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.” Follow Scientific American on Twitter @SciAm and @SciamBlogs. Visit ScientificAmerican.com for the latest in science, health and technology news.
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