This research was supported by BrightFocus
Dr. Paul Lombroso
BrightFocus Foundation funded Dr. Paul Lombroso from 2008 to 2011 for his work testing whether inhibiting the STEP protein could rescue cognitive abilities disrupted in animal models of Alzheimer’s disease and other neuropsychiatric disorders. This finding provided a rationale for drug discovery and for developing therapeutic agents that could inhibit STEP proteins. Dr. Paul Greengard, who was awarded the 2000 Nobel Prize in Physiology or Medicine, was Co-Principal Investigator with Dr. Lombroso.
Alzheimer's disease, which is marked by progressive memory loss, impaired cognitive function, loss of neurons and eventual death, impacts millions of people worldwide and is predicted to increase by many additional millions over the next decade. There are a few drugs to aid in memory loss and others used for behavioral symptoms like anxiety and depression, but no treatments have been found to halt or reverse the progress of the disease. Now, a protein discovered 25 years ago in the research lab of Paul Lombroso, MD, the Elizabeth Mears and House Jameson Professor in the Child Study Center at Yale, may offer new hope.
Lombroso discovered that this new class of protein was directly involved in several neuropsychiatric disorders, including Alzheimer's. Increased levels of these proteins, known as STEP (Striatal-Enriched Phosphatase) prevent neurons in the brain from firing correctly by removing glutamate receptors, which are critical for turning short term memories into stable, long-term memories.
In order to determine that altered STEP levels were actually contributing to the cognitive defects, and were not a consequence of having the disease, the Lombroso lab genetically lowered STEP levels in mouse models with Alzheimer's and showed that this was sufficient to reverse cognitive deficits. They found that the "STEP knockout" mice had better cognitive function and performed better on memory tasks than mice with Alzheimer's in which STEP was present. These findings were published in the Proceedings of the National Academy of Science and included Lombroso and Yale researchers Yong Fang Wang, Jian Xu, Pradeep Kurup, Stephen Strittmatter, Haakon Nygaard, Christopher Pittenger, and Angus Nairn.
This striking finding validated STEP as a target for drug discovery to develop compounds that might lower STEP levels and potentially reverse the terrible hallmarks of Alzheimer's disease—debilitating memory loss and loss of cognitive function.
GlaxoSmithKline (GSK) recently selected Lombroso’s Alzheimer's research for a Discovery Partnership with Academia (DPAc) grant, forming a project working group that will combine Lombroso's biology and medical expertise and GSK’s compound screening and medicinal chemistry to develop new therapies for Alzheimer's that target STEP. The opportunity was facilitated by the Yale Office of Cooperative Research (OCR), which works to accelerate and commercialize faculty research, protect intellectual property, and to connect researchers with industry partnerships.
"We are extremely pleased to be entering into this research collaboration with GSK," said John Puziss, Ph.D., Director of Technology Licensing at OCR. "By pairing one of the leading researchers in Alzheimer's with a premier pharmaceutical company, we hope to accelerate this research and bring new therapies to patients with this devastating disease."
DPAc is a milestone-driven grant. Over the course of three years, the partnership hopes to identify compounds that will inhibit STEP and can be progressed into human clinical trials. Several millions of dollars are earmarked for this work, as individual compounds will be tested in the Lombroso lab in animal models of Alzheimer's disease.
More recent findings in the Lombroso laboratory have suggested that as we normally age, STEP levels are slowly increasing. "STEP levels increase in some individuals as they grow older," Lombroso says. "Moreover, we found that STEP levels are significantly elevated in individuals with mild cognitive impairments compared to unimpaired aged-matched controls."
STEP is disrupted in several additional diseases all with cognitive deficits. The work conducted at Yale and other laboratories around the world suggests that either too much or too little STEP plays a role. These illnesses include Parkinson’s disease, Fragile X syndrome, alcoholism, schizophrenia and Huntington's disease.
"No one had previously considered that a single protein might contribute to pathology of such distinct illnesses," Lombroso says. "But the important finding is that STEP can disrupt how we learn—and a key feature of these illnesses is that they all have cognitive disabilities."
These diseases represent additional candidates for the development of a drug that targets STEP activity. "The data is very exciting," Lombroso says. "Our hope is to develop a drug that improves cognitive function across a number of devastating diseases."
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