While new intervention drug trials are being launched in Alzheimer’s disease, Lewy body dementia (LBD) families still await any news about potential therapies that may someday halt the progression of Lewy body dementias. Cutting edge research demonstrates the potential of immunotherapy to slow or stop the development of Lewy bodies, the underlying disease process behind LBD. Immunotherapy is a medical treatment that uses the body’s own immune system to identify and attack certain types of cells, such as cancer. Specifically, the immune system produces antibodies, a special type of protein, that can identify and neutralize foreign bodies. Antibodies engineered to target a single protein are called monoclonal antibodies.
Researchers from the University of Pennsylvania recently showed that immunotherapy can block the development and spread of Lewy body pathology, using both cell cultures and a new “wild-type” mouse model. Monoclonal antibodies designed to target the main building block of Lewy bodies, alpha-synuclein, were used in this study.
In LBD and Parkinson’s disease (PD), when the naturally-occurring protein alpha-synuclein forms abnormal clumps (Lewy bodies) inside of neurons, the neurons eventually die. Several years ago, researchers at the University of Pennsylvania discovered that Lewy body pathology spreads from cell to cell. This results in the death of neurons in different regions of the brain. In humans, as Lewy body pathology spreads, clinical symptoms like parkinsonism or dementia develop.
To recreate this type of pathology in mice, researchers force the over-expression of the alpha-synuclein gene. These “transgenic mice” are not natural models of Lewy body pathology though, and do not mirror the exact pathology seen in humans.
To create a better mouse model, researchers injected the brains of healthy mice with a synthetic form of alpha-synuclein fibrils (slender, microscopic fibers). The fibrils formed Lewy body pathology inside of neurons. The Lewy bodies then spread to other parts of the brain and led to motor dysfunction in the mice and the loss of neurons that produce dopamine. This “wild-type” mouse model more closely resembles human Lewy body pathology than transgenic mice. The researchers used the new model to conduct both prevention and intervention preclinical studies using immunotherapy. For prevention studies, they injected healthy mice with alpha-synuclein fibrils and immediately treated the mice with monoclonal antibodies called Syn303 and continued weekly treatments for 30 days. A control group of mice was also injected with alpha-synuclein fibrils, but were treated with another type of antibody. The brains were autopsied after 30 days; the control group had Lewy body pathology in multiple brain areas. The mice treated with Syn303 however showed dramatically reduced pathology in the same areas.
For intervention studies, mice were injected with alpha-synuclein fibrils and a week later, when Lewy body pathology would be detectable, they were treated with Syn303. As before, a control group was created and treated with another antibody. At 60 days, the brains were autopsied and reduced Lewy body pathology seen in the mice treated with Syn303.
This experiment was repeated, but instead of a single treatment of Syn303, the mice were treated weekly for 180 days to determine if long-term immunotherapy could reduce motor impairment and the death of dopamine-producing neurons. The mice tolerated the treatment well, gained weight normally and appeared healthy until the experiment ended. Using a grip strength test, the mice treated with Syn303 showed significantly better grip strength and motor coordination than the control group. Brain autopsies revealed the mice treated with Syn303 had less Lewy body pathology and more preservation of neurons that are involved in motor coordination.
This study revealed that alpha-synuclein immunotherapy can intercept Lewy bodies as the disease process spreads. This resulted in prevention of Lewy body pathology and even reversed some of the motor symptoms.
"There are some limitations to experiments in live mice since it is difficult to directly study the mechanism of how it works," says Virginia M.Y. Lee, PhD, senior author on the paper, Director of the Center for Penn’s Center for Neurodegenerative Disease Research (CNDR) and professor of Pathology and Laboratory Medicine. "To do that, we went back to the cell culture model to ask whether or not the antibody basically prevents the uptake of misfolded alpha-synuclein."
The scientists treated mouse cell cultures with different forms of synthetic alpha-synuclein fibrils, resulting in the formation of Lewy bodies, and studied the effect of two different antibodies on the spread of Lewy body pathology. These cultures revealed that the antibodies interacted directly with the disease pathology outside neurons and prevent them from spreading, but did not affect normal alpha-synuclein residing inside neurons.
This was a proof-of-concept study, demonstrating the new models may be used to develop novel therapies for Lewy body disorders like LBD and Parkinson’s disease. While this research is promising, there would likely be a long delay before such therapy would be available for clinical use. To date, these approaches have only been tried in cell cultures and mouse models and have not been studied in humans. There is still much research to be done to develop antibodies that have a stronger ability to bind to Lewy body pathology but not interfere with healthy proteins. When and if better antibodies are created, and safety and efficacy are validated in multiple models, then clinical trials can be launched to determine if the antibodies can be used in humans. Another factor that will influence the ability to use immunotherapy in humans is the ability to identify at which stages of disease progression such treatment may be effective.
This research was published in June, 2014 in Cell Reports. Senior author, Virginia M.Y. Lee, PhD, has served on the Lewy Body Dementia Association’s Scientific Advisory Council. The work was supported by an NIA training grant (T32-AG000235), a NINDS Morris K. Udall Parkinson's Disease Center of Excellence (P50 NS053488), the Michael J. Fox Foundation, the Keefer family, and the Parkinson Council.
Citation: Tran HT, Chung CH, Iba M, Zhang B, Trojanowski JQ, Luk KC, Lee VM. α-Synuclein Immunotherapy Blocks Uptake and Templated Propagation of Misfolded α-Synuclein and Neurodegeneration. Cell Rep. 2014 Jun 11. pii: S2211-1247(14)00427-6. doi: 10.1016/j.celrep.2014.05.033. [Epub ahead of print] PubMed PMID: 24931606.