New Gene Therapy Could Stop Parkinson’s

In almost 70 years, our understanding of how Parkinson’s disease wreaks havoc on the nervous system has grown tremendously. Advances in genetic sequencing, for instance, have revealed that up to 15 percent of all cases of Parkinson’s can be attributed to inherited mutations in a person’s DNA. But large gaps in our understanding remain, including what causes the majority of cases and how to definitively test for the disease. Most astonishingly, today’s gold standard treatment for Parkinson’slevodopa medications—was discovered 68 years ago. Levodopa is effective at reducing Parkinson’s hallmark symptoms like tremors, slowness, and stiffness. The underlying theory is that Parkinson’s patients lose cells that make dopamine, and levodopa acts as a substitute.

Crucially, however, levodopa cannot stop or slow the progression of the neurodegenerative disease—merely provide some respite to the symptoms. Many researchers hope to find a more permanent cure by targeting the source and directly fixing mistakes in patients’ genes that lead to Parkinson’s in the first place. In a new study published April 19 in the journal Science Advances, one group reports having acquired the ability to overcome a (literal) barrier holding genetic intervention back.

New ways to treat Parkinson’s disease can’t come fast enough. More than 8.5 million people worldwide have the disease, and it’s the fastest-growing neurological cause of disability and death. Not only can these new findings introduce a new generation of Parkinson’s treatments, it could fundamentally change the way we treat diseases of the brain.

Our ultimate goal is to treat neurological diseases, such as Parkinson’s, early and non-invasively,” José Obeso, a neurologist at the Abarca Campal Integral Neuroscience Center in Spain and the senior author of the new research, told Spanish newspaper El País. “If all goes well, we could start testing on patients in the summer of 2024.”

Though the roots of Parkinson’s disease remain mysterious, researchers have figured out that dopamine is central to the puzzle. You may know this chemical as a pleasure hormone, but more generally it’s a key component of neurons’ messaging system. A structure in humans’ midbrain called the substantia nigra controls movement and coordination through cells that release dopamine. But in Parkinson’s patients, 80 percent or more of these cells are killed off.

Gene therapies—where researchers can fix a mutation in a person’s underlying genetic code—have shown promise for rare disorders that consist of a single well-described mutation, Rebecca Gilbert, the chief scientific officer of the American Parkinson Disease Association who was not involved in the recent research, told The Daily Beast. Parkinson’s, however, seems to be much more complex, and so the gene therapies that have been trialed have taken a variety of approaches. Some aim to keep dopamine-producing cells alive, while others increase the production of enzymes that turn precursor chemicals into dopamine.

Blood-brain barrier. Illustration of the haematoencephalic barrier between the blood flow and the central nervous system. This system regulates the environment (homeostasis) in the brain by separating it from the blood. Both the endothelial cells (red) that line the capillaries and the surrounding astrocytes (pink) are essential components of this barrier. The blood-brain barrier stops harmful chemicals and bacteria from reaching the brain. The blue cells are the neurons in the brain. Viruses and special types of drugs are able to pass the blood-brain barrier.

But both of these strategies hit the same roadblock: It’s not easy at all to get to the substantia nigra because of a network of blood vessels and tissues called the blood-brain barrier. To protect the brain from infection and inflammation, the barrier lets in substances like water and oxygen while keeping out large proteins. Levodopa naturally crosses the blood-brain barrier, but gene therapy, which is often delivered using a harmless virus, is a definite no-no. If drug delivery were a microscopic-scale version of package delivery, the blood-brain barrier might be a low-clearance bridge and gene therapy an oversized truck.

The [blood-brain barrier] keeps many unwanted substances out of the brain, so it is a very necessary system to protect the brain, but it means that it needs to be circumvented for gene therapy to work,” Gilbert said. In the new study, the researchers injected tiny fat bubbles into the veins of six macaque monkeys and three humans, then performed focused ultrasound in a machine similar to an MRI. The ultrasound waves combined with the bubbles formed millimeter-sized cracks in various parts of the blood-brain barrier, which the researchers found they could control. And though it seems small, a few millimeters is all a gene therapy would need to slip past into the brain.


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