Texas House Committee on Public Health – Testimony, Interim Charge #2 Marc Diamond, MD Director, Center for Alzheimer’s and Neurodegenerative Diseases Professor of Neurology Peter O’Donnell Jr. Brain Institute UT Southwestern Medical Center Chairman Price, members of the Committee, good morning. My name is Marc Diamond and I am a professor of neurology at UT Southwestern Medical Center. Thank you for the invitation and opportunity to tell you about the scope of the problem of Alzheimer’s disease in Texas, and the exciting work going on to diagnose and cure this terrible problem. I am Director of the Center for Alzheimer’s and Neurodegenerative Diseases, part of the Peter O’Donnell Brain Institute at UT Southwestern. Our center is dedicated to diagnosing AD as early as possible, and developing mechanism-based therapies. This is an important part of the O’Donnell Brain Institute’s overarching effort to translate basic neuroscience to cure brain disorders. I am also honored to serve on the Texas Council on Alzheimer’s Disease and Related Disorders, which oversees the Texas Alzheimer’s Research and Care Consortium (TARCC). Alzheimer’s – Background and Status of the Research: Alzheimer's Disease (AD) is the defining medical problem of our generation. It afflicts over 5 million Americans, and about 400,000 individuals in Texas. The cost to Texas for medical care is about $20 billion. Additionally, it's estimated that primarily family members provide approximately $20 billion of uncompensated care to Alzheimer's patients. The incidence of Alzheimer's is estimated to triple in the next 30 years as our population ages. This is a huge human and economic problem, and requires significant investment of resources, time and effort to solve it. I’d like to tell you a little bit about how our knowledge of Alzheimer’s has changed recently, and how this is enabling new types of therapy. It has long been known that the dementia in Alzheimer’s occurs because of the accumulation of a protein, tau, in aggregates. These are much like Lego blocks stacked on one another. They accumulate inside brain cells and cause neurodegenerative disease. Tau aggregates cause a host of related dementias, including chronic traumatic encephalopathy, which afflicts people who have had repeated head trauma, such as football players and soldiers. About 15 years ago, my lab developed the new idea that tau aggregates might form in one brain region and move from cell to cell, much like a virus. Once a healthy cell takes up the pathological aggregates, this would trigger further aggregation, as normal protein was sucked into them. This novel idea has taken hold of the field because it offers a simple explanation for several aspects of dementia such as why they progress through the brain, and why many different types occur. This idea has also captured the attention of the pharmaceutical industry, because it predicts that treatment could target the tau protein as it moves between brain cells. In fact, when I was previously at Washington University in St. Louis, I co-developed a therapeutic vaccine that is now in Phase 2 clinical trials for Alzheimer’s and Progressive Supranuclear Palsy. This uses the immune system to attack tau aggregates as they move between brain cells. Another new type of genetic therapy called an “antisense oligonucleotide” has allowed doctors apparently to halt otherwise fatal neurodegeneration in children. This type of therapy is now being tested for AD and related neurodegenerative diseases. These are just a few of the new mechanism-based therapies that will likely be appearing in our clinics in the coming years. What are we doing at UT Southwestern: When I arrived in 2014, I was given the opportunity to build a truly multidisciplinary research team to attack this problem, which I envisioned much like the Manhattan Project of WWII. We needed expert clinicians to see patients, biochemists, geneticists, and structural biologists who focus on the three- dimensional structure of proteins. Finally, we needed expertise in drug development. With substantial investment from the university, philanthropists, and the State of Texas, I established this multidisciplinary group to find a treatment for Alzheimer’s and related dementias, and to develop diagnostic tests that could predict disease in healthy people, much like we now detect certain cancers. Once patients show symptoms, much damage to the brain has already occurred, so we will need to detect problems presymptomatically, and institute effective, mechanism-based therapies. The center has three major parts. First, the clinic. We see patients who have problems with cognition and memory. We offer them the best, most comprehensive care available, and access to the latest clinical trials. Second, basic research. We employ a team of staff scientists, postdoctoral fellows, and graduate students who are figuring out the specific molecular mechanisms that underlie Alzheimer’s. Third, translational science: therapy and diagnosis. We are developing new types of mechanism-based therapy and diagnostic methods that we hope will detect problems before patients are even aware, much like a simple visit to the doctor can now detect high blood pressure long before any organ damage has occurred. We have a dedicated effort involving industry-grade drug discovery right on campus, and also a collaboration with industry. For example, we have just completed a high throughput screen of 300,000 compounds to find those that bind tau and prevent its pathology. Likewise, we are collaborating with a biotechnology company, United Neuroscience, to develop the equivalent of a flu shot for Alzheimer’s. This involves using our center’s emerging knowledge about the 3-dimensional structure of the tau protein to design specific vaccines that trigger an immune attack on the pathological forms of the protein, while sparing the normal forms. I hope to have the first types of this vaccine entering clinical trials in about 18 months. The future is incredibly rich with opportunity, and consistent support and talent is needed to keep the ball rolling. What the State of Texas has done to date: Since 2005, the Legislature has allocated about $35 million to support the Texas Alzheimer’s Research and Care Consortium. This has established a fantastic cohort of well-characterized patients so that we can identify genetic factors and biomarkers that predict progression of disease. Last year, in my role as a leader within TARCC, I realized that we needed a new direction. The council and I made a decision to transition the program to focus on specific, peer-reviewed projects. In the current biennium, we have approximately $6.8 million to disburse in 2 to 4-year grants focused on investigators in the State of Texas. We issued a call for proposals, and were amazed at the response. We received 65 proposals from researchers across the state. These have been submitted for peer-review by experts in Alzheimer’s from around the country, and a decision will be made later this month based on the scores. We are thrilled by the enthusiasm and the many exciting ideas that have been submitted, all from Texas medical schools. We also anticipate that many projects will eventually bring in more federal research dollars to our medical schools. Finally, we hope that new technologies that emerge from this research will spur economic development in Texas. Unfortunately, we can fund only about 5-10 of the 65 proposals this year, or about 8-15%. And we anticipate even more interest next year as more investigators learn about the program. Given the scope of the problem of Alzheimer’s in Texas, spending $3.6 million per year on research translates roughly to 0.1-0.2% of the total cost of AD to our system. This seems to me like a relatively small investment to help tackle such a huge problem, particularly at a time when the research is showing such promise. As an investigator in this area, and member of TARCC, I appreciate your support, and know that continued investment will speed our progress in finding a cure for Alzheimer’s. Thanks very much for your attention, and I hope I can answer any questions you may have. .