Dr. Roberta Diaz Brinton of the University of Southern California (USC) in Los Angeles knew she needed to take the next step. Her studies showed that allopregnanolone, one of the most common steroids in the brain, boosted the brain’s regenerative abilities and reversed the cognitive deficits in a mouse model of Alzheimer’s disease (AD). Thanks to the NIA’s commitment to translational research, she could begin the preclinical development of allopregnanolone as an AD therapeutic.
In 2008, Dr. Brinton, a professor of pharmacology and a chair in therapeutic discovery and development at USC, received funding for her project through the NIA’s AD Drug Development cooperative agreement (U01) program. This funding initiative provides up to 5 years of support at $500,000 to $1 million per year for preclinical development of novel drugs for AD, mild cognitive impairment, and age-related cognitive decline.
In addition, the program supports the development of biologics and natural compounds and the repurposing of existing drugs used to treat other diseases. This support enables researchers to gather sufficient data to secure Investigational New Drug (IND) status for their candidate therapeutic from the U.S. Food and Drug Administration (FDA). Once a therapeutic has an IND designation, it can be tested in humans.
“The ability to pursue the translational aspect of 20 years of basic science discovery is a dream come true,” says Dr. Brinton. “The U01 program is phenomenal—it provides the support we need to be successful.”
Dr. Brinton is one of a growing number of academic investigators tapping into the NIA’s support of translational Alzheimer’s research. The NIA’s Division of Neuroscience (DN) issued its first Request for Applications for Alzheimer’s drug discovery in 1991. In 2004, the division kicked its support for translational research into high gear by creating funding opportunities directed at drug discovery and preclinical drug development.
“[The] NIA has supported translational research for AD since the beginning of the 1990s, but these special funding initiatives enable the science of drug discovery to flourish,” says Dr. Suzana Petanceska, a DN program director. “The NIH is in a unique position to support the initial translation of basic research into new therapies since academic research is a fertile ground for the discovery of potential therapeutic targets.
“These translational research programs have been supported through set-aside funds, which enabled us to build a sizable portfolio of projects in a difficult budget climate,” Dr. Petanceska continues. In addition, special review panels of experts in drug discovery for neurodegenerative diseases, and Alzheimer’s disease in particular, evaluate the applications. “This is key to bringing as many of the best projects forward as we can,” she says.
The U01 grant program, which funds Dr. Brinton, currently supports 11 other projects. In addition, NIA has a funding initiative of early AD drug discovery that uses the Exploratory/Developmental grant mechanism (R21). This initiative, a collaboration with the New York City-based nonprofit Alzheimer’s Drug Discovery Foundation, provides up to $275,000 over 2 years to researchers involved in the earliest steps of drug discovery.
Before approaching the NIA about translational research funding, Dr. D. Martin Watterson, co-director of Northwestern University’s Center for Drug Discovery and Chemical Biology in Chicago, and colleagues had NIA grants that allowed them to spend about 2 years studying the basics of the neuroinflammatory cycle that characterizes AD.
“Once we had the data on how to intervene in that cycle, we said, okay, we want to make a drug-like molecule, and we went back to NIA in 2005 and submitted a U01 proposal,” he explains. With the U01 grant, Dr. Watterson’s team was able to work out the chemistry of a potential therapeutic compound that penetrates the brain. The end result was a lead compound called Minozac and a family of related compounds that bring the brain’s cytokine levels back into homeostasis. The drug has been licensed to a Canadian biotechnology company, which is doing further preclinical development.
Dr. Watterson says, “It took us about 2 years from when we had the concept written in a lab notebook to when we actually had a group of molecules work in vivo and a potential production scheme that could be transferred to industry.”
He credits good luck for the quick turnaround time but adds, “There’s no opportunity to pursue serendipity without NIA funding.”
Before any potential compound is ready for the next big step of clinical development—human testing—it must undergo rigorous toxicology testing to ensure that it is safe. Here, too, NIA programs can extend a helping hand. Since its inception in 1994, the NIA’s toxicology services program has tested more than a dozen therapeutic and imaging compounds, including the breakthrough imaging agent, Pittsburgh Compound B (PiB). Developed at the University of Pittsburgh Medical Center, PiB binds to amyloid in senile plaques, allowing fibrillar amyloid to show up on PET scans in the living brain.
When a compound has passed these initial safety tests and received IND status from the FDA, it’s time for researchers to step outside their labs and work with pharmaceutical companies, request further support from the NIA or other funding sources, or both. The NIA’s two large clinical trials programs are the Alzheimer’s Disease Cooperative Study (ADCS), supported by NIA through a cooperative agreement grant to the University of California, San Diego, and the Alzheimer’s Pilot Clinical Trials Program.
The Institute began these programs in part to support the development of drugs that industry might not be willing to invest in, including those already used for other conditions. For example, through a partnership between the ADCS and Baxter Pharmaceuticals, researchers at centers across the country are testing the effectiveness of infusions of immune globulin intravenous (IGIV) for reducing beta-amyloid in the brain. IGIV is often prescribed to patients with immunodeficiency and autoimmune disorders, but this trial will test its ability to treat AD. (For more about the IGIV study, formally called the Gammaglobulin Alzheimer’s Partnership or GAP, see www.alzheimers.org/clinicaltrials/fullrec.asp?PrimaryKey=282 .)
“More often than in the past, when it comes to large phase III trials, investigators are partnering with pharmaceutical companies, such as Baxter, because it is very expensive to do these trials,” says Dr. Laurie Ryan, a DN program director. “While the academic investigators have full control over running the trials, companies supply the drug to patients and may provide funds to expand the trial, for example, by adding an imaging component,” she explains.
Dr. Ryan concludes, “It is becoming necessary for everyone to work together to accomplish our goal of getting better treatments out to the patients and families who desperately need them.”
AD Drug Development Program: http://grants.nih.gov/grants/guide/pa-files/PAR-08-266.html 
AD Drug Discovery Program: http://grants.nih.gov/grants/guide/pa-files/PAS-06-261.html 
AD Pilot Clinical Trials Program: http://grants.nih.gov/grants/guide/pa-files/PAR-08-062.html 
AD Cooperative Study: http://adcs.org