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DNA Tags Speed Nanoparticle Gene Therapy Discovery

James Dahlman

James Dahlman holds a microfluidic device used to produce nanoparticles for gene therapies. (Rob Felt, Georgia Institute of Technology)

8 February 2017. Biomedical engineers developed a technique with unique DNA identifiers that makes possible faster screening of gene therapies delivered with nanoscale particles. A team from Massachusetts Institute of Technology published its findings in the 6 February issue of Proceedings of the National Academy of Sciences (paid subscription required).

James Dahlman, the study’s lead author, was a graduate student at the time of the study and is now a biomedical engineering professor at Georgia Institute of Technology and Emory University in Atlanta. Dahlman and colleagues from the labs of Robert Langer and Daniel Anderson at MIT are seeking better techniques to fulfill the potential of gene therapies, particularly when targeting specific cells in the body. Nanoparticles are among the more promising strategies for hitting precise cellular targets.

Finding materials that accumulate in specific cells or tissues is important for discovering drugs that address those cells and tissues. Many new cancer drugs, for example, seek to precisely target tumor cells, while avoiding healthy tissue that surround the tumor. Treatments for heart disease likewise seek to accumulate only in heart tissue and cells. Gene therapies also need that precise level of targeting.

But finding the best nanoscale particle materials for delivering gene therapies is up to now a highly inefficient process, first requiring tests in cell cultures, then testing a few materials at a time in lab animals. The researchers instead designed a technology that vastly streamlines the process and enables the simultaneous screening of many more candidate materials.

The team’s solution uses single strands of DNA, or genetic codes, that act as unique identifiers on the nanoparticles, much like bar-coded serial numbers on inventory items. The nanoparticles are formulated with the DNA codes using a microfluidic, or lab-on-a-chip, device, then injected into lab animals for tracking. The animals’ organs are then examined for the presence of the nanoparticles and samples genetically sequenced to measure their concentrations.

In tests with lab mice, Dahlman’s team reported the simultaneous identification of biocompatible materials in 30 nanoparticles distributed to 8 tissues, as well as quantifying the concentrations of nanoparticles in those tissues. The tests show this technique can identify effective chemical properties of materials for gene therapy, while avoiding problems of particle mixing and genetic analysis interrupting their delivery.

In the tests, researchers compared their results to particles known to address specific lung and liver cells, which helped validate their process. Among the nanoparticles accumulating in the liver were those formulated with small interfering RNA, or siRNA, used in gene therapies to silence specific genes with disease-causing mutations. In this case, the nanoparticles with siRNA silenced specific genes in liver cells.

The team’s work was limited by current nanotechnology measurement tools, which as Dahlman notes in a Georgia Tech statement, “can be very complicated because for every biomaterial available, you could make several hundred nanoparticles of different sizes and with different components added.” Nonetheless, Dahlman adds, “In future work, we are hoping to make a thousand particles and instead of evaluating them three at a time, we would hope to test a few hundred simultaneously.”

Tagging drugs with DNA identifiers is becoming a more mainstream drug discovery tool. As reported in Science & Enterprise in January 2017, Scripps Research Institute made its library of DNA-encoded candidates for drug discovery available to pharma company Pfizer.

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