Translational research is a multidisciplinary effort that creates a two-way bridge between basic science laboratory studies and clinical research. In essence, translational research provides a vital link between “bench” and “bedside,” allowing valuable knowledge from the laboratory to be quickly applied to potential new tests or interventions in the clinical setting. Translational research also serves as a crucial venue for collaboration between scientists who focus on understanding the cellular, molecular, and pathologic dimensions of disease and those who focus on treating people. These collaborations are essential to developing safe and effective treatments. Collaborative and training opportunities in translational research encourage scientists to identify and conduct research on neurobiological questions of clinical relevance, learn how to move knowledge gained from basic research into clinical studies, and appreciate how findings in clinical research inform and refine basic research.
NIA’s Translational Initiative
NIA supports the flow of potentially useful therapeutic compounds from the test tube to treatment of people through the NIH Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STRR) grant programs. These grants enable small businesses to explore the potential of compounds and other AD treatments. They also serve as a valuable link between laboratory work, clinical trials, and commercial development.
However, these programs alone are not sufficient to tap into and leverage the enormous potential of basic research in academic institutions that could possibly be “translated” into new therapies. As a result, in 2004, NIA launched a multi-component translational initiative to facilitate early drug discovery and drug development research by academic scientists and small biotechnology companies for treating and preventing AD, MCI, and age-related cognitive decline. This initiative provides small grants for early, exploratory drug discovery efforts and larger cooperative grants for various stages of preclinical drug development, in which new compounds are tested for safety and efficacy in test tube and animal studies before being tested in humans. The grants are awarded to investigators who have identified new compounds that need to be refined and characterized in relevant animal models in order to receive FDA’s Investigational New Drug (IND) approval. With these programs, NIA is broadening the range of potential treatments and expanding the number of therapeutic targets by investing relatively small amounts of money at critical steps of translational research that are traditionally not supported by the pharmaceutical industry. Undoubtedly, these are high-risk projects, but the compounds that successfully move through the translational process have high potential promise for patients.
To facilitate this process further, NIA offers funding through its longstanding investigational new drug toxicology program for academic and small business investigators who have promising compounds to treat and/or prevent AD, MCI, or age-related cognitive decline, but lack the resources to perform the required safety studies in multiple animal species, which are necessary to obtain IND status.
Finally, the translational initiative is complemented by a grant program that aims to support pilot clinical trials of promising compounds and non-pharmacologic interventions. This mechanism adds to NIA’s existing ADCS and clinical trials
program.
Basic Research Continues to Inform Translational Efforts
Basic research can make significant contributions to the pursuit of effective and safe therapies. Here are two examples that illustrate this contribution.
More Support for Beta-Secretase as a Therapeutic Target
As we described earlier, beta-amyloid is produced as a result of the activity of two APP-cleaving enzymes: beta-secretase and gamma-secretase. Scientists have devoted considerable effort to devising strategies to inhibit the activities or suppress the production of these enzymes in hopes that this could reduce beta-amyloid production and, consequently, slow the progression of AD.
Recent discoveries have provided support for the validity of beta-secretase (also known as BACE1) as a therapeutic target. For example, scientists from the Salk Institute for Biological Studies in La Jolla, California, developed specially engineered RNA molecules known as “small interfering RNAs” (siRNAs), which were attached to a gene delivery system to silence the production of BACE1 in the brains of AD transgenic mice (Singer et al., 2005). Reducing BACE1 levels slowed the production of beta-amyloid peptides and amyloid plaques, and diminished the damage to neurons and synapses in the brains of these mice. Most importantly, the transgenic mice that received this gene therapy treatment had less difficulty in learning a task compared to their littermates that did not receive the treatment.
The Search for Safer AD Immunotherapy
Immunizing people against disease has been a cornerstone of medical practice for decades. With this in mind, investigators wondered whether it might be possible to immunize people against AD by injecting them with beta-amyloid, which would cause their immune systems to make antibodies that lower the levels of brain amyloid (a technique called active immunization). Early animal studies, in which AD transgenic mice were actively immunized with a beta-amyloid peptide, were successful at decreasing the number of plaques and improving performance on memory tests. This led to a clinical trial in humans to test the safety and effectiveness of active immunization with the beta-amyloid immunogen (a substance designed to elicit an immune response). However, because about 6 percent of participants in the trial developed brain inflammation in response to the treatment, the trial was stopped. The adverse reaction was likely due to a T-cell reaction (part of the body’s immune response) against the beta-amyloid immunogen. Despite this setback, the interest in developing an AD vaccine remains high.
The key issue in ongoing immunotherapy work is how to develop a vaccine that protects the brain against beta-amyloid toxicity without promoting or worsening brain inflammation. To this end, researchers at Harvard Medical School tested alternative immunogens that contained only the first 15 amino acids of the beta-amyloid peptide but not the T-cell reactive sites of the full-length peptide (Maier et al., 2006). In trying this approach, the researchers hoped to avoid stimulating the harmful T-cell response. Immunizing non-transgenic mice with this short beta-amyloid peptide resulted in a high, non-inflammatory, anti-beta-amyloid antibody response. When AD transgenic mice were immunized with the same short peptide, they also produced significant numbers of non-inflammatory anti-beta-amyloid antibodies. This was accompanied with a greatly reduced amyloid plaque load and improved learning compared to the control mice. These results are encouraging because they show that this novel immunogen approach may have promise for future AD vaccines.
Another approach that is garnering scientific interest is passive immunization. In this approach, instead of administering beta-amyloid directly, which then leads to antibody production, researchers administer anti-beta-amyloid antibodies. Several studies over the past few years have indicated that passively administered anti-beta-amyloid antibodies can effectively remove beta-amyloid peptides from the brain. Scientists at the University of South Florida carried out a passive immunotherapy trial in aged transgenic AD mice (Wilcock et al., 2004). Over 5 months, the mice were given weekly injections of anti-beta-amyloid antibodies. This regimen resulted in complete reversal of learning and memory deficits in these mice 3 months after the beginning of treatment. At the end of the 5-month treatment, beta-amyloid deposits in the animals’ brains were dramatically reduced, indicating that even well-established amyloid deposits are susceptible to immunotherapy in these mice. However, the amount of beta-amyloid in the micro vessels of the treated mice was elevated and these vascular beta-amyloid deposits were sometimes associated with leakage of the micro vessels (microhemorrhages), presumably as a result of the beta-amyloid being removed into the bloodstream. Because the cognitive benefits of the passive immunotherapy persisted in spite of the presence of vascular beta-amyloid and microhemorrhages, these data suggest that this promising approach needs to be further explored and modified to prevent the potential adverse events associated with microhemorrhages.
The Long and Winding Road to AD Treatment MedicationsIn the mid-1970s, scientists discovered that levels of the neurotransmitter acetylcholine fell sharply in the brains of people with AD. This was a crucial discovery, for it was one of the first pieces of evidence that definitively linked AD with biochemical changes in the brain. Investigators studied acetylcholine intensively and found that neurons in the hippocampus and cerebral cortex, areas heavily damaged in AD, depend on this neurotransmitter in the memory formation process. All but one of the currently approved medications used to treat AD are cholinesterase inhibitors. That is, they stop or slow the action of acetylcholinesterase, an enzyme that breaks down acetylcholine. Because these medications don’t stop or reverse the disease process and appear to help patients for only a relatively short time, many scientists are working to develop alternative AD medications. For example, researchers at NIA’s Intramural Research Program have designed and synthesized a number of novel compounds that have proved useful in defining the role of an enzyme called butyrylcholinesterase (BChE), which is found in the brain (Greig et al., 2005). Like acetylcholinesterase, BChE inactivates the neurotransmitter acetylcholine, so the NIA investigators began to look for ways to disrupt the action of BChE. The investigators were able to develop potent, reversible, and brain-targeted BChE inhibitors. In rats, these compounds caused long-term inhibition of brain BChE and elevated extracellular acetylcholine levels, without inhibiting acetylcholinesterase. The scientists found that the rats showed improved performance on a maze test, which indicated improved cognitive performance. When the scientists examined brain tissue from the rats, they found that BChE inhibition augmented communication across synapses. In cultured human cells, inhibition of BChE led to reduced levels of APP and beta-amyloid peptide without affecting cell survival. Transgenic mice that over-expressed human mutant APP also were treated with the BChE inhibitors and they, too, showed lower beta-amyloid peptide brain levels compared to untreated mice. Though these results appear promising, much additional work needs to be done before the BChE inhibitors can be tested in people. As a first step in that process, the NIA investigators are conducting additional studies to define optimal concentrations of the BChE compounds for further preclinical characterization. |
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