UI team wins grant to improve and advance genome editing

Researchers at the University of Iowa Carver College of Medicine have received a three-year, $2 million grant from the National Institutes of Health (NIH) to develop new methods to carry gene editing tools into cells that line the airway.

The team, led by Paul McCray, MD, UI professor and executive vice chair in the Stead Family Department of Pediatrics (pulmonary medicine, allergy & immunology) and a gene therapy expert, will focus on cystic fibrosis (CF). However, findings from the project may provide opportunities for the treatment of other lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), and other conditions.

Since the discovery of the gene editing system called CRISPR, the ability to remove or repair faulty sections of DNA has become fairly routine. However, significant hurdles remain before successful gene editing in experimental cell models and laboratory animals can be translated into safe and effective treatments for human patients.

Early in 2018, the NIH launched the Somatic Cell Genome Editing (SCGE) program, which aims to create tools for safe and effective genome editing in humans. The new grant is one of the first 21 grants to be awarded through the SCGE program, which was established with NIH Common Fund support.

“Gene editing technology offers new opportunities to modify genes, turn genes off and on, and repair mutations associated with disease,” says McCray, who also is a member of the Pappajohn Biomedical Institute at the UI. “A major hurdle for bringing this technology to the clinic is the difficulty in delivering editing materials into the organs affected by disease. Our project will explore a novel delivery strategy to advance gene editing as a therapeutic approach for diseases that affect the airways.” 

The project, “Delivery of CRISPR Ribonucleoproteins to Airway Epithelia Using Novel Amphiphilic Peptides,” is supported by the National Heart, Lung, and Blood Institute of the NIH under award number UG3HL147366.

The research involves a high degree of collaboration and includes physicians and researchers with expertise in airway epithelial cell and pulmonary biology, lung diseases, gene therapy, gene delivery, and animal models, as well as recombinant protein production, delivery peptides, and CRISPR gene editing. McCray and his team will collaborate with David Guay, PhD, and Thomas Del'Guidice, PhD, at Feldan Therapeutics, a company that has developed a peptide-based technology platform for the direct delivery of protein cargoes to cells. 

The team will use novel amphiphilic peptides to deliver the CRISPR gene editing complex into cells that line the airway. These peptides borrow sequences from nature, such as those present in antimicrobial peptides and some viruses, that allow them to cross cell membranes and escape cell mechanisms designed to control entry into cells.
“Gene editing is beginning to be tested for some diseases of the immune system and blood. For these applications, it is possible to modify affected cells outside the body, then reintroduce them,” McCray says. “Gene editing of specific organs, like the lungs, is not amenable to such approaches currently. The approach we are investigating is one way to advance the delivery of gene editing tools to cells and tissues in living animals.”

The team will optimize the peptides for delivering CRISPR into airway cells and measure the efficiency and safety of the gene editing in cell and animal models. The ultimate goal is to create new gene editing treatments to help people with airway diseases. 

In addtion to McCray and the research team at Feldan Therapeutics, the team also includes David Meyerholz, DVM, PhD, UI professor of pathology; Xiaopeng Li, MD, PhD, UI research associate professsor of internal medicine; Peter Thorne, PhD, UI professor of occupational and environmental health in the College of Public Health: and Patrick Ten Eyck, PhD, in the UI Institute for Clinical and Translational Science.