The following is an interview I was fortunate enough to have with leading neuroscientists from the National Institute on Aging (NIA) at the National Institutes of Health (NIH)—Dr. Suzana Petanceska, Director for Strategic Development and Partnerships and Dr. Lorenzo Refolo, Director for Alzheimer’s Disease, Drug Development in the Division of Neuroscience at the NIA. They candidly answered questions on “translational research” of Alzheimer’s into solutions for this devastating disease.
Q. “Translational research” is a new term for most nonscientists. Can you give me a definition of translation in the context of medical research today?
Dr. Petanceska: The name is a bit of a giveaway. It is the process of converting basic research discoveries about the disease process into treatments, be that drugs or nonpharmacologic interventions, that can ameliorate the disease symptoms or treat the root causes of the disease.
The process of translation can take anywhere from 12 to 15 years. This measures the time from when we discover aspects of the disease process that are causing the disease (such as a mutation in a specific gene, or sets of genes and proteins whose function is disrupted), which we think we can intercept with a therapeutic agent until the time when we have a drug that has been approved by the FDA as a treatment for patients suffering from the disease.
Q. That does seem like a long time, so here is a blunt question. Is translation in the field of Alzheimer’s research being held back because of the long regulatory process, and if so, should that process be speeded up…or does this compromise our safety?
Dr. Refolo: The length of the translational process is largely driven by the complexity of chronic neurodegenerative diseases like Alzheimer’s—Alzheimer’s is a result of the interaction among many genetic and environmental factors over the lifespan. Gaining an accurate understanding of how the disease comes about at the molecular level and then devising a therapeutic that can, with precision, target the disease process while minimizing toxic side effects is an extraordinary challenge.
Q. Keeping in mind that safety comes first, let us focus on clinical trials. Where in the translational process do we bring human trials into the picture?
Dr. Refolo: Clinical trials begin at the tail end of the translational process. Before getting a green light from the FDA that we can begin testing the candidate drug in humans, there is a lengthy, multiyear process of discovering and designing a therapeutic agent that can interfere with the disease process, and refining its chemical and physical properties so the drug can reach the target organ and alter the disease process in the desired direction while minimizing its toxic effects.
These steps are done by conducting numerous experiments in vitro (in cultured cells in the lab) and in animal models. Once we begin the clinical phase of the drug-development process, we start by testing whether the candidate drug is safe in humans and only then go into larger clinical trials that are designed to test whether it is efficacious. Throughout all phases of clinical trials, we continue to monitor for safety.
Q. What is a biomarker, and what is its role in the translational process?
Dr. Petanceska: A key part of the translational process is our ability to measure the progression of the disease and the effectiveness of the treatment. Biomarkers are indicators of a biological process—think of them as tell-tale signs of health or disease. For example, we measure cholesterol levels as one biomarker of our cardiovascular health. In Alzheimer’s disease, one of the hallmark pathologic features is the accumulation of amyloid beta protein in the brain; thanks to the development of imaging agents, we can now track its accumulation in living patients. Biomarkers also allow us to test whether the therapeutic agent has reached the target organ and whether it has altered the disease process in the right direction—or simply said, whether the patient receiving the treatment is responding to it.
Q. Is there sharing of information among scientists, or is this a competition? And if so, can this kind of secrecy also delay results?
Dr. Refolo: Traditionally, the translational process, whether conducted in academia or in the pharmaceutical industry, is competitive and proprietary. This siloed approach has adverse effects on our ability to deliver effective treatments to patients— this is why there is an increased push toward an open-science approach to translation. The National Institute on Aging is investing heavily in building large-scale team-science programs that break the traditional mold and bring open science principles to translational research.
Q. How is the NIA helping to break down silos?
Dr. Petanceska: Over the past six to seven years,during which the funding for Alzheimer’s has been steadily increasing, theNIA launched a series of translational programs and research centers (Accelerating Medicines Partnership for AD, AMP-AD, MODEL-AD and TREAT-AD) that are taking a collaborative, open-science/open-source approach to some of the key steps of the translational process. This includes the discovery of better targets for treatment and development of big-data resources and high-quality translational research tools (i.e., animal models, chemical tools, cellular assays).
One of the signatures of these programs is that they bring together scientists from academia and the pharmaceutical industry working in many different disciplines, from epidemiology and genetics to data science and computational biology, molecular and cell biology, medicinal, chemistry and pharmacology.
Dr. Refolo: In a way, we are building a virtual Manhattan Project. By making the data, knowledge and research tools available to all researchers not just in the US but also around the world, they can do better translational research. We are hoping that this creates a multiplier effect and accelerates the development of effective therapies for Alzheimer’s disease.
Q. If you had a wish list of what you would like to see right now, what would give you the most significant breakthrough if you could make it happen?
Dr. Refolo: I think it is to continue the movement toward a fully collaborative, open-science approach to research and drug development that brings together all the stakeholders in academia, industry and regulators to compete against the disease and not compete with each other.
Dr. Petanceska: This is something that is not just on our wish list but is part of NIA’s long-term strategy for developing and delivering the desperately needed treatments for Alzheimer’s.
For further information: The NIA recently published a breakthrough study on Anti-Amyloid Treatment of Asymptomatic Alzheimer’s Called A4. For further discussion and more on the translation of findings into real-world medical solutions, visit GenerationBoldRadio.com and listen to my interview with Dr. Laurie Ryan, chief of the Dementias of Aging Branch of the NIA.