June 29, 2012

In a perfect world, we’d eat blueberries for breakfast, savor a glass of wine and salmon for dinner, power walk three times per week, take up yoga, join a bridge club and fend off Alzheimer’s disease.
But this is the real world. Given that prevention does not guarantee protection and many don’t follow healthy lifestyle recommendations, it’s heartening to know researchers are making breakthroughs in combating an  illness that can linger for years and impose considerable financial and personal burdens.

At the Alzheimer’s Research Center at Regions Hospital in St. Paul, researchers are fine-tuning a homegrown therapy, developed decades ago, that could arrest or delay the course of the disease.

PET scans of Alzheimer’s patients’ brains have revealed there is very little uptake of blood sugar compared with a normal brain, leading to the notion that Alzheimer’s disease is a type of diabetes of the brain, said Leah Hanson, Ph.D., co-director of the Alzheimer’s Research Center. Poor regulation of glucose in the brain may cause memory problems, she explained.

That theory generated questions. Would replacing insulin improve memory and cognitive functioning? If so, short of drilling a hole into the patient’s brain and inserting a pump, what method would bypass the protective blood/brain barrier and deliver insulin to the brain without disrupting blood levels of patients who didn’t have Type 1 or Type 2 diabetes?

In 1989, William Frey II, Ph.D. (now Hanson’s co-director of the Alzheimer’s Research Center) had a dream in which he conceived of a solution so simple that many in the scientific community scoffed at it.

It had long been understood that harmful matters like viruses could pass through the nose to the brain. Why, Frey wondered, couldn’t therapeutic substances follow the same course?

He put his theory to the test. When he administered insulin through the nasal cavity the hormone traveled along the olfactory nerves involved in smell and the trigeminal neural pathways involved with pain and entered the brain — but not the bloodstream.

The intranasal insulin treatment was born.

But bypassing the blood/brain barrier wasn’t Frey’s only obstacle. Though he obtained a patent on intranasal delivery, funding agencies like the Alzheimer’s Association and NIH were unreceptive to his grant requests. They couldn’t imagine that since the body had developed a barrier to protect the brain that there was such a simple way to get around it, Frey said.

Such skepticism impeded funding for his research through normal channels for more than a decade. Fortunately, donors and pharmaceutical companies provided financial support to Frey’s group, Hanson said.

And Suzanne Craft, Ph.D., and her colleagues at the University of Washington were able to obtain grants. After an initial collaboration with Frey, Craft conducted an NIH-funded four-month trial that validated some findings.

In September 2011, Craft reported that daily use of the nasal spray by adults with mild to moderate Alzheimer’s demonstrated improvement in memory and recall within 15 minutes. The findings are preliminary, represent only a short period and warrant further investigation, she noted.

Decades after Frey had his dream, some early questions have been answered and his intuition has been affirmed. Researchers around the world are investigating applications. NIH is funding a multi-million dollar study of the therapy.

“Science is often that way where you have one theory or hypothesis and it takes a long time to shift the way of thinking,” Hanson said.“To see NIH funding this large trial of intranasal insulin feels very validating for us.”

Soon philanthropists will fund another small trial at Region’s involving preservative-free insulin (unlike the drug that has been studied thus far). “We’re concerned that everything that is in the bottle will be traveling to the brain. So we are using a form of insulin that we feel is safer and, hopefully, more effective,” Hanson said.

It’s too soon to know how pervasive the delivery system will be but Alzheimer’s is not the only brain disease that might benefit from it.

“One of the things we found with intranasal delivery is we are able to deliver a wide range of therapeutics. We haven’t found a limit. Even stem cells can go along this route and into the brain,” Hanson said.

“The way we treat brain disease now is we often have to give large doses of the drug to force it into the brain and in doing that we have the potential for side effects in the body. Intranasal delivery allows you to target the brain so you have a small dose going into the body exposed to the liver and the kidneys,” Hanson said. There are also fewer side effects.

But the research will be for naught if the FDA does not approve the treatment.

If the drug is a pill or an injection, the approval process is clear, Hanson said. There is no precedent for seeking approval for something that is delivered directly from the nose to the brain. There are significant unknowns: what would the FDA want; how long would the process take and cost. Thus far, none of the pharmaceutical companies is actively pursuing approval, she said.

Perhaps someone will have a dream and take the next step.