Five previous winners of the prestigious Melvin R. Goodes Prize came together in New York City recently to honor this year’s winner, Miranda E. Orr, PhD, Assistant Professor of Gerontology and Geriatric Medicine at the Wake Forest University School of Medicine, and to discuss how their research is working toward the same goal – to conquer Alzheimer’s. Each of them is developing a treatment against a novel target in the aging brain that they hope will be part of precision combination therapy that can be tailored to each patient’s unique Alzheimer’s pathology.
In his opening remarks, ADDF CEO Mark Roithmayr commented on the changes to the Alzheimer’s research landscape since the last time the Goodes Prize was awarded in person (three years ago due to COVID). “The science has shifted,” said Roithmayr. “Plaques and tangles are part of it, but there is much more talk now and work being done around prevention, precision medicine and combination therapy.”
Panel moderator Dr. Howard Fillit, Co-Founder and Chief Science Officer at the ADDF, zeroed in on the role of aging in Alzheimer’s. “Aging is the leading risk factor for Alzheimer’s and today’s research is translating that knowledge into new drugs for the disease,” said Dr. Fillit. “Today we’ll be talking about new drugs and new treatment pathways, but all of the science is related to the biology of aging.”
Innovative Approaches from our Goodes Prize Winners
Frank Longo, MD, PhD, Professor and Chairman of the Department of Neurology and Neurological Sciences at Stanford University School of Medicine and Founder of PharmatrophiX, winner of the inaugural Goodes Prize in 2015, talked about his work to prevent or slow degeneration and failure of the brain’s synapses. Early in the Alzheimer’ disease process, neurons begin to fail and synaptic connections in the brain are lost. The goal of his program is to create a brand-new class of drugs to stimulate receptors on neurons to protect these vital brain cells.
D. Martin Watterson, PhD, John G. Searle Professor of Molecular Biology and Biochemistry and Professor of Pharmacology at Northwestern University Feinberg School of Medicine, 2016 winner, began by noting that he and his fellow winners were all supported by the ADDF at inflection points in their research. These early investments, he said, were instrumental in getting their research where it is today. His work focuses on brain inflammation and keeping small molecules called cytokines balanced in the brain to keep inflammation in check. Cytokines play a vital role in acute inflammation—needed to help deal with short-term injuries—but the trouble starts when the inflammation continues and becomes chronic.
Commenting on the discussion, Roberta Diaz Brinton, PhD, Director of the Center for Innovation in Brain Science at the University of Arizona, said two things have always struck her about the ADDF’s unique contributions to Alzheimer’s research: its early focus on a precision medicine approach even before the term “precision medicine” was commonplace and its willingness to support innovative, high-risk ideas that others shy away from. Dr. Brinton’s work focuses on repurposing a hormonal treatment that can activate neural cells to generate new brain cells, potentially restoring lost cognitive function. Repurposed drugs face funding challenges because, unlike novel drug molecules, they do not hold the promise of patent protection and a clear commercialization strategy. The 2017 Goodes Prize helped Brinton and her team develop a patentable formulation of the hormone, called allopregnanolone.
The 2020 Goodes Prize has helped Jerri Rook, PhD, Research Instructor in the Department of Pharmacology at Vanderbilt University in the Vanderbilt Center for Neuroscience Drug Discovery Research Instructor in the Department of Pharmacology at Vanderbilt University in the Vanderbilt Center for Neuroscience Drug Discovery, start a new drug discovery program, an area she says does not easily get financial support. She is focused on slowing production of the neurotransmitter glutamate, which when overproduced in the brain, kills neurons even before Alzheimer’s symptoms start. She is developing a novel drug compound to selectively target receptors in the brain that are implicated in overproduction of glutamate.
Alzheimer’s prevention expert, Miia Kivipelto, MD, PhD, Founder of the FINGERS Brain Health Institute, Professor of Clinical Geriatrics at the Karolinska Institute Center for Alzheimer Research, and Senior Geriatrician and Director for Research and Development of Medical Unit Aging at Karolinska University Hospital, winner of last year’s Goodes Prize, aims to prevent dementia by combining a leading anti-aging drug called metformin with proven lifestyle approaches that her team uncovered in the landmark FINGER trial. According to Dr. Kivipelto, FINGER 2.0 is a more individualized model, which considers participants’ personal risk and genetic profile. Metformin, which is used widely to treat diabetes, works on brain metabolism, which is another target implicated in early development and ongoing progression of Alzheimer’s. Dr. Kivipelto says she sees a future where the FINGER trial could also add in the new drugs her colleagues are working on.
The final speaker at the panel was 2022 winner Dr. Miranda Orr. Her work is solidly rooted in the biology of aging, focused on ridding the body of malfunctioning aging (senescent) cells that have found a way to avoid the natural cycle by which old cells die. These so-called zombie cells can’t die; instead, they live on and create toxins that damage nearby cells. In landmark work, Dr. Orr characterized the presence of senescent cells in the brain and is now working on ways to clear them.
In another nod to the importance of combining treatments, Dr. Orr said she sees a day when her work can help rid the brain of these toxic cells, clearing the way for the work of others to be more effective, for example allowing Dr. Brinton’s repurposed drug to regenerate new, healthy cells, or making room for Dr. Kivipelto’s prevention methods to work more effectively.
Biomarkers Play Key Role in Clinical Development and Practice
During the robust question and answer session that followed the presentation, the researchers touched on the importance of biomarkers in advancing Alzheimer’s drugs and treatment of the disease. Biomarkers have greatly improved the quality of trials, according to Dr. Longo, because they allow researchers to assess a drug’s ability to hit its target in patients more accurately, with speed and less cost than ever before. Researchers used to have only one measure in dementia trials—change in cognition, which can take months to years to measure and is not terribly precise.
Dr. Kivipelto added that simple biomarker tests, for example blood tests, will have a very important role in the practice. Some doctors still think Alzheimer’s disease is a normal part of aging, she said, but if they can see that the biomarkers are not present in every patient, they can start to see that this is not a normal process of aging, but a pathology associated with the biology of aging that can be addressed by effective drug combinations.
All the panelists agreed that the rigor these advances in biomarkers are adding to today’s clinical trials, allowing drugs to advance more efficiently and precisely than ever before, is one of the most exciting aspects of today’s Alzheimer’s research. These trials, which represent an impressively diverse array of drug targets, are bringing us closer to the day when we will have multiple treatments that can be used in combination to treat each Alzheimer’s patient with precision medicine approaches and change the course of this disease.
View the full symposium here.