Systems and methods to provide therapeutic factor viii using ultrasound-mediated nucleic acid delivery
AssigneeSeattle Children’s Hospital d/b/a Seattle Children’s Research Institute
InventorCarol Hsing Miao
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Abstract
Systems and methods that provide therapeutic levels of coagulation factor (FVIII) or variants thereof following ultrasound mediated gene delivery (UMGD) are described. The systems and methods can be used in the treatment of hemophilia A (HA). Depending on the needs of a particular patient, the systems and methods can use gene or base editing components that correct genetic mutations responsible for HA and/or can use safe and repeatable intravenous dosing of nucleic acids that result in expression of functional FVIII or variants thereof.
Claims76
A method for preferentially delivering plasmid DNA comprising a Factor VIII rescue sequence to liver sinusoidal endothelial cells over hepatocytes in a subject comprising:
- intravenously administering a composition comprising the plasmid DNA and neutral or cationic microbubbles, wherein the composition has 0.011 pg plasmid DNA per microbubble, and
- transcutaneously applying a pulsed ultrasound to the liver for 50-70 seconds wherein the pulsed ultrasound parameters comprise
- a center frequency of 1.1 MHz,
- a pulse repetition frequency of 14 Hz,
- 14 cycles of a 1-second ON and 2-seconds OFF pulse train;
- and
- a peak negative pressure of 1.5 MPa with a pulse duration of 150 μs,
- thereby preferentially delivering the plasmid DNA to liver sinusoidal endothelial cells over hepatocytes in the subject.
A method for delivering a nucleic acid to a liver in a subject comprising:
- administering a composition comprising the nucleic acid and microbubbles, and
- applying ultrasound to the liver
- thereby delivering the nucleic acid to the liver in the subject.
A kit comprising a nucleic acid and components to form microbubbles.
Dependencies are inferred from the claim text.