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A Trojan Treatment for Parkinson’s Disease

Scientists use immune cells to smuggle molecules across the blood-brain barrier in the hopes of treating neurodegenerative diseases.

Deep in the base of the brain, a cascade of events including oxidative damage and inflammation can kill neurons, resulting in the debilitating symptoms of Parkinson’s disease.

An international team of researchers has now developed a technique that might be used to prevent this cell death. They engineer immune cells to carry protective stowaway molecules, and the hope is that these Trojan cells can help prevent neuron death by delivering treatments across the blood-brain barrier—a layer of cellular structures that blocks most molecules from passing into the brain. The researchers have so far tested the approach successfully in mice.

The hope is that one day these immune cells could be extracted from a patient’s own blood, engineered to carry a therapeutic payload, and injected back into the body. The approach might be able to slow the progress of other neurodegenerative diseases associated with neuron death such as Alzheimer’s and Huntington’s disease.

Using the new method for traversing the blood-brain barrier, researchers from the University of Nebraska Medical Center, the University of North Carolina, and the Lomonosov Moscow State University in Russia delivered an enzyme to the site of cell death in mice with an experimental model of Parkinson’s. As reported earlier this year in the journal PLoS One, the Trojan therapy prevented motor defects seen in untreated mice.

The researchers used a common antioxidant enzyme, called catalase, to prevent cell death in the brain. And they engineered immune cells called macrophages to carry the genetic blueprints for catalase into the brain. Together they could travel across the protective blood-brain barrier. The macrophages are attracted to dying neurons, which release signals into the blood calling for help.

After giving mice oxidants in the base of the brain to simulate the degenerative effects of Parkinson’s, the researchers injected some of the mice with the macrophages engineered to make catalase. The mice without this treatment performed poorly on a test designed to assess balance. But the mice treated with the macrophages performed as well as normal, healthy mice. Under the microscope, the team observed that macrophage cells containing catalase had fused with neurons, providing direct drug delivery.

Macrophages “may have several advantages,” over alternative treatments says Andrew Feigin, a neurologist at Hofstra North Shore-LIJ School of Medicine, who was not involved in the study.

A traditional yet short-lasting treatment for Parkinson’s is to prescribe a precursor of dopamine. Surviving neurons use this to release more dopamine, compensating in part for the lack of dopamine release after their neighbors perish. However, the brain eventually stops responding to this treatment.

Gene therapy is another treatment currently being researched. By delivering genetic instructions to produce certain proteins using viruses, gene therapy can supply protective enzymes or other molecules that promote cell growth to these dying cells. Feigin is helping lead the first human trials for virus-delivered gene therapy for Parkinson’s, a solution that would be more permanent than macrophages currently provide.

Unfortunately, it is still difficult to transport these viruses past the blood-brain barrier. Even when that is achieved, it can be difficult to get the viruses to the site of damage. Moreover, the body’s immune system will fight these viruses; no virus is as welcome in the brain as a macrophage.

Macrophages face none of these issues. “You can accomplish targeted, active drug delivery across the blood-brain barrier,” says Elena Batrakova, associate professor of pharmaceutical sciences at the University of North Carolina, and senior author of the study.

Batrakova hopes macrophages will ultimately cure Parkinson’s, and she is exploring other ways of using them. Her next step is to promote the growth of new neurons in the brain by smuggling in growth factors past the blood-brain barrier the same way. “We don’t only want to stop the progression of Parkinson’s disease, we want to reverse it,” she says.

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