By Queen Muse
Imagine the journey of medical innovation as a stretch of dominoes winding along a branching, curving path. Each domino is a crucial step in the process from fundamental biological discoveries to the introduction of new medications and treatments. At the very beginning of this intricate chain, clusters of dominoes symbolize discoveries in basic research. When first set on an empty plane, these tiles may look modest, but each one represents a crucial scientific revelation—a biochemical pathway that describes a disease mechanism, or a molecule that a future drug might be designed to target. And each is filled with potential energy, waiting to set a next line of dominoes in motion. The field is ready for new branches to be added for preclinical and clinical testing of new drugs—some that turn out to be dead-end paths, and others that continue to stretch on toward the promise of better treatments and cures.
In the realm of neurodegenerative diseases, the foundational work of scientists like Virginia M.-Y. Lee, PhD, MBA, and the late John Q. Trojanowski, MD, PhD at the University of Pennsylvania’s Perelman School of Medicine, formed crucial early placements in the scientific framework. Their discoveries set the field on the path toward advancements in the development of new medicines for Parkinson’s disease, Alzheimer’s disease, and other memory- and aging-related conditions.
Lee and Trojanowski, research partners who were also partners in life as a married couple, entered the field four decades ago when researchers had only recently developed standardized methods for diagnosing neurodegenerative conditions and neuropathologists were still in the beginning stages of understanding how these conditions progress through changes in the brain. Few treatments existed for diseases like Parkinson’s and epilepsy; other conditions like amyotrophic lateral sclerosis (ALS) and Alzheimer’s had none.
Fast forward to 2023, and it appears that a major cascade of dominoes is finally in motion. Seen from above, the result is a picture of hope for patients with these diseases—particularly Alzheimer’s. In July, the Food and Drug Administration (FDA) granted full approval to Leqembi (lecenemab), a biologic drug developed by Japanese pharmaceutical company Eisai and Massachusetts-based biotech company Biogen. Leqembi has shown promise in removing amyloid plaque in the brain—one of the known primary causes of Alzheimer’s disease—slowing cognitive decline in early Alzheimer's patients. It is the first and only fully approved anti-amyloid drug. Indiana-based pharmaceutical company Eli Lilly is on the verge of introducing another.
Researchers have undergone decades of flawed hypotheses, mismeasurements, and failed clinical trials—dominos toppled, realigned, and reset, to arrive at what some are calling a historic moment.
Connecting the dots
When Trojanowski came to Penn in 1981, Alzheimer's disease research centers didn’t exist, researchers had yet to launch a single clinical trial for an Alzheimer’s drug, and the pathophysiology of the disease was still largely unknown. In the years that followed, the field saw its first burst of important discoveries. In 1984, biochemists George Glenner, MD, and Caine Wong, PhD, of the University of California San Diego, identified a key component of the plaques that form in the brains of patients living with Alzheimer’s, a protein now known as beta-amyloid. In 1985, Trojanowski established the Penn Medicine Brain Bank, where families could donate specimens from patients who died with dementia to inform future research. And in 1987, the National Institute on Aging (NIA) and Warner-Lambert Pharmaceutical Company (now Pfizer) launched a clinical trial for tacrine, the first drug created to specifically target Alzheimer's disease symptoms.
It was amid this momentum that Lee joined the Penn faculty and began partnering with Trojanowski on research focused on Alzheimer’s and Parkinson’s disease, ALS, frontotemporal degeneration, and other related disorders. Together, Lee and Trojanowski set out to understand these disorders from multiple angles with Lee, the biochemist, using her extensive knowledge of basic science, and Trojanowski, the neuropathologist, tapping into his unique access to brain samples from patients with Alzheimer’s disease.
Lee and Trojanowski made their first major discovery in 1991, when they determined that neurofibrillary tangles in Alzheimer’s brains are made up of tau, a protein that causes the structure of nerve cells to collapse. Until then, the makeup of these tangles was unknown. This critical finding was the first clue that the tau protein would be equally important to amyloid in Alzheimer’s disease research. A year later, the duo launched the Center for Neurodegenerative Disease Research (CNDR) at Penn. It was one of the region’s first centers dedicated exclusively to investigating the causes and mechanisms of neurodegenerative diseases and, according to Edward B. Lee, MD, PhD, a scientific hub that demanded innovation.
“I think the most important thing they [Lee and Trojanowski] did was create a space and environment where people were expected to be excellent. They provided all the resources you needed to achieve that,” said Edward Lee (no relation to Virginia), who was once a graduate student and then post-doc fellow in the CNDR and is now an associate professor of Pathology and Laboratory Medicine and the leader of Penn’s Brain Bank. “We never felt like we weren't able to do an experiment or pursue something, because all the resources were there. They were very rigorous about [their work].”
In the following years, Virginia Lee and Trojanowski’s work extended beyond Alzheimer's disease. Lee and Trojanowski identified the abnormal protein alpha-synuclein, accumulating in areas of the brain known as Lewy bodies, as the primary contributor to Parkinson's disease; and were the first to discover that the abnormal folding of a protein known as TDP-43 causes what is now recognized as frontotemporal dementia, a rare neurodegenerative disorder that primarily affects the lobes of the brain responsible for personality, behavior, language, and decision-making. Lee’s research further demonstrated that cell-to-cell transmission of these pathological proteins explains how each disease progresses.
These discoveries were groundbreaking, not only because they provided a better understanding of the underlying mechanisms of these diseases, but also because they offered potential targets for drug development.
Setting up and toppling down
Watching research discoveries unfold for neurodegenerative diseases can be an emotional roller coaster for families of patients, researchers, and clinicians alike. As early scientific discoveries and biomarkers have moved into clinical trials over the last few decades, there has been a shared sense of hope and anticipation, a belief that these promising treatments might finally result in a cure.
But more than a few of those trials have failed. The pipeline of once-promising treatments for Alzheimer’s disease exemplifies the ebb and flow from progress and failure. These moments of setback, however, are often the very thing that keep researchers going—because understanding why a treatment fails can ultimately pave the way for more effective therapies in the future.
Attempts to develop anti-amyloid treatments for Alzheimer's, such as Eli Lilly’s semagacestat, often encountered challenges in clinical trials that led to failure after years of testing. Similarly, trials of Merck’s experimental drug verubecestat were discontinued due to inefficacy. Biogen and Eisai's aducanumab, designed to reduce amyloid beta buildup, also faced setbacks, with Phase 3 trials halted in 2019. In 2021, the FDA granted aducanumab (now known as Aduhelm) accelerated approval, which means the company will be required to submit further proof of the drug's clinical benefit before full approval can be granted. The decision was controversial, as the FDA granted accelerated approval against the advice of an advisory panel whose 10 out of 11 members voted against it.
These failures show just how difficult it is to develop effective treatments for diseases that plague our brains, even when those treatments are based on ever-growing knowledge of how the disease develops. Years spent at the bench, followed by decades of clinical testing, can still end with hopes dashed. Yet at long last, researchers now believe drug discovery for neurodegenerative disease has reached a tipping point: the critical moment when a crucial, well-placed domino initiates a chain reaction that causes a whole new picture to emerge.
The FDA’s July 2023 approval of Leqembi can be seen as that first domino push along a new branch. Although the monoclonal antibody treatment requires biweekly infusions, Leqembi has spurred the development of multiple complementary treatments, including oral pills. These new medications aim to work alongside Leqembi or to be used in individuals with mild cognitive impairment, or even before people have any symptoms, to prevent the progression to dementia. There are also new treatment breakthroughs for ALS. In April, the FDA approved tofersen, a medication designed to treat ALS in adults with a SOD1 gene mutation, further expanding treatment options for ALS patients.
Time, Virginia Lee says, will be the truest determining factor for whether the new treatments being introduced will become long-term cures.
“The state of the art right now is to treat and then follow [the patient] for two to three years to see if beta-amyloid goes up or down,” she said. “Now we want to see whether five or 10 years from now they're still cognitively fine, that they haven't declined or that they’ve declined much more slowly.”
The domino chain of discovery
Penn Medicine continues to be a hotbed of neurodegenerative disease research advances. Virginia Lee and Trojanowski’s discoveries were foundational, but equally so is the impact they have had on a community of research activity on Penn’s campus and far beyond, with a whole new generation of researchers now committed to standing up the next critical dominoes in the chain building toward faster diagnoses and better cures.
A groundbreaking test, unveiled in April 2023 at Penn, promises to detect Parkinson's disease before symptoms even manifest. Penn Medicine researchers, in collaboration with the Parkinson's Progression Markers Initiative and the Michael J. Fox Foundation, confirmed the accuracy of the alpha-synuclein seed amplification assay in identifying individuals with Parkinson's disease and categorizing them according to genetic and clinical indicators. This early detection could potentially be a game-changer in managing the disease and developing interventions at an earlier stage.
Another discovery in July 2023 pinpointed a new protein as a promising target for Alzheimer's treatment. Penn researchers discovered that the gene responsible for encoding tripartite motif protein 11 (TRIM11), a protein linked to tau production, effectively inhibits degeneration in small animal models of neurodegenerative disorders similar to Alzheimer's disease. Their findings identified TRIM11 as a pivotal player in the removal of the protein tangles responsible for multiple neurodegenerative conditions.
The direct impact of Virginia Lee and Trojanowski’s mentorship can also be seen in the success stories of their mentees, like Alice Chen-Plotkin, MD, who, in addition to making significant contributions to our understanding of Parkinson's disease and ALS, today leads the first-of-its-kind Molecular Integration in Neurological Diagnosis (MIND) Initiative in the Perelman School of Medicine at Penn. The MIND Initiative collects medical data and blood samples from Parkinson's patients to analyze their genetic makeup, aiming to categorize patients based on genetic and biomarker contributions, improve diagnosis, and eventually develop more effective treatments for the disease.
Another of Virginia Lee and Trojanowski’s mentees, Daniel Skovronsky MD, PhD, currently serves as the executive vice president and chief scientific and medical officer for Eli Lilly and Company. As a graduate student at Penn, Skovronsky worked under Lee throughout his residency training in pathology. Skovronsky went on to found a company called Avid Radiopharmaceuticals, which developed the first FDA-approved agent for brain imaging of amyloid plaques in patients with cognitive impairment. Now as CSO of Lilly, Skovronsky is overseeing the development of donanemab, which soon may become the second FDA-approved anti-amyloid drug for the treatment of Alzheimer’s disease. The company unveiled data from a late-stage clinical trial of the drug in July, showing it slowed cognitive decline in patients in the early stages of the illness. It’s anticipated that Lilly might secure FDA approval for the drug by the close of 2023 or in early 2024.
The continued success of their mentees, and the continued trail of scientific discoveries, not only reaffirm the importance of Virginia Lee and Trojanowski's early work but also represent a significant leap forward in the quest for a cure.
“Within my lifetime we may actually prevent people from having bona fide dementia. I don’t think I would have been able to say that 10 years ago,” said Lee, who, at 77, has no plans to ever retire from science. “We know these new treatments can prevent decline. In the next three years or so, we’ll be able to see if it can last longer. I'm optimistic that it will.”
Changing the picture for dementia
Read more in this collection of stories:
- A legacy of love and learning: Virginia-M.Y. Lee’s life in science, together with her late partner John Q. Trojanowski, is a testament to her dedication to understanding the brain.
- The gift of knowledge: The fundamental answers to the core questions of neurodegenerative diseases—how and why these diseases develop—are found within the brain itself, including from specimens donated to the Penn Medicine brain bank.
- The connection to care: With innovative memory disorder drugs on the horizon, Penn Medicine is working to address the challenges patients and families still face, from diagnosis, to treatment, to supportive care.