William Frey of the University of Minnesota in Minneapolis believes in the BBB. Rather than dealing with the pesky obstacle, though, he’s trying an end run around it. His route of choice is the nose, where his work suggests one gains access to the brain via olfactory and trigeminal neurons that are hanging out in the nasal passages. Many substances might enter the brain this way—neuropeptides, neurotrophins, cytokines, and DNA are all potential candidates, Frey believes. The nasal route offers the bonus of reducing systemic exposure.
Frey illustrated the promise of nasal delivery with data on IGF-1 delivery to mice (Thorne et al., 2004). When given via the nose very little IGF-1 enters the blood stream, while substantial amounts arrive at the olfactory bulb, and intermediate amounts reach more distant parts of the brain. Frey observes significant accumulation in the hippocampus, with a caudal distribution and hot spots in the pons, suggesting the protein is coming in via the trigeminal nerves. Activation of map kinase signaling pathways in whole brain extract after intranasal IGF-1 treatment suggest the peptide is biologically active. IGF-1 protects against neuronal damage in stroke models, offering an opportunity for neuroprotection in AD.
This work was done in mouse. Frey said his group has seen delivery of IGF1 to the olfactory bulb in primates, but has not shown it in humans. Other researchers have administered intranasal insulin to humans and found it improved memory without affecting blood sugar or insulin levels. (Reger et al., 2005; Benedict et al., 2004; Benedict et al., 2006). Importantly, this formulation is different than that used for diabetes, as it contains no permeation enhancers to boost blood entry but still reaches the brain (See also ARF Madrid ICAD story).
Frey does not know how the peptide gets to the brain. He suspects it may move through perivascular channels in the axon bundles. That raised the question of what happens in AD; loss of smell is an early symptom of the disease, but would that affect transport? Frey thinks not because olfaction is lost before olfactory neurons degenerate. Even if the neurons do fail, he believes the delivery route might remain intact, as it does not depend on axonal transport. For its part, the trigeminal pathway does not appear to degenerate in AD. “If you have a drug that doesn’t cross the BBB, and you don’t think of trying this, then you’re missing the boat,” Frey says.
If it works, the second advantage of nasal delivery might be to avoid systemic toxicity. Henry (Rick) Costantino from Nastech Pharmaceutical in Bothell, Washington, showed that nasal delivery of galantamine abolished the known gastrointestinal toxicity that occurs when this drug is taken by mouth, though this was not a case of direct delivery to the brain. In rats, a nose spray delivered drug rapidly to the bloodstream, from where it made its way to the brain. In ferrets, a common model for GI toxicity, intranasal delivery gave good drug exposure without the retching and vomiting caused by oral dosing. According to Costantino, this is the first time anyone has shown amelioration of GI side effects by sending a medication in through the nose, rather than orally.
Looking to the future, Gabriel Silva of the University of California, San Diego, talked about the prospect that nanotechnology might one day outwit the BBB, while stressing that this line of research is in its infancy. One possible strategy is to engineer smart nanoparticles that perform a sequence of different steps, for example, particles that cross the BBB, target specific cells, and finally release compound. Current work along these lines focuses on cancer treatments, using particles coated with polysorbate 80 (to access the receptor-mediated endocytosis pathway) or thiamine (to induce transport, reviewed in Silva, 2006). In another nanotech application, Silva showed an example of self-assembling nanoscaffolds that support neuronal cell growth and might one day be used to support tissue regeneration (Silva et al., 2004). Silva labors in the trenches of bioengineering, where he finds material scientists and chemists looking for applications for their technologies. For example, quantum dot imaging, which allows high-resolution imaging of cell structure and function, is now being used in vitro and in situ, and awaits applications to in-vivo systems.
Knock, Knock, Knocking on Pharma’s Door
So you finally have a good compound, target, or assay—what next? The last session of the conference dealt with how to set your discovery on its way to commercialization. The first step is to talk to your tech transfer office. The people there can guide researchers through the intricacies of intellectual property, patent applications, and disclosures, including publications and their impact on patent rights. Tech transfer officers can help with contract or licensing negotiations, and a growing trend is for the offices to take part in the early organization of start-up companies. Researchers can help by becoming familiar with university policies, says John Zawad, director of tech transfer at the University of Pennsylvania in Philadelphia. The mission of technology transfer, as set out in the 1980 Bayh-Dole act, is to get inventions (in this case, new medicines) out of universities and into commercialization to benefit the public. While researchers undoubtedly have the same goals, it has not prevented them from reporting frustration, at times, with these interactions.
Lawrence Zaccaro of Pfizer listed what big pharma is looking for from academics. Put simply, companies are asking researchers for help solving their problems. Current areas of interest include drug candidates to enhance their pipeline, special skills and resources, development enablers such as biomarkers and diagnostics, platform technologies and, plainly, new ideas. If you have one or more of those—whom should you call? Academic conference participants pointed out how difficult it can be to penetrate big pharma and introduce themselves and their research. Zaccaro recommended making contact at the scientific level, for example seeking out company scientists at meetings. They will start the ball rolling if they see value in the work and want to bring it in. An entrepreneurial academic may opt to start his or her own company. Richard DiRocco, CSO of Secant Pharma in Langhorne, Pennsylvania, noted pluses and minuses to this approach. On the plus side, he said, you don’t work for anyone else. However, the downside is that no one pays you. Now that’s risky business.—Pat McCaffrey.
- Thorne RG, Pronk GJ, Padmanabhan V, Frey WH. Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience. 2004;127(2):481-96. PubMed.
- Reger MA, Watson GS, Frey WH, Baker LD, Cholerton B, Keeling ML, Belongia DA, Fishel MA, Plymate SR, Schellenberg GD, Cherrier MM, Craft S. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging. 2006 Mar;27(3):451-8. PubMed.
- Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, Kern W. Intranasal insulin improves memory in humans. Psychoneuroendocrinology. 2004 Nov;29(10):1326-34. PubMed.
- Benedict C, Hallschmid M, Schmitz K, Schultes B, Ratter F, Fehm HL, Born J, Kern W. Intranasal insulin improves memory in humans: superiority of insulin aspart. Neuropsychopharmacology. 2007 Jan;32(1):239-43. PubMed.
- Silva GA. Neuroscience nanotechnology: progress, opportunities and challenges. Nat Rev Neurosci. 2006 Jan;7(1):65-74. PubMed.
- Silva GA, Czeisler C, Niece KL, Beniash E, Harrington DA, Kessler JA, Stupp SI. Selective differentiation of neural progenitor cells by high-epitope density nanofibers. Science. 2004 Feb 27;303(5662):1352-5. PubMed.