Bacterial infections are one of the main causes of mortality and long-term patient complications worldwide. For example, pneumonia is the number one cause of death in children under 5. The primary driver of toxicity resulting in organ failure and death during these infections are components of the bacteria themselves, called endotoxins. These are components of the bacterial membrane that the body’s immune system senses and then triggers massive inflammation as a result, and this causes associated organ damage. When present in high abundance, this can cause severe inflammation resulting in death. The condition in which an infection results in high levels of endotoxin in the blood is referred to as endotoxemia and is the main driver of mortality in these infections. Endotoxemia conditions include pneumonia, and others for which few good therapeutics exist. Developing drugs to reduce the time to resolution of endotoxemia is the goal of this proposal.
Over decades it has been established that endotoxins are sequestered and cleared from circulation via high- and low-density lipoproteins (HDL and LDL respectively). These complexes bind endotoxin and are then cleared into the bile via the liver in a pathway overlapping that of cholesterol metabolism. From extensive clinical studies, it was recently discovered that patients with mutations in genes that result in increased function in the HDL and/or LDL pathways have superior outcomes from severe endotoxemia-related infections such as sepsis than the average population. For example, patients with mutations in the PCSK9 gene have a ~85% overall survival rate after 1 year, whereas this is ~60% in the average population. This and other proteins are largely made in the liver, which is a highly druggable organ using genetic drugs delivered via lipid nanoparticles (LNP).
Resolve Nanotherapeutics is a preclinical drug development company creating LNP RNA drugs that will either mimic or improve on these clinical observations by upregulating endotoxin clearance pathways after intravenous infusions. RNTx has significant expertise in RNA LNP drug development but critically lacks disease challenge models to test its drugs – a non-trivial task that will dictate the direction of clinical development of any new drug formulations. We have identified a strong bacterial infectious disease post-doctoral fellow interesting in developing and testing of drugs in at least 3 in vivo challenge models, and setting these up and doing efficacy testing is the basis of this proposal.
The aims are as follows:
1. Develop an in vivo model of bacterial pneumonia for at least 4 diverse bacterial pathogens
2. Develop and in vivo model of bacterial sepsis
3. Develop an in vivo model of chemotherapy induced (febrile) neutropenia
The fellow will develop hands on skills for in in vivo infection models and testing drug formulations therein. They will also gain experience in drug development, both by exposure to the drug development process in terms of design, but critically learn to assess in vivo requirements such as pharmacokinetics, biodistribution, toxicity, efficacy, and many other evaluations. These are invaluable skills highly translatable to other sectors of drug development.
The project will greatly accelerate the capacity of Resolve NTx to perform drug candidate efficacy testing and ultimately chart the fastest path to clinical to get these potentially critical drugs into patients as fast as possible.