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Gene therapy innovations at Professor Philip Leopold’s lab

By Julia Vance

“In fifty years, people will be receiving gene therapy just as often as you would receive a vaccine.” After a visit to the lab of Stevens Institute of Technology Clinical Professor and Program Director of Biology Philip Leopold, this remark was what stuck out the most. Dr. Leopold has a way of explaining the complicated things he and his associates do every day in his genetic therapy lab in a way that even a grandmother could understand, without coming across as even the slightest bit condescending. Obviously optimistic about the future of gene therapy, Leopold has published a plethora of academic papers, and holds a patent on a method of hair growth. The research he and the doctoral, masters, and even undergraduate students do in his lab is cutting edge.

Ciara Agresti, a doctoral student working toward her PhD in Chemical Biology, focuses her research on developing an alternate method of delivering gene therapy to the mitochondria located in your cells. According to Leopold, there is only one other method in existence for the delivery of gene therapy to the mitochondria. He likens her work to that of a baseball pitcher. “Of course every pitcher knows the various ways to throw the ball over home plate, but what Agresti is trying to do is similar to figuring out how to throw a ball so that on its way to home plate it abruptly turns and travels straight to first base.” She demonstrated a process she was conducting with DNA samples called electrophoresis, which uses electric current to separate fragments of DNA according to size. These fragments will be assembled into the “vector” that will carry therapeutic DNA into the mitochondria.

Another graduate student, Bowen Luo, is working on ex-vivo gene therapy, which is when cells are removed from the organism, genetically modified, and then placed again into the organism. Leopold describes his work as “doing surgery on the genome itself” as he modifies the patterns in the DNA using high-tech tools that literally cut and paste DNA inside of the cell. Primarily, his work focuses on the treatment of a disease called polycythemia vera, in which the bone marrow produces too many red blood cells. This disease is a prime candidate for Luo’s research because it is relatively simple to remove cells from the bone marrow, and when the removed and modified cells are inserted into the bloodstream through injection, they easily find their way back to the marrow.

Yunfei “Wendy” Wen, a third graduate student, works on the growth of adenoviruses. These viruses are used for in-vivo human genetic therapy, in which viruses, called vectors when used for genetic therapy, are modified so they can’t reproduce and are given a part of the DNA that will replace a mutant gene in the cell. These adenoviruses are described as a sort of “viral syringe” used to inject healthy DNA into a patient – this DNA could be a vaccine, a missing growth factor, or even anti inflammatory molecules to help treat rheumatoid arthritis. Wen is specifically studying the stage of infection right before the virus gets to the nucleus. This stage of infection has never been studied or modeled before.

The problem with widespread use of adenoviruses, or “viral syringes” is that the body produces an immune response to these modified viruses. Ordinarily, this ability is great for the body’s health as it is necessary to remove pathogenic viruses. However, when the virus is used to deliver a beneficial fragment of DNA, the immune response can be troublesome. Because of this immune response, an adenovirus can only be used in a patient once. That’s why undergraduate researcher Colin Gilech is working to fabricate gene therapy delivery vectors using DNA. The process he uses to create these vectors is often referred to as “DNA origami”. DNA is useful for this purpose because the body doesn’t recognize it as a foreign object like it does with a virus. This means the same vector could be used multiple times in a single patient. Unfortunately, it’s not as simple as it sounds. The different configurations of DNA are classified by the number of junctions between the “arms.” In the lab, there are models of DNA clusters with up to six arms in the junction. DNA naturally occurs in the cell in configurations of four arms in the junction, so there is a concern that the cell may mistake the DNA vector for a typical DNA structure and break it down like it ordinarily would, rendering the vector useless. This is what Gilech is studying: figuring out how a cell will react to the different types of DNA configurations and whether or not they work as vectors.

Dr. Leopold’s enthusiasm for the work he and his students are doing is immediately visible and a little bit contagious. According to Leopold, “the technology is here, and the approval will come” when it comes to genetic therapy. The thought that someday a patient could take a pill or receive an injection to fix the genetic mutations in his or her genome has the potential to be disruptive in the medical community. If Leopold’s predictions about the future of gene therapy come true, the world should look forward to the day a doctor can fix the mutated genes in the cells of patients everywhere.

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