edasalonexent.
Important to note that in light of overly positive phase 2 results, the company appears open to a potential dialogue that would result in an increased understanding of not only their drug but DMD as well. We believe and will show evidence to support our theory that the ability to transmit DHA into the unhealthy cell membranes of DMD patients plays a much bigger role in the effectiveness of Edasalonexent than is currently understood.
Furthermore, we think that apart from being misunderstood, the ability to transmit DHA directly into cells with very low toxicity offers is incredibly undervalued. We see tremendous potential for this low toxic therapeutic treatment to one day be applied across a wide range of metabolic disorders and rare diseases.
The problem with the NF-kB thesis:
To be perfectly blunt, the company and the medical community at large have a deeply flawed view on Nuclear factor kB (NF-kB). This is evident in the model above which suggests that NF-kB is purely an arbitrator of doom. NF-kB is an important transcription factor typically activated by pro-inflammatory cytokines and other specific stimuli and is involved in the regulation of a variety of biological responses. It is one of the cell’s main 911 response calls. Its activation is an adaptive, protective response. In and of itself NF-kB is not harmful.
Furthermore, the company’s belief that NF-kB suppresses muscle regeneration is incorrect. NF-kB, and inflammatory signaling in general, is an important piece of regeneration and cellular growth in all tissues throughout the body, muscle growth being an obvious example. NF-kB is a sign, a piece of the bio-semiotic information processing entity that is the cell. It simply acts to convey meaning.
To use an imperfect analogy, picture a house (cell) in a neighborhood (organism) on fire (inflamed) with the accompanying smoke (NF-kB). Smoke is elicited by the fire. The smoke doesn’t start the fire, it conveys meaning to onlookers about the presence of the fire as well as the extent and nature of the fire as well as its relative location. From the meaning conveyed by the smoke, help can be marshalled to stop the fire and furthermore, once the fire is put out, to rebuild the house. Initially the smoke may harm anyone or thing left in the house, and the firemen may hack down a few doors and cause some extra damage, but in the long run the damage is reduced and anything damaged can be rebuilt.
In the case of DMD patients, the problem is not the smoke (NF-kB), but the fire (inflammation). The mutation isn’t in NF-kB, but in the genome coding for dystrophin and actually as we will later argue, the dysfunctional dystrophin isn’t even the largest contributor to said fire.
But by removing the smoke without affecting the fire you remove the threat of smoke inhalation and you prevent the doors or walls being broken down by the firemen but you prevent the firemen from putting out the fire and the builders from rebuilding the damaged house. Using this simple analogy, you can see how the inhibition of NF-kB in DMD patients would not lead to an improvement in function over time, and instead merely act to slow the damage done by the body’s response system.
DMD is misunderstood:
As we alluded to in the opening, a major issue with using this simplified and inaccurate picture (shown above) is that the lack of dystrophin in DMD is not the cause of the disease per se as is commonly thought, but a secondary finding that goes along with the mitochondrial/metabolic problems observed in the disease. In fact, patients with certain types of muscular dystrophy have no dystrophin in their system whatsoever and have a milder form of the disease due to the metabolic dysfunctions found in muscular dystrophy. Prior to the discovery of dystrophin (and by several research groups afterwards), DMD was considered to be a disease of metabolic origin, with a strong body of literature demonstrating deficiency of key metabolic systems and regulators, including the mitochondria.
Metabolic impairment is also evident in a variety of tissues and cells from DMD patients and animal models that express a different dystrophin isoform – these include liver, heart, and brain, i.e. tissues with the highest mitochondrial density. Note that the liver and brain which are not muscular tissues, according to the standard model of DMD should be relatively unaffected by the disease. Furthermore, mitochondrial deficits are often seen prior to dystrophin expression. Thus, attributing DMD first and foremost to mutations in dystrophin is putting the cart before the horse.
This however, is actually good news for Edasalonexent’s potential to treat the disease as DHA plays far more important roles outside of its management of NF-kB signaling, all of which converge on the mitochondria.
The importance of mitochondria:
Mitochondria are responsible for creating (liberating) more than 90% of the energy needed by the body to sustain life and support organ function. When they fail, less and less energy is generated within the cell. Cell injury and even cell death follow. If this process is repeated throughout the body, whole organ systems begin to fail. The parts of the body, such as the heart, brain, muscles and lungs, requiring the greatest amounts of energy are the most affected. It’s no coincidence that these are the tissues most often affected in DMD.
Mitochondrial DNA has only 37 genes. From those 37 genes comes just 13 proteins. Those 13 proteins code for the electron chain transport complexes. The remainder of the genes code for tRNA. Mitochondria also can’t grow outside the cell. These special cells require the 30,000 genes in the nucleus to make up another 1500 proteins for them to function properly.
Mitochondrial DNA and nuclear DNA have to have precise lock and key fit to generate energy production. If not, the cell eliminates itself by apoptosis fast. If the two genomes work well together, this combination is naturally selected for future cell division to generate energy.
Aging and disease can be quantified largely by how “leaky” our mitochondria are – How many free radicals leak from the electron transport chain. The mitochondria’s DNA is adjacent to the first complex in electron chain transport. So, the more leakage, the more damage is done to its DNA creating a positive feedback loop and a further decline in energy production.
DHA’s role in mitochondrial function:
This communication between the two genomes of the mitochondria and the nucleus is therefore paramount to cell health, and underlies the role in which mitochondria play in cellular communication throughout the body. Said communication is even more important given the real-time adaptation that mitochondria must undergo in order to match changing demands to supply. A failure in cellular and organismal communication thus precipitates mitochondrial decline and the systemic failure of the entire body. This is why DHA is so important in treating DMD because DHA is critical in deciphering environmental signals to and from the mitochondria.
Few people realize the possibility that DHA in vivo plays a more direct role in cellular signaling, in which some special properties conferred on the membrane by DHA chains exert an influence on membrane electrical, optical, and biochemical phenomena. This implies that the DHA molecule itself has some special electrical abilities and can exert quantum effects in vivo. The 6 double bonds in DHA allow for its electron cloud in the molecular structure of DHA to become a very special fatty acid with unique properties.
Quantum Properties of DHA:
With the understanding that the following explanation is somewhat in-depth and more theoretical we offer a simplified explanation of our research at the end of this section.
The unique molecular structure of DHA (shown below) allows for quantum transfer and communication of pi-electrons. The planar structure of the energy-minimized DHA conformation is a fundamental characteristic of six double bonds separated by –CH2– groups.
The pi bonds always have a directionality at the molecular level. The shape of their probability orbits will lean towards a positive end of a dipole moment. Thus, these three coplanar double bonds immediately have at least two different potential energy states: two with the pi bonds up or three with the pi bonds up (and the mirror image of two down or three down).
Structurally the other three double bonds are not symmetrical. Two are above the plane, one below. It is not possible for DHA to be a symmetrical molecule because the pi bond field effects are always unequal.
Each of the CH2 hydrogens in –CH2–CH=CH–CH2– have an unequal charge density, corresponding to above or below the –C–CH=CH–C– pi bonds which lie perfectly flat at the molecular scale. Given a dipole across the molecule, the pi bonds will have partial positive charge up whilst the CH on the same side of the plane will correspondingly be slightly negative. So, in a sequence of double bonds as in DHA, the sign of partial charges alternate.
In this conformation (geometrically best packed/lowest energy) the second CH=CH group at the carboxyl end is in effect upside down and the signs of the partial charge on the –CH2– groups next to it are opposite those of the other two adjacent CH=CH pairs. Thus, the energy barrier [moment of inertia] to flip the second CH=CH group is lower than that of any other CH=CH group. The arrangement of the double bonds with this CH=CH group flipped creates a conformation similar to conjugated double bonds, and conjugated double bonds can store energy in the ultraviolet to visible range.
With the pi-bond energy distributed above and below the plane of the molecule and polarization of the –CH2– intervening groups, the outer orbit electrons could communicate in a way leading to conduction. In other words, there is a probability of coherent communication between two pi-electron sets on either side of a –CH2– which could include the participation of the methylene group and electron tunneling. Cohesion could conceivably extend along the whole molecule.
In the cell membrane, the polar head group on the outer face is dominated by a phosphate and a strong quaternary amine (choline). On the inner side there is the same phosphate but a weak primary amine (ethanolamine). The bilayer in its resting state will be charged, with the probability of finding an electron greater in the direction of choline. There are two conditions which could pull an electron out of DHA (i) a sufficient electrical charge as in hyperpolarization and (ii) the Einstein photo-electric effect; neither is mutually exclusive.
If one electron is delocalized and pulled out by hyperpolarization, an immediately distal electron will take its place and this electron tunneling would lead to a flow of current. Thus, energy minimized structures, molecular polarization and moment of inertia allow for the theoretical possibility of DHA operating in the realm of supra-molecular chemistry with electron quantum coherence.
DHA simplified (sort of):
It has been put forth that some polarization of π-electron clouds might occur in the DHA structure, and perhaps even be transmitted from one double bond to another, either within a given chain, or between neighboring chains in the membrane. In other words, DHA has different properties in the lipid structures of the brain than it does when a researcher studies it in the lab.
The importance of these properties underlies DHA’s dominance as the primary fatty acid in the membrane phosphoglycerides of the photoreceptors, neurons and synapses for at least the last 600 million years of animal evolution. DHA is one Darwin’s ‘‘Conditions of Existence’’ which has made DHA the master of DNA since the beginning of animal evolution. Proteins are selected to function with the constancy of DHA: it was the ‘‘selfish DHA’’ not DNA that ruled the evolution of the nervous system and cell membrane based signaling.
Protein–lipid interactions operate in a multi-dimensional fashion similar to what has been described for proteins. This relationship is a two-way system. During cell differentiation, the specialist proteins that arrive will seek a lipid match and vice versa. This means lipids and proteins have to be multidimensional in configuration and proteins must be thermodynamically matched to the lipids in our membranes. This means the configuration requires a very precise biochemistry to work in the brain. If the matching lipids are not present, the system may fail. DHA is that “magic lipid” that proteins need to match.
If the DHA match in the cell membrane is not found, and there is an omega 6 or DPA we lose proper electrical, chemical, and optical signaling. If DHA is absent from mammalian cells, then the entire system suffers electrochemical failure at some level.
The unique molecular structure of DHA makes coherent communication probable along the length of the molecule and between adjacent molecules, possibly via electron tunneling. Electron tunneling occurs when an electron acts like a wave or probability cloud and can tunnel through a barrier or across a gap. The smaller the distance or gap between adjacent molecules, the easier (more likely) it is for electrons to tunnel.
When DHA molecules are adjacent to each other in a tissue like the brain the π-electron clouds actually are closer together in space than they are when the DHA molecule is alone. This unique ability not only reduces the amount of energy required for tunneling (increasing the effectiveness of signal transmission) but allows for DHA in a membrane to become its own receptor in a membrane to allow for amazing electrical and optical abilities. This is why DHA is so special and has been conserved by evolution in the nervous system of all life forms and not replaced with the more common land-based form of PUFA’s like DPA.
The extraordinary conservation and irreplaceable nature of DHA as well as its high concentration in the cell membrane can be explained by its function as an electron tunneling device providing quantized signals. In short, DHA is a quantum version of Maxwell’s Demon which humans exploit more so than any other mammal on this planet.
DHA is incorporated into cells via two routes, what are known as the short loop and the long loop. The short loop is the system by which DHA is recycled. The long loop is the system by which DHA is incorporated from the Diet. This long loop depends on the liver’s ability to process and transform DHA into the appropriate bioavailable form. This is dependent on the overall functioning of the liver, but also specifically on adiponectin signaling which is tied to a complex system involving other signaling molecules such as insulin and leptin.
Unfortunately, DMD patients have decreased liver function as well as dysfunctional adiponectin, insulin, and leptin signaling. This means that even if they were to have a high dietary intake of DHA they wouldn’t be able to properly incorporate it into their cells. Furthermore, as DMD patients’ cells are under considerably enhanced stress their cells metabolize DHA to make the various protective breakdown products. In addition, their ability to recycle DHA in the short loop is also lack luster. The end result being that DMD patients have a considerable deficiency of DHA in their membranes and thus suffer from a loss of coherent signaling.
This is where Catabasis’ drug Edasalonexent (CAT-1004) comes in. Catabasis utilizes their SMART Linker drug platform to conjugate salicylic acid and docosahexaenoic acid (DHA). This unique chemical linking enables the compounds to be shepherded directly into cells. Upon entry into the cells specific enzymes release the component bioactives inside the cell.
Edasalonexent essentially bypasses the dysfunctional DHA processing systems in DMD patients and allows for a massive amount of DHA to be safely delivered directly into the cells where it can be incorporated into cell membranes to improve all aspects of cellular functioning, and in times of need to be broken down to protective metabolites to provide the cell with resistance to stress.
This process, however, takes time, as the main mechanism of action is not simply NF-kB inhibition, as promoted by the company, but rather correction of cellular DHA deficiency. This is far more effective in terms of treatment, but the effects accumulate overtime and are therefore less apparent from shorter term treatment. This has been shown in the results reported at each successive analysis interval in the phase 2 trial Catabasis has been running.
If the effects of Edasalonexent stemmed solely from NF-kB inhibition, then there would not have been such a dramatic change in the results from one analysis to next. NF-kB inhibition would be expected to slow disease progression, but not halt it or even reverse it. The effects would be limited and the progression of the disease in these patients would still be apparent.
However, in the most recent analysis it can be seen that, at least in certain measures, disease progression has effectively been halted. This can be ascribed to the accumulation of DHA in the cell membranes of these patients and the corresponding correction of cellular signaling and all its ramifications, perhaps most importantly a decrease in mitochondrial dysfunction.
Once again, this is not to dismiss the role played by salicylic acid, which has been shown to be effective in treating various diseases in its own right. But we believe proper emphasis should be placed on DHA as it has far more important cellular functions and forms the backbone of Catabasis’s entire platform. We welcome the opportunity to discuss our views in greater depth. Thank you.
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 Revisiting the dystrophin-ATP connection: How half a century of research still implicates mitochondrial dysfunction in Duchenne Muscular Dystrophy aetiology
 A quantum theory for the irreplaceable role of docosahexaenoic acid in neural cell signalling throughout evolution