Almost a decade ago, 2013 Harrington scholar and gastrointestinal cancer pioneer, Dr. Sanford Markowitz, and Case Western Reserve University School of Medicine Dean, Dr. Stan Gerson, identified a little known enzyme,15-hydroxyprostaglandin dehydrogenase (15-PGDH), as a major culprit in suppressing healing and promoting inflammation of damaged tissues. With support from Harrington Discovery Institute, they went on to develop a new small molecule (SW033291) to therapeutically target 15-PGDH. Demonstrating remarkable therapeutic results in mouse models of ulcerative colitis, bone marrow transplantation, and lung fibrosis, the physicians licensed SW033291 to the global pharmaceutical company Amgen, where it is being developed further for advancement to clinical (human) trials.
More recently, a unique collaboration between Dr. Markowitz and Dr. Andrew A. Pieper, psychiatrist and neuroscientist in the Department of Psychiatry at Case Western Reserve University and University Hospitals Cleveland Medical Center, and Director of Harrington Discovery Institute’s Brain Health Medicines Center, resulted in two striking discoveries with SW033291 that have tremendous potential for treating— even preventing—neurodegenerative diseases.
Each year, more than 55 million people are diagnosed with Alzheimer’s disease (AD). Among the three known risk factors—genetics, aging, and traumatic brain injury (TBI), the latter is gaining more attention. Drs. Markowitz and Pieper focused on a novel target connecting AD and TBI, inflammation and the blood brain barrier (BBB). Most people understand the BBB’s importance in preventing bacteria and viruses from attacking the brain directly. It does that and much more.
Dr. Pieper describes the BBB as a fascinating and complex structure. It’s not like shrink wrap, he notes. It is a highly dynamic multi-cellular interface between peripheral vascularity and the brain, which performs regulatory functions such as controlling blood vessel constriction in response to nerve cell demand so that only the right amount of blood—no more and no less than is required—is delivered to various parts of the brain.
“The BBB is an energy intensive, interrelated set of cells involving the vasculature, immune, and nervous systems that is constantly adjusting and repairing itself,” Dr. Pieper notes. “What we found together with Dr. Markowitz is that two important inflammatory immune cells at the blood brain barrier—microglia and perivascular macrophages—are highly enriched in the 15-PGDH enzyme that Dr. Markowitz has been studying.”
Elevated 15-PGDH in the BBB got the physician-scientists thinking. Would blocking the enzyme heal the BBB? What other therapeutic effects might it have? Next came two thrilling discoveries, they both recall.
“With the levels of 15-PGDH in the BBB as our focus, we tested SW033291 in mice with TBI,” Dr. Markowitz recounts. “We found that inhibiting 15-PGDH with SW033291 protected the mice from neurodegeneration and cognitive impairment even when the drug was given a full day after injury. By blocking 15-PGDH, we prevented brain inflammation and preserved BBB integrity, thereby blocking neuronal damage.”
The same therapeutic pathway also worked in a mouse model of Alzheimer’s disease (AD). Most research in neurodegenerative disease has focused on brain neurons, and currently approved AD drugs are amyloid-targeting antibodies developed to prevent the accumulation of amyloid plaque, a sticky substance that’s been found in brains of AD patients.
“We showed a novel way of treating Alzheimer’s disease,” Dr. Pieper says. “SW033291 did not influence the amyloid plaque pathology in the mouse model we tested, yet it was completely protective. Without reducing any of the amyloid plaque buildup in the Alzheimer’s mice, SW033291 prevented amyloid induced brain inflammation, protected BBB integrity, stopped all other signs of Alzheimer’s disease in the brain, and preserved normal cognitive function.”
Dr. Pieper noted that this could be related to a well-known but not understood phenomenon of non-demented individuals with Alzheimer’s disease pathology, in which people who never developed any symptoms of dementia are found after death to have prolific amyloid plaque accumulation in their brains that would otherwise prompt a diagnosis of Alzheimer’s disease. “It’s recognized that these individuals may be fortunately endowed with compensatory protective mechanisms that allow them to remain cognitively intact despite developing typical Alzheimer’s pathology, and our results suggest that protecting the blood-brain barrier could be a factor in this phenomenon,” explained Dr. Pieper. “Protecting or healing the BBB— a site not traditionally treated in AD—gives SW033291 outstanding potential as a small molecule therapeutic for the disease,” he said.
Drs. Markowitz and Pieper hope to one day see SW033291 offered in pill form for protective treatment in patients developing Alzheimer’s disease and in those who are within 24 hours of a TBI, potentially saving millions of people from the heartache and hardships of these currently untreatable and chronic neurodegenerative diseases.
Cardiovascular, Gastroenterology, Oncology
Case Western Reserve University
Harrington Scholar-Innovator
Neuroscience
University Hospitals - Cleveland
Harrington Investigators