Researchers from the University of Minnesota (UM) successfully boosted factor VIII levels in mice with hemophilia A through a type of gene therapy that targets cells in the liver. The study was published in the Journal of Clinical Investigation. The lead investigator was Betsy T. Kren, PhD, Department of Medicine, UM Medical School, Minneapolis.
Kren and colleagues took nanocapsules (submicroscopic drug carrier systems made of an oily or watery core surrounded by a thin membrane) and coated them with hyaluronan, or hyaluronic acid, which improves cell binding. They then augmented the nanoparticles by encapsulating segments of DNA known as transposons. Also known as, “jumping genes,” transposons can move independently to different positions in the genome of a single cell, making them well suited to carry therapeutic genes into targeted cells. Investigators used a Sleepy Beauty transposon, which was first discovered more than 10 years ago when a laboratory found that the seemingly outmoded gene could be “awakened,” becoming a key vehicle for transporting genetic material into the nucleus of a cell.
The hyaluronan-coated/Sleepy Beauty-encapsulated nanoparticles, further customized with the FVIII therapeutic gene, were then delivered to the sinusoidal endothelial cells of the mice by intravenous injection. These endothelial cells were targeted because they are the primary source of FVIII production. Measurements taken 5 and 50 weeks after the injection showed that FVIII levels and clotting ability improved significantly in the mice with hemophilia A. In addition, no inhibitor antibody response was reported. Researchers hope that these successful animal studies will eventually lead to human trials of this type of gene therapy.
Source: Kren T, Unger G, Sjeklocha L, et al. Nanocapsule-delivered Sleeping Beauty mediates therapeutic Factor VIII expression in liver sinusoidal endothelial cells of hemophilia A mice. The Journal of Clinical Investigation, June 2009.