It used to be that diseases were treated only with medications ingested, injected, inhaled or applied to the skin—if treatments were available at all. But scientific breakthroughs in recent years have revolutionized treatment therapies to the nano level, making it possible to target treatment to specific cells.
Samuel Y. Sheng Professor of Biomedical Engineering
—Photo by Matt Lenz
Delivering therapeutic treatments for devastating diseases at the molecular level is the future of genetic medicine, according to Kam Leong, Samuel Y. Sheng Professor of Biomedical Engineering. And direct cellular reprogramming, or trans-differentiation, in which adult cells are converted from one type to another without going through an intermediate stem cell-like stage, represents the next frontier of regenerative medicine and tissue engineering.
Leong’s research is actively focused on both.
“The therapies are DNA- and peptide-based and must cross the cell membrane,” explains Leong. “Nanoparticles can carry these drugs into the cell, but there are many potential challenges associated with bringing the therapeutic agents to the site through the right intracellular pockets.”
Researchers have already proven it’s possible to edit the genome—cutting out a dysfunctional or mutated gene at a particular site and inserting a healthy gene in its place—using a virus as the nanoparticle that transmits the therapeutic agent. However, there are safety concerns associated with using viruses—including toxicity, immune and inflammatory responses, and even a potential for the virus to recover its disease-causing potential within the patient.
Therefore, Leong’s research focus in this area—and his long-term vision for genetic medicine—is to develop a non-viral genome-editing nanoparticle.
Recently, his research using such nanoparticles to treat hemophilia was highlighted in Nature. Leong’s team demonstrated success using pills made from bacterial DNA (with a gene encoding one of two clotting factors absent in patients with hemophilia) and nanoparticles made of chitosan, a polysaccharide found in the exoskeleton of crustaceans. These pills were able to deliver the genes and produce blood-clotting factors without activating an immune response.
However, says Leong, while the genes transferred, the efficacy of the non-viral approach is still very low, meaning insufficient levels of the factors were being synthesized.
“My efforts are focused on improving this non-viral gene transfer and genome editing process,” he says.
Leong says this approach can also be used in cell engineering and regenerative medicine.
“Our studies have shown we can use genome editing to activate a gene to directly convert a fibroblast (connective tissue cell) into a specialized cell like a neuron,” he says. “If we can do this effectively with the nanoparticle approach, it would be tremendously exciting. We could begin to deal with the many intractable neurodegenerative diseases that plague our society.”
Leong explains that creating a cell-based treatment for diseases like Alzheimer’s and Parkinson’s has been difficult because researchers had few ways to acquire the cells.
“But now, through advances in stem cell engineering, we no longer have to use an embryo or convert adult cells into embryonic stem cells and then differentiate them,” he says. “Using trans-differentiation, we can directly convert fibroblasts—or other cell types—into the neurons we need.”
Once again, this gene-activating process has been demonstrated using viral nanoparticles. But Leong’s research vision is to develop a non-viral approach that is equally effective without the associated risk. The idea would be to manipulate these cells in a culture and then put them back into a patient’s brain.
Down the road, Leong hopes to develop a way to inject nanoparticles containing these reprogramming factors directly into a patient’s brain—converting that patient’s cells into properly functioning neurons in situ and reversing neurodegenerative disease.
“We’re nowhere near that point yet, but it’s the ultimate goal,” he says. “The fundamental underlying technology is the same as with gene therapy. We need a safe and effective intracellular delivery system.”
A member of the National Academy of Engineering and the National Academy of Inventors, Leong holds 50 patents and has authored more than 280 journal articles. He earned his PhD in chemical engineering from the University of Pennsylvania, and he was a professor and researcher at the Johns Hopkins School of Medicine and Duke University before he joined Columbia University’s Fu Foundation School of Engineering and Applied Science. While at Duke, he worked on nanoparticle-mediated non-viral gene delivery and cancer immunotherapy.
BS, UC Santa Barbara, 1977; PhD, University of Pennsylvania, 1987
—by Jessica Driscoll