Carol Miao, PhD, on Delivering Gene Editing Tools With Nonviral Methods in Hemophilia A Models


The principal investigator at Seattle Children’s Research Institute discussed her lab’s preclinical research on nonviral delivery methods for gene editing tools in the context of treating hemophilia A.

“We found that in ultrasound–mediated gene delivery, when we explored different parameters with certain specific conditions, we can specifically target liver sinusoidal endothelial cells, where the factor VIII gene is synthesized—its natural synthetic site. We're still trying to improve the editing efficiency, but we can already see persistent correction of at least 5% of factor VIII expression for a very long time. That's already therapeutic for severe hemophilia patients—you can bring the severe phenotype to the mild phenotype and that's actually very beneficial for these patients.”

Great strides in the treatment of hemophilia have been made in recent years with adeno-associated virus (AAV) vector-based gene therapies for both hemophilia A and hemophilia B reaching or nearing the commercialization stage in the United States and Europe. Despite this, there remains interest in developing new, nonviral genomic medicines to treat these indications to overcome the inherent limitations of AAV-based methods.

Carol Miao, PhD, a principal investigator at Seattle Children’s Research Institute, and a professor in the Department of Pediatrics at the University of Washington School of Medicine, is currently evaluating several nonviral alternatives to AAV vector-based delivery, with a specific focus on delivering gene editing tools for the treatment of hemophilia A. Investigators from her lab gave a total of 6 presentations detailing the lab’s research at the American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting, held May 16-20, in Los Angeles, California.

In an interview with CGTLive™, Miao discussed 2 of the nonviral methods her lab is evaluating—ultrasound mediated gene delivery and targeted delivery by lipid nanoparticles—and gave an overview of the key results that were presented at the conference. She noted that in the preclinical models, their ultrasound mediated gene delivery method was capable at least 5% correction efficiency for factor VIII expression in liver sinusoidal endothelial cells (LSECs) and that their lipid nanoparticle delivery method enabled up to approximately 20% correction efficiency at higher doses in LSECs.

1. Lawton SM, Fan MN, Chao TY, et al. NHEJ gene editing of hemophilia A mice show therapeutic levels of FVIII following ultrasound mediated gene delivery of CRISPR/Cas9 plasmid. Presented at: American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting. May 16-20, 2023; Los Angeles, CA. Abstract #31.
2. Chen CY, Cai X, Miao CH. Liver-specific targeting CRISPR/Cas9 mRNA LNPs achieve long-term FVIII expression in hemophilia A mice. Presented at: American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting. May 16-20, 2023; Los Angeles, CA. Abstract #26.
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