Making the Most of Translational Research

Translational research is a multidisciplinary effort that creates a two-way bridge between basic science studies and clinical research. In essence, it allows valuable knowledge from the laboratory to be applied as quickly as possible to potential new tests or interventions in the clinical setting. Translational research also offers an important opportunity for collaboration between scientists concerned with the cellular, molecular, and pathologic dimensions of disease and clinicians who focus on treating people.

NIA is engaged in a variety of translational initiatives to expand possible avenues for AD therapies and, eventually, the number of clinical trials to test them in humans. For example, NIA is working to stimulate the discovery, development, and preclinical testing of various novel compounds to prevent and treat the cognitive impairment and behavioral symptoms of aMCI, AD, and age-related cognitive impairment. The Institute’s Translational Research Initiative aims to increase the number of submissions of investigational new drug (IND) applications to the FDA, so that more clinical trials to test promising therapies can be started and can use a wider variety of intervention strategies.

In addition, NIA supports toxicology services for investigators and small companies that have a potentially viable drug for AD treatment but lack the resources to begin the formal drug toxicology testing process needed for an IND. Two program announcements have been issued for this initiative—one for early-phase drug discovery grants and another for later-phase cooperative agreement drug development grants. The first cooperative agreement awards under the drug development initiative were made in 2006. The first annual Investigators Meeting for Translational Research was held in September 2007.

To date, NIA has funded more than 60 translational research grants, using various funding mechanisms, directed at discovery or development of multiple therapeutic targets, including:

• Anti-amyloid approaches. Researchers are conducting studies to identify compounds that can activate alpha-secretase (an enzyme that cleaves APP in such a way that harmful beta-amyloid is not formed), liver X-receptor activators, and different metal-complexing strategies.
• Anti-tau approaches. Researchers are discovering and developing drugs that stabilize microtubules, the structures that guide nutrients and other molecules from the cell body to the end of the axon.
• Cognitive enhancer approaches. Researchers are working to discover novel nonsteroidal anti-inflammatory drugs (NSAIDs), nitric oxide/cyclic guanosine monophosphate/CREB pathway enhancers, and dual gamma-aminobutyric acid and nicotinic receptor activators, all of which are designed to enhance cognitive processes.

In other funded translational research projects, investigators are developing a range of novel compounds and drugs that may eventually be used to treat AD.

• Investigators at the Center for Drug Discovery and Chemical Biology at Northwestern University have developed an innovative, safe, and water-soluble small molecule that prevents increases in selected injury-induced inflammatory proteins in the brain (Hu et al., 2007). The development of this molecule presents scientists with an opportunity to explore new approaches for potentially useful AD therapies.
• Because of the associations between diabetes and AD, scientists are looking at whether a class of drugs that includes rosiglitazone, which increase a person’s sensitivity to insulin, may be useful in treating AD. However, the mechanisms underlying the potential beneficial effects of rosiglitazone in AD remain unclear. A study conducted by scientists at Creighton University Medical Center, in Omaha, Nebraska, demonstrates that rosiglitazone lessens learning and memory deficits in a transgenic mouse model of AD (Pederson et al., 2006). The drug’s beneficial effects on learning and memory were associated with reduced accumulation of beta-amyloid in the brain. The data also suggest that these effects may be mediated by the glucocorticoid-lowering actions of the drug. A clinical trial is underway to test rosiglitazone’s effects on attention and memory in adults with aMCI.

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