Penn Medicine Researchers Pinpoint Potential New Drug Target for Protection against Certain Neurodegenerative Diseases
March 2015 | Corey T. McMillan, Jenny Russ, Elisabeth M. Wood, David J. Irwin, Murray Grossman, Leo McCluskey, Lauren Elman, Vivianna Van Deerlin, Edward B. Lee
Penn Medicine researchers have discovered that hypermethylation - the epigenetic ability to turn down or turn off a bad gene implicated in 10 to 30 percent of patients with Amyotrophic lateral sclerosis (ALS) and Frontotemporal Degeneration (FTD) - serves as a protective barrier inhibiting the development of these diseases. Their work, published this month in Neurology, may suggest a neuroprotective target for drug discovery efforts.
"This is the first epigenetic modification of a gene that seems to be protective against neuronal disease," says lead author Corey McMillan, PhD, research assistant professor of Neurology in the Frontotemporal Degeneration Center in the Perelman School of Medicine at the University of Pennsylvania.
Expansions in the offending gene, c9orf72, have been linked with TAR DNA binding protein (TDP-43) which is the pathological source that causes ALS and FTD. "Understanding the role of C9orf72 has the possibility to be truly translational and improve the lives of patients suffering from these devastating diseases," says senior author, Edward Lee, PhD, assistant professor of Neuropathology in Pathology and Laboratory Medicine at Penn.
McMillan and team evaluated 20 patients recruited from both the FTD Center and the ALS Center at the University of Pennsylvania who screen positive for a mutation in the C9orf72 gene and were clinically diagnosed with FTD or ALS. All patients completed a neuroimaging study, a blood test to evaluate C9orf72 methylation levels, and a brief neuropsychological screening assessment. The study also included 25 health controls with no history of neurological or psychiatric disease.
MRI revealed recuded grey matter in several regions that were affected in patients compared to controls. Grey matter is needed for the proper function of the brain in regions involved with muscle control, memory, emotions, speech and decision-making. Critically, patients with hypermethylation of C9orf72 showed more dense grey matter in the hippocampus, frontal cortex, and thalamus, regions of the brain important for the above described tasks and affected in ALS and FTD, suggesting that hypermethylation is neuroprotective in these regions.
To validate these findings, the Penn team also looked at autopsies of 35 patients with C9orf72 expansions and found that their pathology also suggested that increased methylation was associated with reduced neuronal loss in both the frontal cortex and hippocampus.
Longitudinal analysis was performed in 11 of the study patients to evaluate the neuroprotective effects of hypermethylation in individuals over their disease course. This showed reduced changes in grey matter of the hippocampus, thalamus, and frontal cortex, associated with hypermethylation suggesting that disease progresses more slowly over time in individuals with C9orf72 hypermethylation. Longitudinal neuropsychological assessments also showed a correlation between protected memory decline and hypermethylation.
These findings are consistent with a growing number of studies which have suggested the neuroprotective effects of the hypermethylation of C9orf72. "We believe that this work provides additional data supporting the notion that C9orf72 methylation is neuroprotective and therefore opens up the exciting possibility of a new avenue for precision medicine treatments and targets for drug development in neurodegenerative disease," says McMillan.
This research was funded by the National Institutes of Health (AG043503, AG017586, AG039510, AG10124, AG032953) and the Wyncote Foundation. Dr. Lee is supported by the Doris Duke Charitable Foundation Clinical Scientist Development Award.
Penn Medicine News Release
New Models for Testing Parkinson's Disease Immune-based Drugs
June 2014 | Hien T. Tran, Charlotte Hiu-Yan Chung, Michiyo Iba, Bin Zhang, John Q. Trojanowski,Kelvin C. Luk, Virginia M.-Y. Lee
Using powerful, newly developed cell culture and mouse models of sporadic Parkinson's disease (PD), a team of researchers
from the Perelman School of Medicine at the University of Pennsylvania has demonstrated that immunotherapy with
specifically targeted antibodies may block the development and spread of PD pathology in the brain. By intercepting the
distorted and misfolded alpha-synuclein (a-syn) proteins that enter and propagate in neurons, creating aggregates, the
researchers prevented the development of pathology and also reversed some of the effects of already-existing disease.
The a-syn clumps, called Lewy bodies, eventually kill affected neurons, which leads to clinical PD.
Earlier studies by senior author Virginia M.-Y. Lee, PhD, MBA, and her colleagues at Penn's Center for Neurodegenerative Disease Research (CNDR) had demonstrated a novel pathology of PD in which misfolded a-syn fibrils initiate and propagate Lewy bodies via cell-to-cell transmission. This was accomplished using synthetically create a-syn fibrils that allowed them to observe how Parkinson's pathology developed and spread in a mouse and in neurons in a dish. The present study is a proof-of-concept of how these models might be used to develop new PD therapies.
"Once we created these models, the first thing that came to mind is immunotherapy," says Lee, CNDR director and professor of Pathology and Laboratory Medicine. "If you can develop antibodies that would stop the spreading, you may have a way to at least retard the progression of PD." The current work, she explains, uses antibodies that were generated and characterized at CNDR previously to see if they would reduce the pathology both in cell culture and in animal models.
Lee's team focused on anti-a-syn monoclonal antibodies (MAbs). "In animal models," Lee explains, "the question we want to ask is, can we reduce the pathology and also rescue cell loss to improve the behavioral deficits?"
Using their previously established sporadic PD mouse model, the researchers conducted both prevention and intervention preclinical studies. For prevention studies, they injected mouse a-syn synthetic preformed fibrils into wild-type, normal mice, as a control, and then immediately treated the mice with Syn303, one of the MAbs used (or IgG, another type of common antibody, for the control mice).
The control group without MAb administration showed PD pathology in multiple brain areas over time, while the mice treated with Syn303 showed significantly reduced pathology in the same areas. For intervention studies, they treated PD mice with Syn303 several days after fibril injections when Lewy bodies were already present. They found that the progression of pathology was markedly reduced in the Syn303-treated mice versus mice that did not receive Syn303.
"But there are some limitations to experiments in live mice since it is difficult to directly study the mechanism of how it works," Lee says. "To do that, we went back to the cell culture model to ask whether or not the antibody basically prevents the uptake of misfolded a-syn." The cell culture experiments showed that MAbs prevented the uptake of misfolded a-syn fibrils by neurons and sharply reduced the recruitment of natural a-syn into new Lewy body aggregates.
Next steps for the team will be to refine the immunotherapeutic approach. "We need to make better antibodies that have high affinity for pathology and not the normal protein," says Lee.
The team's models also open up new opportunities for studying and treating PD. "The system really allows us to identify new targets for treating PD," Lee says. "The cell model could be a platform to look for small molecular drugs that would inhibit pathology." Their approach could also serve as a foundation for genetically based studies to identify specific genes involved in PD pathology.
"Hopefully more people will use the model to look for new targets or screen for treatments for PD. That would be terrific," concludes Lee.
The work was supported by an National Institute on Aging training grant (T32-AG000235), the National Institute of Neurological Disorders and Stroke Morris K. Udall Parkinson's Disease Center of Excellence (P50 NS053488), the Michael J. Fox Foundation, the Keefer family, and the Parkinson Council.
Penn Medicine News Release
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