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.

The newest intranasal delivery devices differ from conventional sprays (such as those used for allergies) in that they are designed to specifically target the upper portion of the nasal cavity. For example the “Precision Olfactory Device” in this picture projects aerosolized drugs towards nerve fibers at the top of the nose, allowing more efficient transport across the blood brain barrier.
Image: Courtesy of Impel NeuroPharma

Technically the patent covered any drug or therapeutic protein delivered to the brain via the nose. Working at an Alzheimer’s research center, however, Frey had a special interest in AD and had reason to focus on insulin as a pharmacologic candidate. Like other cells, neurons need insulin in order to absorb glucose and obtain energy; and research had shown deficits in glucose uptake and utilization in the brains of patients with AD. Thus, investigators had suspected a connection between insulin and AD for some time, but prior to the emergence of IN therapy this association was clinically moot.

Frey’s invention did not lead to the widespread therapeutic use of IN insulin that he might have hoped for. Researchers continued experimenting with the drug, but they did not have sufficient funding for the type of large-scale clinical trials that would bring it to market. The pharmaceutical industry hadn’t entirely ignored the IN method: biotech firm Chiron bought the patent almost immediately after it went public in 1997. But when Chiron changed leadership and decided to go into the business of flu vaccines, the patent was relegated to nothing more than impotent intellectual property. Eventually Chiron was bought by Novartis pharmaceuticals, “but they had a strict policy: they don’t develop generic drugs,” says Frey, “so they didn’t do anything with it.”

Frey came to realize that pharmaceutical companies generally were not inclined to pour money into clinical trials for a drug they didn’t own. The quality that made IN delivery so exciting—a new way to use old drugs—also made it unattractive from a business perspective. And though Novartis’ ownership would not preclude government-funded development of IN, reviewers at the National Institutes of Health (NIH) were hesitant to explore novel technology and remained narrowly focused on attempts to improve cholinesterase inhibitors.  “Even though I had the patent, even though all these papers had come out…the NIH basically wouldn't fund anything on intranasal,” says Frey. “They didn't believe in intranasal.”

Of course, with time and proper inspiration nonbelievers can be converted. In May 2012 the NIH and the Obama administration announced the allocation of $7.9 million specifically for clinical trials of IN insulin. The NIH’s amended stance on the drug comes as part of an ambitious national initiative to effectively prevent and treat AD by 2025—a goal that, Frey speculates, puts pressure on the government to seek new avenues of research. “Jeez, we spent all this money for 35 years and what have we got to show for it? Nothing?” Frey mocks gently. “Let's look around and see if anything's working…Oh! What's this? Intranasal insulin?”

The funding also follows an enhanced understanding of how insulin may mediate disease progression: The hormone seems to interact with amyloid-β (Aβ), the peptide comprising toxic amyloid plaques characteristic of AD.  Studies suggest that insulin protects against Aβ’s neurodegenerative effects and that Aβ interferes with normal insulin signaling.  Confirming this relationship are promising therapeutic results from a team of researchers led by neuropsychologist Suzanne Craft of Wake Forest Baptist Medical Center. In a 2011 study Craft and her colleagues demonstrated improved memory and cognition among individuals with AD or amnestic mild cognitive impairment (MCI) after IN insulin treatment. In this trial, insulin therapy was also associated with reduced loss of glucose uptake and utilization in brain areas linked to disease.

Funded by the new NIH resources, Craft, along with the Alzheimer’s Disease Cooperative Study, a national research consortium, is now planning phase II and III clinical trials to evaluate the safety and efficacy of the medication. Quaintly titled “SNIFF,” or Study of Nasal Insulin to Fight Forgetfulness, Craft’s investigation will examine the cognitive effects of IN insulin versus placebo in 240 participants with either AD or MCI.  In addition to tests of memory, researchers will measure biological correlates of disease such as neural atrophy and cerebrospinal fluid biomarkers.

If the trials go well IN insulin could be available to patients are early as 2017—perhaps sooner if a pharmaceutical company jumps on board to expedite the process. Frey is excited about this prospect, but cautious not to oversell the drug. “I'm not claiming that intranasal insulin is going to solve the entire problem of the disease or that it's going to cure everyone who has the disease or help everybody or anything,” he clarifies. “I'm only saying, let's not be stupid. Let’s stop just looking at one thing. Here’s something that seems to help.  Let's develop this and see what good [it] can do for people.”