Mark Saltzman, pictured with Maya Kotas (left) and Margaret Cartiera
Biomedical engineer Mark Saltzman, pictured with medical student Maya Kotas (left) and graduate student Margaret Cartiera, has developed a nanoparticle to deliver gene therapy. The particle has proven successful in vitro and in mouse models in introducing genes that thwart tumor cells while avoiding toxicity.
The particles injected into the tail of a lab mouse course through the animal’s veins, eluding immune surveillance as they make a stealth run toward the tiny tumor growing on its flank. When the particles hit the tumor, the raid begins in earnest. The particles slip through the outer cellular membranes and into the rogue cells. The genes packaged within the particles shed their protective polymer veil and hijack the cellular machinery. From there, the covert DNA instructs the cells to produce apoptosis-inducing proteins, which trigger cell suicide and ultimately sabotage tumor growth.
This gene therapy success story, published online in December in the journal Nature Materials, marks a paradigm shift in the method for delivering therapeutic genes to diseased cells. At the root of this triumph is a biodegradable nanoparticle created by Yale biomedical engineers that upends previous dogma.
As W. Mark Saltzman, Ph.D., the Goizueta Foundation Professor of Biomedical Engineering, co-principal investigator with associate research scientist Jiangbing Zhou, Ph.D., and research scientist Zhaozhong Jiang, Ph.D., explains it, researchers previously used viruses to ferry genetic material into animal cells. These foreign particles, however, appeared as red flags to the host’s immune system, resulting in their swift demise. Earlier engineers replaced the viral vectors with synthetic nanoparticles, which they believed needed a high positive charge to glom onto negatively charged DNA and condense it into a neat little package for intracellular delivery. These charged nanoparticles did the job, but their excess positive charge also destabilized cell membranes, causing considerable toxicity.
The Yale researchers hypothesized that replacing some of the excess positive charge with hydrophobic regions might reduce the toxicity of the polymers yet still allow for condensation of DNA. They developed a controlled system of polymer synthesis that allows them to tune the polymer constituents, tweaking where necessary to find the right balance between positively charged and water-insoluble units.
Among the 20 polymers that the Yale team constructed, one exhibits the ideal mix of sticky positive charges and hydrophobic regions. When mixed with DNA, the polymer condenses to create nanoscale spheres that resemble minuscule water droplets on a pane of glass. The compacted DNA tucked within the nooks and crannies of the polymer blobs is protected from enzymatic assault when circulating in the body. Equally important, the nanoparticles pose no harm to the animal host.
When tested in vitro, the nanoparticles delivered genes to target cells with 50- to 170-fold-greater efficiency than commercially available gene therapy vectors. Furthermore, tumor-bearing mice regularly dosed with the apoptosis-inducing gene therapy showed no toxicity during the entire course of treatment, and their tumors grew to only a fraction of the size of those in control mice. Closer inspection of the tumor tissue revealed that the suicide gene dramatically promoted the death of tumor cells.
Saltzman envisions someday using the new polymer delivery system in humans to enable gene therapy for several diseases, including cystic fibrosis, Huntington disease, and cancer, particularly brain tumors—a devastating disease that he says demands heroic efforts. “We’ve been developing techniques for introducing particles like these directly into the brain to treat malignant brain tumors for some years. Our hope is that these polymers give us another tool—a very safe tool—that we can use in that arena,” Saltzman says.
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