This is part 2 of our 5-part series on the Drug Discovery for Neurodegenerative Disease conference. See parts 1, 3, 4, and 5.
8 March 2007. 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.