The newest chemical under investigation for managing Alzheimer’s disease (AD) is actually not new at all. Insulin, the therapeutic hormone all-too familiar to individuals with diabetes, has been around for decades. In fact December will mark 90 years since its discoverers earned the Nobel Prize in Physiology or Medicine for the extraction of insulin for clinical use. Yet to say that insulin has been under our noses all these years wouldn’t exactly be correct. Because if it had been under our noses, we might have sensed its neurologic benefits sooner.
The latest insulin therapy is not delivered via injection like its diabetes-treating counterparts, nor does it come in the form of a pill or a patch like the cholinesterase inhibitors often prescribed to patients with AD. Instead this novel therapeutic enters the body through the nose—the only entry point that gives insulin a chance of reaching the brain.
A large peptide molecule, insulin from the blood cannot float easily into the brain because the blood brain barrier (BBB), a sort of neuroprotective moat, prevents its transport. Fortified by cellular guards called tight junctions, the BBB rejects many pharmacologic hopefuls, allowing entrance only to certain types of substances. Namely small or lipophilic molecules can be administered orally (or via injection, or through the skin) and as long as the relevant chemicals end up in the blood stream, they can casually saunter across the BBB and act on the brain. Large and cumbersome, insulin does not have this luxury and must therefore take a more creative route across the moat.
The nose, conspicuous and sometimes even goofy, provides that creative route. Yet it’s a route that, for many years, researchers were hesitant to take.
“They would say things like, ‘Well, why would there be a blood brain barrier if all you had to do was put something in the nose and it would go to the brain?’” says William H. Frey II, Ph.D., Research Director at HealthPartners Center for Memory & Aging. As of 1989 Frey had been “in the Alzheimer’s deal” for over a decade. At that time he was conducting clinical trials of a neurotrophic factor (a therapeutic protein) to treat AD and, because of the seeming insurmountability of the BBB, the work had been less than fruitful. “It became clear to me that, once again, this neurotrophic factor was not getting effectively into the brain,” he says. So Frey decided to sleep on it. “I went to sleep and I had a dream. And this is how I discovered the intranasal method of getting around the blood brain barrier,” he says. “It had been known since the early 1900s that a number of different viruses that got into the nose would travel up the olfactory nerves and the trigeminal nerves—both of these are nerves that go directly from the nasal mucosa right into the brain. The idea that came to me in this dream in 1989 was: if bad things can do it, why can't good things do it?”
When Frey revisited the idea upon waking, it registered as simultaneously intuitive and absurd—a logical fantasy like so many dreams. Despite pushback from his colleagues (“Pretty much people thought that I was crazy,” he says), Frey decided to pursue the development of an intranasal (IN) system to deliver drugs to the brain. Awake as ever, his first step was to obtain a patent for his new technique. Here he would meet the first of many hurdles—barriers—in bringing his dream to fruition.
“The patent office said that they didn't believe that it would work, that I couldn’t patent it because it didn’t makes sense,” Frey says. Yet Frey and others continued experimenting with IN delivery (mostly in rodents), and showed that drugs administered in this fashion reliably reached the central nervous system. “By the time four years had gone by, there were so many published papers showing that this did work, the patent office said, ‘Well, we won't give you the patent, because it's obvious that this would work,” Frey says. In 1997, however, the patent office landed somewhere between “nonsense” and “obvious” and Frey’s request was granted.