LAS VEGAS—The nasal mucosa in the upper third of the nasal cavity provides a direct pathway from the external
environment to the brain and, according
to William H. Frey II, PhD, that pathway
can be used to noninvasively deliver therapeutics into the brain. This pathway effectively bypasses the blood–brain barrier
and avoids the systemic exposure and side
effects associated with therapeutics that
enter the bloodstream. At the 19th Annual Meeting of the North American Neuromodulation Society, Dr. Frey presented an in-depth
look at intranasal delivery of therapeutics to the brain.
“We have learned from experience that therapeutics
sprayed into the nose or even given as nose drops can
travel extracellularly and paracellularly along the olfactory axon bundles and along the trigeminal nerve pathway
from the nose to the brain,” said Dr. Frey, who is Founder and Codirector of the Alzheimer’s Research Center at
Regions Hospital and Senior Director of HealthPartners
Neuroscience Research in St. Paul.
Therapeutics that can be delivered intranasally include
proteins like insulin, small molecules, charged molecules,
oligonucleotides, therapeutic cells like stem cells and Treg
cells, nanoparticles, and microparticles. “You do not have
to modify your drug or therapeutic in any way in order
to do this, but this method only works for really potent
therapeutics that are active in the picomolar, nanomolar, or
very low micromolar concentration range,” Dr. Frey said.
This technique is being investigated in various disorders. “Most of the studies have been done in animal
models, but the Alzheimer’s work has also been done in
humans,” Dr. Frey said.
The Neuroanatomy of Intranasal Delivery
The cribriform plate of the skull separates the upper
part of the nasal cavity from the brain. The primary
olfactory nerves are located in the roof of the nasal cav-
ity under the cribriform plate and include the olfactory
sensory neurons and odorant receptors. Sniffing brings
molecules into the nose, thus allowing them to bind to
odorant receptors and send a signal. In-
tranasal delivery of therapeutics involves
spraying therapeutics into the upper part
of the nasal cavity to enable them to follow
these olfactory axon bundles directly into
the brain through foramena in the crib-
riform plate. Once across the cribriform
plate, the therapeutics penetrate the sub-
arachnoid space and enter the perivascular
spaces of the brain’s blood vessels.
When the heart pumps, a correspond-
ing pulsation in the cerebrovasculature cre-
ates a perivascular pumping mechanism that moves the
therapeutics throughout the brain. “They are near the
blood vessels, but on the brain side of the blood–brain
barrier throughout the brain,” Dr. Frey explained. Drugs
also follow the trigeminal nerves that innervate the entire
nasal mucosa and follow the trigeminal neural pathway
through the trigeminal ganglion and into the brain and
upper spinal cord.
“[This method] results in rapid delivery—within 10
minutes in mice, rats, and monkeys—to the brain and
upper spinal cord,” Dr. Frey said. In humans, intranasal
neuropeptides reach the CSF within 10 minutes.
Preclinical studies have examined intranasal therapy for
stroke. Researchers gave rats a stroke by occluding the
middle cerebral artery. Two hours of occlusion were followed by reperfusion. Ten minutes after the reperfusion
was initiated, investigators administered nose drops containing insulin-like growth factor 1—a 7,600-Da neurotrophic protein naturally found in humans. Compared
with controls, rats that received 150 mg of this peptide
intranasally had an infarct volume or amount of brain damage that was reduced by 63%. Benefit was also seen when
treatment was delayed for two or four hours.
A different intranasal treatment uses GRN163, a
polynucleotide that inhibits the enzyme telomerase.
Intranasal Drug Delivery
Bypasses the Blood–Brain Barrier
William H. Frey II, PhD