The National Institutes of Health awarded assistant professor of biomedical engineering Christopher Nelson a little more than $1.8 million to study the long-term efficacy of gene therapy. The five-year award will be used to consider the genetic and cellular determinants that may be limiting the success of new gene therapies.
The ultimate goal is to enable improved design of gene therapy approaches with the aim of life-long correction across a range of genetic diseases.
Nelson notes that gene-editing tools, like CRISPR, and viruses engineered to safely shuttle replacement human genes into cells are helping doctors make rapid advances when it comes to addressing the molecular basis of a disease. Ongoing progress in the treatment of spinal muscular atrophy, inherited blindness and hemoglobinopathies, such as sickle cell disease, illustrate the rapid development of these life-saving tools.
But there are still many unknowns, including how long gene replacement therapies last, whether the body will fight a therapy with a strong immune response, which could be fatal, and whether gene therapies will result in unintentional genomic changes, which can trigger undesirable side effects.
“There’s really two things we’re concerned about safety-wise,” Nelson said. “The first is genomic toxicity. Basically are we doing more harm than good to the cells we are trying to fix? And then the other is, are we triggering really deadly immune responses? And then the thing we want, efficacy-wise, is for the therapy to last a long time.”
Nelson’s previous work has shown that in the absence of an immune response, CRISPR-mediated genome editing effects last for the lifetime of an animal. However, an adaptive immune response can reverse this gene therapy. Additionally, his team has observed a high level of vector integration, which is when the gene-edited material makes deeper, unwanted changes to a patient’s genome.
Overall, Nelson’s goals are to better understand:
“If the scientific community can answer these questions,” Nelson said, “we can build more effective therapies for some of the most devastating genetic diseases.”