Smells alert us to danger and induce satisfaction. They trigger old memories and create new ones. Such reactions are the result of odors inhaled through the nose and of signals transported into various regions of the brain through the olfactory nerve.
The olfactory nerve, which starts at the olfactory epithelium in each nostril, leads to the olfactory bulb in the brain. The olfactory bulb dispenses information along the olfactory tract into several specific regions in the brain, including those associated with depression, Alzheimer’s and Parkinson’s diseases, dementia, psychiatric disorders, among others.
Intranasal administration of drugs to the olfactory tract provides direct access to the brain, bypassing the difficult to cross blood brain barrier. But to navigate the olfactory pathway requires a suitable delivery system for all kinds of therapeutics. An effective delivery system is particularly important for the latest innovative biologics such as RNAs (mRNA, siRNA, miRNA), proteins, peptides, oligonucleotides.
AGS in Paris, has a potential solution to this challenge: microalgae extracellular vesicles (MEVs), a new universal and highly competitive drug delivery system. MEVs can be loaded with any kind of biologic and small molecule for intranasal administration. MEVs also are intrinsically safe, and studies demonstrate they have a most interesting natural tropism for the brain.
AGS’ animal studies have revealed that MEVs easily reach various regions of the brain when administered intranasally in liquid drops. Once in the nose, the MEVs are internalized by sensorial neurons of the olfactory epithelium. From there, they travel through the olfactory bulb to internal structures in both hemispheres of the brain.
Brain regions reached by MEVs are involved in perception; management of emotions; memory; learning; reasoning; functions related to various senses; sleep and wakefulness; sexual appetite and behavior; depression and deep depression. By reaching these regions, intranasally-administered MEVs hold the potential to deliver therapeutics for a wide variety of serious brain disorders irrespective of the presence of a blood-brain barrier.
What AGS’ initial studies have shown is that intranasal administration of MEVs overcomes the obstacles of delivering drugs through the blood brain barrier to treat brain disorders. Only a small number of hydrophobic and low molecular weight molecules can cross the blood brain barrier and other kinds of therapeutics are restricted by the barrier’s characteristics. The direct anatomical connection between the nasal cavity and the brain opens it to potential treatment of many of the intractable diseases that have frustrated drug makers.
anterior olfactory nucleus
olfactory tubercle
tenia tecta
piriform cortex
amygdala
entorhinal cortex
primary motor cortex
frontal cortex
agranular insular cortex
primary somatosensory cortex
auditory cortex
retrosplenial granular cortex
temporal association cortex
basolateral amygdaloid nucleus
arcuated hypothalamic
corpus callosum
internal capsule
thalamus
hippocampus
MEVs are natural nanoparticles used by the microalgae to communicate with surrounding cells. They are literally nanocarriers of biologically active molecules to cells.
Drug companies have focused on developing mammalian EVs for the delivery of specific molecules. Mammalian EVs are derived primarily from human cells, and their use is primarily based on using the EVs as a substitute for cell therapies. The strategy is that EVs could deliver biological payloads introduced by the cells that secrete them. Mammalian EVs have progressed to early clinical trials, but have not proved their effectiveness yet. As far as the brain is concerned, the only disease targeted with mammalian EVs so far is cancer.
Synthetic lipid nanoparticles (LNP) also are seen as promising vehicles to deliver a variety of therapeutics, especially following their success in delivering COVID-19 vaccines. But LNP have not yet been used as a delivery vehicle for transporting therapeutics to the brain, and among LNP’s drawbacks are the potential for generation of an immune response after repeated use and toxic side effects.
The challenge of drug discovery for CNS pathologies always has been to access targets in the brain without changing the structure of the therapeutic molecule to preserve its potency. The traditional route through the blood brain barrier has thwarted many of these efforts.
MEVs have the ability to ferry therapeutics to specific tissues and cell types relevant to the targeted disease, avoiding along the way any premature degradation or inactivation, and make their way into the right cell compartments for proper processing and expression of their therapeutic payloads. Coupling this with intranasal administration and MEV therapeutics may offer the best hope of ushering in a new era of treatment for patients with brain diseases.
