From identifying foreign viruses to removing dead or dying cells, the immune system is comprised of a variety of cells performing distinct tasks. These cells develop from hematopoietic stem cells which are undifferentiated cells that reside in bone marrow, a spongy tissue inside of bones. Depending on a number of cues, hematopoietic stem cells will differentiate into specialized cells.
When something goes awry in the DNA of hematopoietic stem cells, individuals have primary immune deficiency diseases, or an immune system that is not firing at all cylinders. Sometimes the issue in the DNA of the hematopoietic stem cells is a single nucleotide error.
One strategy to treat these diseases is to fix errors in hematopoietic stem cells. For years, researchers at the University of Minnesota have led in research and treatment for primary immunodeficiency, sickle cell disease and Fanconi anemia. A new grant will help make treatment for these diseases more effective and safe by using newer techniques driven by advances in precision gene-editing.
The research requires robust partnerships with researchers in the U of M Medical School in the Department of Medicine, Department of Pediatrics and the Department of Lab Medicine and Pathology, in addition to the Department of Biomedical Engineering, part of the U of M College of Science and Engineering.
A new 1.25-million dollar grant is slated to run for three years and is split into three main project teams. R. Scott McIvor, professor in Genetics, Cell Biology, and Development leads the primary immunodeficiency research team, Dr. Gregory Vercellotti, the overall program PI, leads a team on sickle cell disease and Dr. John Wagner leads a team on Fanconi anemia.
“Thirty years ago, we started inserting ‘corrected’ genes using a randomly integrating vector to hematopoietic stem cells. We weren’t fixing the genetic defect, but instead complementing the defect in the cell,” says McIvor.
This gene-addition therapy worked, but there was risk of off-target effects. A targeted approach is better, but also required technology that at the time didn’t exist. Years later, gene-editing tools like TALENS, developed by GCD Professor Dan Voytas, and later CRISPR entered the scene. This was groundbreaking and opened up a new era of treating these diseases.
“The technical prowess of my colleagues Dr. Branden Moriarity and Dr. Beau Webber in the Department of Pediatrics is the key reason we proposed these projects in the AIRP grant. We want to use CRISPR to specifically target areas of the gene in hematopoietic stem cells and fix those errors.”