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 cavity 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. Intranasal 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 cribriform plate. Once across the cribriform plate, the therapeutics penetrate the subarachnoid space and enter the perivascular spaces of the brain’s blood vessels.
When the heart pumps, a corresponding pulsation in the cerebrovasculature creates 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. Telomerase is expressed highly in brain tumors and is required for the brain tumor cells to keep dividing. Investigators tagged the negatively charged large polynucleotide with a fluorescent label and administered it. They observed that GRN163 accumulated in the brain tumor over a period of four hours but did not accumulate in the normal brain. After 24 hours, GRN163 was completely cleared from the brain. Survival time was doubled following treatment with the intranasal polynucleotide.
Iron accumulates abnormally in the brain in all of the neurodegenerative disorders. “Obviously, our bodies need iron, but the abnormal accumulation of free iron is damaging because it is a strong promoter of free-radical damage,” Dr. Frey said. Data also indicate that the key receptor for memory, the human brain muscarinic cholinergic receptor, is rapidly inactivated by free iron or free heme, which are present at increased levels in the brains of people with Alzheimer’s disease. “We have a potent iron chelator, deferoxamine mesylate, that has been around for about 40 years. It has a high affinity for iron and it is a generic drug. It has been used to treat beta thalassemia, sickle cell anemia, and various conditions where too much iron is accumulated in the blood. When given intramuscularly over a period of two years to patients with Alzheimer’s disease, it reduced their cognitive decline by 50%. That’s a far bigger benefit than any drug on the market today for Alzheimer’s disease,” Dr. Frey noted. But there were significant side effects at the injection site, and deferoxamine does not cross the blood–brain barrier well. “Consequently, we’ve been developing and have patented intranasal deferoxamine to treat Parkinson’s disease, Alzheimer’s disease, stroke, and traumatic brain injury,” Dr. Frey said.