Is Genome Editing the Next Big Thing in Gene Therapy?

April 28, 2014

Proponents say the precision of genome editing could finally lead to big successes in gene therapy.

In March, The New England Journal of Medicine published the first peer-reviewed study to demonstrate the successful modification of human DNA by genome editing. Researchers at the University of Pennsylvania removed T cells from 12 patients with HIV, disabled a gene that produces a protein the virus uses to enter the cell, coaxed the cells to reproduce, then returned the engineered cells to the patients. It was just a safety trial, but preliminary results suggest that patients with the engineered cells had decreased levels of HIV three months after the procedure.

Then, in April, the first U.S. patent for genome editing technology was awarded to scientists at the Massachusetts Institute of Technology and Harvard University. CRISPR is a genome-engineering tool that allows scientists to add or delete genes at precise locations on a chromosome. The technology utilizes a modified set of bacterial proteins that normally defend against viral invaders.

The developments have created a stir in the field of gene therapy, especially among scientists such as Matthew Porteus, MD, PhD, a pediatric hematologist/oncologist at Lucile Packard Children’s Hospital and a deputy editor of Molecular Therapy, which publishes mostly gene therapy research. Dr. Porteus’ lab is using genome editing techniques in studies of sickle cell disease, severe combined immunodeficiency (SCID), thalassemia and hemophilia.

With conventional gene therapy techniques, a gene engineered in the lab (called a transgene) is packed inside a vector and inserted either directly into tissue or the bloodstream. The transgene mimics the function of a human gene that is either missing or malfunctioning. In the majority of cases, the vector used is a virus whose own DNA has been largely or completely removed to make room for the transgene and the components that help the transgene and virus integrate into the genome and begin expression.

Genome editing takes a different approach. With the aid of an enzyme called a nuclease, scientists are able to break DNA at a specific spot in the genome. They can then remove the mutated section of DNA and replace it with a functioning transgene — essentially editing the genome. The new gene and nuclease can either be packaged inside a lone circular piece of double-stranded DNA, called a plasmid, or a non-integrating viral vector. When the cell repairs itself from the nuclease cut, it takes in the transgene and incorporates it into the genome.

“Genome editing is significantly more precise than other strategies,” says Dr. Porteus, who also is an associate professor of pediatrics at Stanford Medical School. “This precision should translate into improved safety and perhaps even improved efficacy.”

Because the vectors used in genome editing aren’t integrated into the genome, scientists can sidestep the issues with immune response that often thwart gene transfer attempts via conventional techniques.

“We are working on ex vivo nonviral methods of gene therapy by gene editing. In this way, we hope to avoid some of the immunologic issues that using viral vectors in vivohas,” Dr. Porteus says. “In addition, because we are using nonviral delivery approaches, our packing sizes are not limited and we can deliver large genes or many genes at once.”

While genome editing has been successful in animal models, it remains to be seen if the technique will have similar success in the clinic. The first clinical trials involving genome editing are just getting under way, and it will be several years before scientists have results from human studies.

“There remain important technical problems to address, but the biologic rationale for gene editing is so powerful that there will be a strong driving force to resolve those technical problems,” Dr. Porteus says. “In the long run, I think most people would agree that genome editing will probably supplant more conventional gene therapy approaches.”