CONFERENCE COVERAGE SERIES
Drug Discovery for Neurodegenerative Disease 2007
New York, New York
05 – 06 February 2007
New York: Can Academia and Industry Work Hand-in-Glove?
Researchers Huddle in Frigid New York
New York felt like the windy city on February 5 and 6, when scientists gathered there for the conference on Drug Discovery for Neurodegenerative Disease. The 150 troupers who left their dens despite the bitter cold were rewarded with a warm, cozy venue and a full slate of speakers. Sponsored by the Alzheimer’s Disease Drug Discovery Foundation, the meeting brought together academic and pharmaceutical industry researchers to talk about finding new treatments for Alzheimer disease, with a goal of educating and engaging more academic researchers in the search. Meeting host Howard Fillit directs the ADDF, and was a founding director of its parent organization, the Institute for the Study on Aging. He called neurodegenerative diseases the greatest unmet medical need today, as the number of affected people is expected to triple in the next generation.
AD drug development comes with special risks and challenges, said keynote speaker Barry Greenberg of Neurochem, Inc. in Laval, Quebec, Canada. The hurdles line up to make a formidable obstacle course: Long, slow-moving disease, difficult diagnosis, lack of surrogate biomarkers for progression, poor preclinical animal models, challenging trial design, and an evolving regulatory scene. In addition, drugs need to act in the central nervous system, which raises special problems of delivery and toxicity. But the rewards will be great as well, as any reasonable disease-modifying drug will be a blockbuster, Greenberg said.
The meeting aimed to educate academic researchers about work on the other side of the fence. Drug discovery is a distinct discipline from academic science, and quite foreign to many academic researchers. Representatives from industry sketched out the process, explaining the path a potential therapeutic takes from screening, through hits to leads, then on to candidates that undergo pharmacology, toxicology, and preclinical testing in animal models. The hope is that by understanding how the pipeline flows, academicians see where their efforts can best feed into the venture.
An important take-home message was that drug development is a risky business—the pipeline looks more like a funnel than a river. For every drug that reaches the market, dozens of compounds and projects fail, most at early stages. At every step in the process, companies are looking for ways to minimize their risk, and appreciating that mind-set seemed the key to understanding what industry wants from academia. How, then, can academic researchers aid drug discovery? The theme that emerged was “complement, don’t compete.” Rather than try to duplicate pharma’s efforts, academicians could look for ways that their research can help reduce the risks of carrying programs forward. That can mean more targets, better assays, promising compounds, new animal models, or just about anything that offers new information on which to base decisions.
The talks ran the gamut from target identification and screening compound libraries to animal models, drug delivery, licensing and patents, and even some thoughts on starting your own company. Our coverage offers details on all. As always, we welcome reader comments and contributions from others who attended the conference.—Pat McCaffrey.
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New York: Back to School—R and D in Academia
Judging by the growing number of academic centers that focus on screening or other phases of drug discovery, it might seem that universities ignore the mantra of “complement, don’t compete.” But they don’t, said Ross Stein, who directs the Laboratory for Drug Discovery in Neurodegeneration (LDDN) at Harvard Medical School in Boston, Massachusetts. Stein noted that academic discovery centers complement industry by taking on projects that are too risky or financially unattractive for companies. This includes new target identification, screening, and even development, for orphan diseases as well as mainstream indications such as AD. It also includes approaches and targets that pharma tend to shy away from, such as cell-based assays, protein-protein interactions, and strategies for enzyme activation.
For the academic centers, the final goal is less ambitious. Rather than having to take a drug to market, these centers aim toward intermediate goals such as developing a better assay, discovering ‘hits’ against a target, optimizing a lead compound, showing efficacy in animal models, and partnering with pharma. Importantly, the centers are training new scientists to discover the next generation of new medicines. The projects the LDDN pursues are rich in basic science, Stein said, so that they can fulfill the academic mandate to publish and bring in grant money.
The LDDN started 6 years ago with part of a $37 million private donation that funded the Harvard Center for Neurodegeneration and Repair, and Stein returned from the pharmaceutical industry to head it. Unlike other academic drug discovery centers, the LDDN is disease-specific, focusing on lead discovery for neurodegenerative diseases ranging from AD to neglected diseases such as Huntington’s and ALS. The permanent staff includes researchers with pharma backgrounds. They collaborate with researchers from outside labs to develop and run high throughput screens and then optimize hits using medicinal chemistry. Currently 15 HTS assays are in development, 16 screens are ongoing and 27 are finished. The researchers there have started one biotech company and have licensed one compound to another company. Their founding grant is now spent, as was the plan, and the center supports itself with grants, philanthropy, and company partnerships.
Marcie Glicksman, who directs leads discovery at the LDDN, described screening work against two therapeutic targets that might be unattractive in industry. In the first, the researchers collaborated with Ken Kosik at the University of California, Santa Barbara, to screen for inhibitors of tau phosphorylation by the enzyme CDK5. Rather than approach the assay like a company would, using ultra-high throughput kinase assays with model substrates, the LDDN scientists developed a specialized assay with full-length tau as the substrate. The choice of a physiological substrate made the assay more complicated, and required an Elisa format. Nonetheless, Glicksman reported that her group screened 115,000 compounds and is now characterizing the hits. The cumbersome format paid off, as the screen turned up novel hits (see ARF related news story), including many that display activity in cell-based assays of tau phosphorylation.
As an example of a cell-based screen, Glicksman described a search for compounds that block Aβ toxicity. Their strategy focused on calpain. This protease is activated by calcium influx after Aβ treatment of cells, and it in turn activates CDK5. Glicksman and colleagues established an assay for the inhibition of Aβ-induced calpain activation in cultured cells, in collaboration with Mary Lou Michaelis at the University of Kansas in Lawrence. The scientists tested compounds from the calpain assay for inhibition of Aβ toxicity, and so far have identified about 70 leads that pass both tests. Some are direct calpain inhibitors; others interfere with other steps in the pathway, and several are neuroprotective in other cell assays, as well.
After drug discovery comes development, and academic centers play a role there, too, said Elias Michaelis, also from the University of Kansas. Michaelis directs the Higuchi Biosciences Center, which aims to bridge the gap between the discovery phase and drug development. The center helps investigators get promising compounds ready for tests in humans. It offers scaled-up drug synthesis, pharmacokinetic and pharmacodynamic studies, as well as help with drug formulation and bioavailability, stability testing, design of production and early toxicology studies. The Higuchi center is known for its expertise in pro-drug formulation.
The idea behind the center is that once compounds are ready for Phase I, they will appeal to companies who have the knowledge and resources to proceed with human clinical trials. The center helps investigators with that, too, by forging links with companies and investors. So far, the center has created eight small companies. Similar centers exist elsewhere: the University of Iowa in Iowa City has two, the Center for Advanced Drug Development and the Division of Pharmaceutical Service. Purdue University in West Lafayette, Indiana, hosts the Chao Center. The University of Kentucky has the Center for Pharmaceutical Science and Technology.
While the focus in many of these centers is on development and manufacturing, Michaelis mentioned that the Higuchi Center also keeps its hand in the earlier stages of drug discovery. The researchers collaborate with colleagues at nearby medical schools and hospitals, and have recently begun to work with the Mayo Clinic in Rochester, Minnesota. As an example of an AD therapy they are pursuing, Michaelis mentioned a novel HSP90-targeted compound that upregulates cellular chaperones to counteract protein misfolding and tau aggregation. (For more on HSP-targeted therapies, see ARF related news story and Waza et al., 2006). The scientists have produced new compounds by altering the structure of the antibiotic novobiocin, and shown they protect cells against Aβ toxicity (Ansar et al., 2007). The compounds are now being tested in mouse models.
Hit the Road(map)
The NIH strongly believes in an academic role for drug discovery and development, said Neil Buckholtz, who heads the Dementias of Aging Branch of the Neuroscience and Neuropharmacology of Aging Program of the National Institute on Aging (NIA). Buckholtz’s talk was a joint effort with Lorenzo Refolo, who moved from the ADDF to the National Institute of Neurological Disorders and Stroke (NINDS). They described an array of resources available to support the translation of pre-clinical drug discovery research into clinical trials. Programs include both institute-specific initiatives and programs that span multiple institutes, as laid out in the NIH Roadmap for Medical Research. In toto, the NIH offers funding, or provides research resources, to support every stage of the process, from target identification to assay development and screening (see ARF related coverage of the Molecular Libraries and Imaging Initiative), through to phase 3 clinical trials.
To move promising compounds faster between early discovery and the clinic, the NIH is offering the pilot program RAID (Rapid Access to Interventional Development). Rather than offer grants, RAID supports investigators with resources to prepare their compounds for phase 1. That can include synthesis, scale up, analytic method development, and assistance preparing the investigational new drug (IND) application. Grant-based programs are available to provide direct funding from the NIA and NINDS for all stages of research, from early drug discovery through phase III trials (stay tuned for an upcoming Alzforum Webinar, in which Refolo will present the many funding opportunities now on offer).—Pat McCaffrey.
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References
News Citations
- Picking Cdk5’s Pocket for New Kinase Inhibitors
- Toxicity of Polyglutamine Expansion Follows Normal Channels
- Cold Spring Harbor: A Grab Bag from the Drug Discovery Folks
Paper Citations
- Waza M, Adachi H, Katsuno M, Minamiyama M, Tanaka F, Sobue G. Alleviating neurodegeneration by an anticancer agent: an Hsp90 inhibitor (17-AAG). Ann N Y Acad Sci. 2006 Nov;1086:21-34. PubMed.
- Ansar S, Burlison JA, Hadden MK, Yu XM, Desino KE, Bean J, Neckers L, Audus KL, Michaelis ML, Blagg BS. A non-toxic Hsp90 inhibitor protects neurons from Abeta-induced toxicity. Bioorg Med Chem Lett. 2007 Apr 1;17(7):1984-90. PubMed.
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New York: So Many Targets, So Little Time
With most drug discovery efforts ending in failure, all early-stage projects are by definition high-risk. The process of selecting candidates for advancement while mitigating that risk resembles natural selection as much as the competition on American Idol. As pathways or compounds reveal flaws—typically toxicity or lack of therapeutic effect—projects are abandoned, leaving more resources to the survivors. With more research, contenders continue to drop out until just a few future stars are left heading off to clinical development. Basic research provides the underlying knowledge of neurodegeneration to come up with the starting lineup of potential targets, said Linda Van Eldik at Northwestern University in Chicago, Illinois. From there, academics should aim to validate their new targets or compounds in vivo as rapidly as possible. Many targets or compounds are not viable because of poor pharmacokinetics, toxicity, or because patients don't tolerate the compounds, and developers want to get this information as quickly as possible. Several speakers characterized this approach as “Fail early, fail fast.”
Barbara Sahagan, from Pfizer Global Research and Development in Groton, Connecticut, reiterated this idea in her talk on target validation, which she defined as a process that increases confidence in the relationship between a target and a disease. After that, company scientists also consider the “drugability” of a target, a measure of the likelihood of finding compounds that will modulate its activity. Some targets are considered highly “druggable”—many enzymes with their substrate-binding pockets, for instance, or receptors that sit on the surface of cells. But others, such as transcription factors or adaptor proteins, present less attractive prospects for inhibition or stimulation. Finally, there is the safety of the target to consider. The overarching question in target selection is: how much do we need to know about this target to feel comfortable investing in it? Each different target is its own research project, and these smaller, high-risk projects make excellent opportunities for academic-industry collaborations, Sahagan said.
Richard Mohs from Eli Lilly in Indianapolis, Indiana explored what he called an “incredible array” of potential AD targets, gleaned from the range of neuropathology (plaques, tangles, vascular issues), to genetics (Abeta) to simply empiric data from previous drug discovery efforts. Lilly scientists are convinced that Abeta is a worthwhile target, but are less sure whether the important species is plaque or soluble amyloid, Mohs said. Other pathologies contribute to dementia and may present viable targets, as well. While Lilly plans to move ahead with its gamma- and beta-secretase inhibitors and monoclonal antibody to Abeta, in-licensing of new targets is important to the company, as well. In this regards, Mohs sees a strong demand for animal models and biomarkers. Dale Schenk, of Elan Pharmaceuticals in South San Francisco, is looking for new hypotheses and appropriate animal models to guide drug development. “We are lucky to understand 10 or 15 percent of the biology of this disease,” he said. “It’s impossible to predict what will work.” He recommended that researchers invest in model systems to get ahead. “The best groups have the best model systems,” he said.
While the only true validation of an AD target will be a clinically active drug, the gold standards for pre-clinical proof of concept are animal models. Manfred Windisch heads JSW-Research http://www.jswresearch.com/, a contract research organization in Graz, Austria, that specializes in neurodegenerative disorders. Windisch reviewed the strengths and weaknesses of animal models of AD, from mice to dogs to nonhuman primates. He concluded that each model can give part of the picture, while none gives all. He advised researchers to try to obtain quick proof of concept in animal models, but said “Don’t hassle around too long. If the compound is safe, get it into the clinic.” In the future, non-human primate models of AD will need to be used more, said Oppel Greeff, of the contract research organization Quintiles Transnational http://www.quintiles.com/. The experiments are very expensive and supplies of animals are limited, but breeding efforts by Australian and Singaporean researchers might provide many more aged primates for AD research in the coming years.
With more trials launching, patient populations could become a limiting factor, and the cost of a clinical trial depends in part on how quickly it can enroll. Both Greeff and Peter Schuler, from PRA International, another CRO, stressed the role of international trials. Both firms offer clinical trials world wide, which gives researchers and companies access to more patients, cheaper trials, and perhaps the chance to try new kinds of studies. Up-and-coming countries for clinical trials are China, South Africa, and India.
Furthermore, Greeff brought up the idea of pre-screened patient populations. Starting a trial with a well-characterized cohort that has already been followed for some time would yield faster results and improve the chance of statistical significance. Having such groups in place in the future will speed up development more than any other single factor, Greeff said. Michael Weiner of the University of California at San Francisco described a variation on this theme with a delayed start design for a phase II study. Rather than compare treatment and placebo groups as in a standard design, Weiner proposed to begin imaging on subjects a year ahead of the trial to determine rates of change off treatment. Then, the entire cohort could be treated and further monitored for alterations in their clinical course. This approach might allow for faster results, and require fewer study subjects.
In his own research, Weiner showed that he could distinguish subfields in the hippocampus by using high-resolution MRI. Moreover, he could distinguish people who were aging normally from those with MCI or AD by a characteristic pattern of changes in subfield volumes. Other recent work measuring white matter tracts by diffusion tensor imaging also reveals changes that differentiate normal aging from AD, he showed (see Zhang et al., 2007).
Weiner further updated the audience on the Alzheimer Disease Neuroimaging Initiative (ADNI). To date, 700 people have enrolled. The study is on track to enroll the remaining 100 by this May, with data collection complete by the end of 2010. Already, imaging data on 450 subjects is publicly available (see http://www.loni.ucla.edu/ADNI/). Similar efforts are starting up in Japan, Europe, and Australia, raising the prospect of a worldwide ADNI that can eventually provide tools for clinical trials. (This project, in particular, reminded scientists of the great hole Leon Thal’s death has left the field. Thal championed international collaboration on ADNI. Fillit and all conference participants honored Thal with a moment of silence at the outset.)
The Q and A session brought out the idea of enrolling late-stage patients in trials. This is a common practice in cancer, where people with advanced disease can enter chemotherapy trials. One practitioner mentioned he had 1,000 patients in his practice with single-digit MMSE scores, many of whom might participate with the consent of their caregivers. Mohs replied that the challenge is to define therapeutic objectives that are testable in modest-size studies in such a population.—Pat McCaffrey.
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References
Paper Citations
- Zhang Y, Schuff N, Jahng GH, Bayne W, Mori S, Schad L, Mueller S, Du AT, Kramer JH, Yaffe K, Chui H, Jagust WJ, Miller BL, Weiner MW. Diffusion tensor imaging of cingulum fibers in mild cognitive impairment and Alzheimer disease. Neurology. 2007 Jan 2;68(1):13-9. PubMed.
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New York: Better Living Through Chemistry?
When it comes to treating AD and other brain diseases, there is always something standing between the therapeutic pill and the cells needing help. That something is the blood-brain barrier (BBB), and it is a killing field of many a promising treatment. Two lively talks on medicinal chemistry drove home just how the need for brain penetration complicates compound design for AD. Then, researchers offered some novel ideas about what the BBB is (and is not), and what drug developers might do about it.
It’s the Compounds, Dummy
Medicinal chemist Christopher Lipinski, formerly of Pfizer, is now a scientific advisor to Melior Discovery in Exton, Pennsylvania. He sees chemical space, that is, the universe of possible small-molecule chemical structures, as mostly barren of candidate therapeutics. Lipinski is known for his “rule of 5. ” Derived from an analysis of existing drugs, this set of criteria tries to define which physico-chemical properties a drug must have to be orally bioavailable—that is, suitable to be taken as pills. (For a comprehensive review, see Lipinski and Hopkins, 2004). Only a small fraction of possible compounds fit the rule of five, and of those only a subset satisfies the more stringent criteria defining CNS penetrance.
Because of the scarcity of compounds that exhibit favorable properties, commercial libraries are mostly useless for CNS drug discovery, Lipinski said. They can yield valuable research and probe compounds, because drug discovery is different from chemical biology. There, the criteria for tool-like compounds are more relaxed, and the compounds themselves can be cheaper. But for real medicines, Lipinski stressed, permeability, potency, and solubility must all coexist in one compound. These properties must be worked in at the beginning, making good compounds expensive. As an example, Lipinski said the library the NIH is putting together is tool-quality, whereas to amass good compounds for serious drug discovery would cost ten to 20 times more per compound. Moreover, a standard pharma library of compounds for high-throughput screening runs to 500,000 compounds. With such high-cost libraries, target selection for drug development requires an increased measure of stringency. The developers want biologists to find relevant targets, but they also want to know if the target is druggable, in other words if there is a good chance of finding drug-like compounds that will affect the target?
Camille Wermuth of France’s University Louis Pasteur in Strasbourg, and president/CSO of Prestwick Chemical Company added his perspective on the selection and refinement of drugs for the brain. He ties the massive investment in high-throughput screening (HTS) for identifying hits and leads directly to decreased productivity and a higher failure rate of compounds, either because of poor pharmacological properties (called ADME for absorption, distribution, metabolism and excretion) or toxicity. Wermuth recommends that besides HTS, researchers also employ other methods to identify promising compounds, such as feedback from clinical experience and building off existing drugs. Companies would do well to spend more time optimizing structures for better ADME and toxicology, and to use chemistry to aid formulation, he said.
The discussion brought up the question of how large useful chemical space is in terms of compound numbers, and how an academic lab can acquire such compounds. Lipinski said the number of compounds that have been synthesized barely scratches the surface compared to the number of theoretically possible compounds. To make real inroads into chemical space, Wermuth suggested using libraries that consist of marketed drugs, which would represent 1,000-2,500 good compounds.
Believing in the BBB
The caveat to Lipinski’s rules for predicting compound behavior and CNS penetrations is that they only apply to small molecules, and only those that are not transported across the BBB. The rule of five does not hold for natural products, or substances that bind p-glycoprotein pumps or other transporters. What are the rules for peptides, antibodies, or RNAi? William Banks, of St. Louis University, Missouri, opened his talk with the disclaimer that there are no absolutes. When it comes to the BBB, he said, “Every rule has a major exception, every exception has a caveat, and every caveat has an aside.” Researchers can treat the BBB as a black box, or they can try to understand its properties. Either way, data trumps theory, so researchers should not make assumptions for any compound but test it anyway, Banks noted.
What exactly is the BBB? It is the special structure and function of the blood vessels in the brain that limits passage of substances from the blood to the CNS. Circulating drugs enter the CNS by diffusion through cells if they are lipid-soluble, or by active transport. Whether a compound accumulates in the CNS depends on its rates of efflux or degradation at the BBB. A medicine can be effective even if little of it gets in; in the case of morphine, less than 1 percent of the total given dose enters the brain yet its potency ensures that is enough.
Banks showed data on CNS entry of several potential therapies. Small, lipid-soluble peptides that interfere with beta-sheet formation cross the BBB by transmembrane diffusion (Permanne et al., 2002). Grehlin, (a feeding hormone and neurotrophic factor) is subject to saturable transport, but its fate differs across the CNS. It preferentially enters the hippocampus, where it has been shown to enhance synaptic density and promote LTP, and to have beneficial effects on learning and memory in a mouse model of AD (see ARF related news story). With antibodies, Banks’ data shows slow uptake, which seems to occur via an extracellular pathway. Continuous efflux further slows down CNS accumulation of these large proteins (Banks et al., 2002). Even antisense oligonucleotides are transported across the BBB slowly and accumulate in the brain after intravenous injection, despite the literature saying otherwise, Banks noted. Because antisense oligonucleotides are so stable, they can accumulate to therapeutic levels. Antisense to the Aβ peptide, given intravenously to the SAMP8 mouse model, decreased Aβ levels by 50 percent and reversed learning and memory impairments (Banks et al., 2001). Banks said he has started a company based on this approach.
In the discussion, participants’ opinions ranged from “the BBB is a misnomer—everything in the blood gets into the brain” to “we tried for years and couldn’t get any of those neurotrophic factors across.” One caveat in penetration studies done in rodents is the potential for species differences in brain penetration. More important, perhaps, is the idea that the BBB itself changes with aging and disease. The idea that alterations in the BBB may play a role in AD will be an important area to pursue, both for understanding the disease, and for creating new therapies. For more on circumventing the BBB, see part 5 of this series.—Pat McCaffrey.
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References
News Citations
Paper Citations
- Permanne B, Adessi C, Saborio GP, Fraga S, Frossard MJ, Van Dorpe J, Dewachter I, Banks WA, Van Leuven F, Soto C. Reduction of amyloid load and cerebral damage in a transgenic mouse model of Alzheimer's disease by treatment with a beta-sheet breaker peptide. FASEB J. 2002 Jun;16(8):860-2. Epub 2002 Apr 10 PubMed.
- Banks WA, Terrell B, Farr SA, Robinson SM, Nonaka N, Morley JE. Passage of amyloid beta protein antibody across the blood-brain barrier in a mouse model of Alzheimer's disease. Peptides. 2002 Dec;23(12):2223-6. PubMed.
- Banks WA, Farr SA, Butt W, Kumar VB, Franko MW, Morley JE. Delivery across the blood-brain barrier of antisense directed against amyloid beta: reversal of learning and memory deficits in mice overexpressing amyloid precursor protein. J Pharmacol Exp Ther. 2001 Jun;297(3):1113-21. PubMed.
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New York: The Nose, Your Magic Portal?
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.
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References
News Citations
Paper Citations
- 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.
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