Enabling Intranasal Therapies for Brain Invading Pathogens

The blood-brain barrier (BBB) plays the role of maintaining brain homeostasis and preventing foreign invaders from infiltrating the brain tissue from the blood; however, an alternative pathway exists for opportunistic pathogens to enter the brain and cause severe damage. Infiltrating either through the olfactory or trigeminal nerves (in the nose), these pathogens, whether bacterial, viral, fungal, or parasitic, bypass the BBB and cause devastating symptoms. Like brain tumors, these neural infiltrating pathogens are free to grow with the protection afforded them by the BBB, which prevents the passage of greater than 98% of small molecule drugs. Because of the difficulty associated with treatment, pathogenic infections can lead to meningitis, with insufficient treatments available, demonstrated by mortality rates that range from ~10% to 98%, depending on the etiology. Although these pathogens vary in their etiology and pathology, many of them are linked by enolase, an enzyme that plays a role in plasminogen binding and glucose metabolism, which seems to enable their infiltration. The Larsen Lab is a leading expert in the development of treatments for diseases of the central nervous system using polymer-based nanoparticles to encapsulate and deliver drugs across the BBB. We will leverage this expertise towards the treatment of brain-invading pathogens. Learning from these opportunistic pathogens, we will encapsulate enolase inhibitors in polymer-based nanoparticles called polymersomes and deliver them via intranasal administration. In this proposal, we specifically focus on brain-eating amoeba, or Naegleria fowleri, as our first model to provide proof of concept for our approach due to its extremely high mortality rate. We plan to leverage discoveries for treatments of other pathogens involving enolase.