The cells in your body are pretty good at monitoring themselves, but they don’t always signal what’s going on to the outside world. A Rice University bioengineer has plans to enhance their ability to communicate. Jerzy Szablowski, an assistant professor of bioengineering at Rice’s George R. Brown School of Engineering, is developing technology to measure gene expression in deep tissues, particularly in the brain. His noninvasive, site-specific reporters will be secreted by cells to report on what they find.
This could be particularly useful to monitor gene therapy treating neurodegenerative disorders like epilepsy, amyotrophic lateral sclerosis, or Huntington’s disease, as cells modified to make their own drugs would also make proteins that confirm their expression.
Szablowski’s research now has support from the National Institutes of Health through a three-year Exploratory/Developmental Research Grant (aka the Trailblazer Award) to develop these reporters, which can be easily transported from known regions of the brain into the blood. Then a simple blood test can be used to analyze them.
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“This is a critical problem in gene therapy research,” said Szablowski, an assistant professor of bioengineering. “In most cases, once the therapy is delivered, there are few, if any, methods to evaluate whether the genes are being expressed in cells deep in the body.
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“There are markers that naturally tell you about the disease, but there are also diseases or processes that don’t have markers in the blood, and that’s inconvenient,” he said. “So why not make markers for these processes, so they are easy to detect? Why not equip the cells with the capability of informing us about these diseases?”
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Szablowski’s proposed solution is elegant in its simplicity. Reporters are the marker molecules cells are programmed to make only if they’ve incorporated the newly delivered genes. The number of reporters in a sample is often a gauge of the success of the gene delivery treatment: The more reporters, the more cells that have accepted and incorporated the new genes.
Finding and measuring reporters is typically done through microscopic analysis of tissue samples. In clinical trials, such samples could only come from major surgery, which is often either financially infeasible, too risky for patients, or both.
“It’s impractical or impossible to bring the tissue to the microscope, but we don’t have to if we can design the reporters to leave the cells and enter the bloodstream,” Szablowski said.
If the method works as intended, measuring the success of gene therapy in any tissue in the body could be as simple as drawing blood and submitting it for lab tests.
To demonstrate the technique, Szablowski is designing reporters that can tell whether gene expression is taking place in the brain, one of the most inaccessible parts of the body. That means getting reporters expressed by cells through the blood-brain barrier and into the bloodstream, where they can be collected.
His lab’s strategy is to enhance vascular permeability in selected regions of the brain and allow proteins to diffuse into the blood. The project will also incorporate protein engineering, pharmacology and biodistribution studies, as well as gene delivery to the brain.