COVID-19 AN ‘UP TO DATE’ PRIMER
INTRODUCTION
It is likely that some may not realize but given our R&D team’s experience in wound healing, surgical intervention, and wide ranging basic science research, over the past two+ years we have been tasked with investigating strategies intended to treat COVID. Among our efforts, we developed, tested, and successfully deployed a nano-enabled bolus containing Mark VII phytonadione, cholecalciferol-D3 & cyclodextrin. Here, the intention “as well as the result” was to formulate new combinatorial therapies designed to down regulate key gene markers linked to auto-immune triggered clinical decompensation (i.e. debilitating serious illness). For purposes of this discussion, the upshot is that our team has established a somewhat better than average comprehension of COVID-19. Our work in this area has also lent us insight into some less well-publicized challenges and also cutting-edge treatment studies underway in labs and hospitals across the globe.
Thus, in this monograph, it is our hope to provide several data points that may help our valued clients and other interested parties come up to speed on COVID.
HOW VIRUSES WORK
Viruses are microscopic entities with a core of genetic material, based either on DNA or RNA. This core is covered with a capsid (a protective coat made of protein). Some virions (individual viral units) have an additional coat called the envelope. This may be spiky, and this helps the virus latch on to and enter host cells. Viruses can only replicate inside of a host. Viruses also lack critical cellular machinery called ribosomes, so they cannot make proteins. This renders them unable to reproduce independently and are thus totally dependent upon their host.
Within phenotypic categories exist many different kinds of viruses. A coronavirus, for example, has a sphere-like shape as well as a helical capsid containing RNA. It also has an envelope with crown-like projections on its surface. It is believed that seven coronaviruses can affect humans, however each can mutate, thus producing many variants. When a viral disease emerges in humans, its source is not always immediately clear. For example, though originally thought to arise in bats, SARS-CoV-2 is now believed by many medical experts to have subsequently been modified -- and perhaps weaponized -- in a Wuhan Level IV biohazard laboratory; at which point it may have been either accidentally or deliberately released.
Significant conformational changes tend to make a virus more transmissible over time, as has been the case with many SARS isolates, including the B.1.1.7 variant of SARS-CoV-2.
HOW COVID EVADES OUR IMMUNE SURVEILANCE
Researchers in Japan and the United States have found SARS-CoV-2 can knock out an important molecular pathway linked to an immune complex called MHC class I. The results showed that a protein from the SARS-CoV-2 virus, called ORF 6, suppresses a host cell protein, called NLRC5, responsible for activating the MHC class I pathway. Without the activation of the MHC class I pathway, viruses in the infected cells are essentially hidden from the immune system. That helps to explain why SARS-CoV-2 virus persists in the body and why it keeps infecting others, leading to the ongoing pandemic.
Related studies have shown this happens in two ways. ORF6 hampers cell signaling, which turns off the expression of NLRC5. ORF6 also blocks the function of NLRC5. Other infectious viruses, including HIV and MERS, are known to also target the MHC class I pathway. Researchers surmised that SARS-CoV-2 probably did as well, but this study is among the first to unravel the mechanism. Further work could help find and test drugs that block the activity of the ORF6 viral protein, to restore host cell ability to activate the major histocompatibility complex (MHC). If successful, such drugs could encourage the host immune system to clear the virus independently, effectively boosting immune responses.
NATURAL IMMUNITY / THE FACTS
Some who have not yet been vaccinated against COVID-19 worry about the safety of the vaccines and some articulate a desire to develop natural immunity. Unfortunately, there are several disadvantages and dangers in following this approach. Numerous published studies suggest that should you contract COVID-19 the natural immunity you develop renders another COVID exacerbation unlikely for approximately 90-days. And yet, the medical professionals most familiar with the epidemiology of the disorder remain unsure as to how long a clinically relevant level of protection in such individuals persists. As many have come to realize, if one is stricken with COVID, reinfection is most definitely possible, and in some instances highly likely. Recent data suggests that COVID-recovering unvaccinated persons appear more than twice as likely than vaccinated individuals to sustain another bout of the disease.
LOOMING THREATS
Recent published work suggests that a mutated SARS-CoV-2 isolate from a chronically infected immunocompromised patient may be capable of evading both naturally occurring antibodies from COVID-19 survivors as well as lab-made antibodies now in widespread clinical against COVID. The published study, which builds on an initial case report, shows something even more alarming. Certain changes found in the patient-derived virus have not been identified yet in dominant viral variants circulating in the population at large. However, the changes have already been detected in databases of publicly available viral sequences. Thus, though the mutations remain as yet isolated, the report suggests they could be the progenitors of new far more robust COVID mutants that may eventually spread widely across the general population.
AN INTERESTING NEW APPROACH
Perhaps ironically, in many who have suffered and died from COVID-19 it is not the virus but their own “out of control” immune system that is the culprit. Specifically, pulmonary macrophages in COVID-19 derived from infiltrating inflammatory monocytes are in a “hyperactivated” state resulting in a detrimental loop of pro-inflammatory cytokine release and recruitment of cytotoxic effector cells thereby exacerbating tissue damage at the site of infection. It is as though the fire alarm in one’s body has inadvertently caused the responding fire department to throw gasoline on the flames rather than water.
Thus, a key facet of current research involves turning down the burner of a COVID-affected patient’s out of control auto-immune system. Here, an excellent drug “remdesivir” has been shown to do just that. Unfortunately, this drug is, so far, only available as intravenous therapy. And because the drug must be delivered in a relatively massive dose the risk of negative side effect is profound. One company’s drug delivery vector may solve this challenge. Matinas Biopharma has developed a proprietary intracellular lipid nano crystal “LNC” platform designed to safely deliver a broad range of potent medicines – including small molecules, drugs with blood level-limiting toxicities, nucleic acid polymers, proteins, peptides, vaccines, and gene editing technologies. The delivery molecule is formulated as a natural, non-toxic and highly efficient spiral crystal, or “cochleate,” with a unique ability to be administered orally and through various other routes.
In the case of LNC oral remdesivir, the drug molecules are encapsulated in a layered design, which protects them from harsh environmental conditions or enzymes until the moment they enter a target cell. Following non-destructive fusion with the cell membrane, the molecules are naturally released to the interior of the cell, thereby avoiding the systemic toxicity of intravenous administration.
To date, this drug delivery platform has been validated in multiple preclinical studies and is protected by a robust IP portfolio. To support all phases of further development, Matinas has begun operating a scalable GMP manufacturing facility. In coordination with the NIH and drug partner Gilead Pharmaceuticals, LNC oral remdesivir is being tested right now at the University of North Carolina. Given that remidesivir attacks the SARS-2 virus in a different way than vaccines – and viral mutations don’t seem to reduce potency, it is possible that an LNC oral remdesivir version could be the silver bullet we’ve been waiting for. Only time will tell.