The clinical trial will use non-invasive ultrasound-based techniques to better understand how Parkinson's disease develops and progresses at a molecular level.
The technique, developed by researchers at Rice University in Houston, can flush proteins from the brain into the bloodstream and has previously been used in mouse studies to evaluate the delivery of gene therapies based on gene products from small numbers of brain nerve cells, or neurons.
By extending this work to patients with Parkinson's disease, the researchers hope to reveal valuable insights into the molecular mechanisms of the disease and aid in the development of targeted therapies.
“We are particularly excited about this technology because our research has already led to funded clinical trials with colleagues at Baylor College of Medicine and MD Anderson Cancer Center,” Dr. Jerzy Zabrowski, assistant professor of bioengineering at Rice University and leader of the study, said in a university press release.
The study, “Acoustic targeted measurement of transgene expression in the brain,” was published in Science Advances.
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Each gene can be thought of as a set of instructions that tells cells how to make a particular protein. These instructions affect how the cell functions and responds to its environment. Knowing which genes are active and which are inactive in the brain could provide insight into what happens in neurodegenerative diseases such as Parkinson's.
Current methods for studying gene activity in the brain are limited: for example, biopsies can provide molecular data based on samples of cells taken from the brain, but this is an invasive procedure and can interfere with normal brain function.
To get around this limitation, Zabrowski's team developed a technique they called Retrieval of Ultrasound Markers in the Brain (REMIS) to noninvasively measure gene activity, including gene therapy, in the brain.
“Gene therapy is one of the most exciting frontiers in medicine, but we need tools to know if gene therapies will reach the right parts of the brain and work as intended,” Zabrowski said. “REMIS gives us the option to do that without surgery.”
To test the technique, the researchers injected mice neurons with genes that allowed them to produce their own protein markers, which were designed to exit the neurons and enter the brain's interstitial space (the fluid-filled areas between neurons), from where they were released into the bloodstream.
When ultrasound waves are applied to specific brain areas, they temporarily open the blood-brain barrier (a protective layer that keeps many substances out of the brain). This controlled opening allows the markers to pass from the brain into the bloodstream, where they can be detected by standard laboratory tests.
“Our study shows that a relatively simple ultrasound test can measure gene expression (activity) and the delivery of gene therapy in specific brain regions,” Zabrowski said.
The researchers also wanted to see whether REMIS could measure naturally occurring gene activity in the brain. To do this, they created a system in mice where a protein called GLuc was produced when neurons were active. This system was controlled with a compound called CNO, which makes neurons fire.
Mice treated with CNO had significantly higher levels of GLuc in their blood compared to untreated mice, demonstrating that REMIS can be used to peer into gene activity and its products in the brain.
“These results suggest that REMIS can be used successfully in small cohorts of animals, which is of great importance for larger animal studies and any potential clinical applications,” the researchers wrote.
