# Ultrasound-mediated gene delivery to achieve therapeutic correction of hemophilia A

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2021 · $774,401

## Abstract

Project Summary
The goal of this proposal is to achieve long-term therapeutic correction of hemophilia A (HemA) via a noninvasive
protocol of ultrasound (US) mediated gene delivery (UMGD) of factor FVIII (FVIII) plasmids in the dog model.
HemA is a genetic disorder characterized by a deficiency of the blood clotting FVIII. Patients are treated acutely
or prophylactically by protein replacement therapy, which is very costly and inconvenient. Gene therapy is highly
promising for treating HemA patients by delivering hFVIII transgene into targeted cells to persistently produce
therapeutic levels of FVIII protein. Recent clinical trials for HemA gene therapy using recombinant adeno-
associated viral (rAAV) vectors have shown very promising results. However, significant obstacles remain to
prevent treatment to a significant portion of patients especially patients who have high-titer anti-AAV antibodies.
Repeated treatment is also prohibited. UMGD has emerged as an effective gene transfer approach with great
clinical relevancy and translational potential. In comparison to viral gene transfer, UMGD transfers plasmid
vectors that are easier to prepare and more cost-effective; it also elicits less immune response and toxicity due
to specific tissue targeting, prevents random integration, and allows for repeated delivery of the vectors. Other
nonviral gene delivery method such as DNA-packaged nanoparticle encounters the challenge of crossing the
nuclear envelope for DNA transcription. We have established a minimally invasive, transhepatic venous
approach to efficiently deliver plasmid DNA (pDNA)/microbubble (MB) mixture into the target liver lobe combined
with transcutaneous US applications in large animal models. We showed that high levels of luciferase reporter
gene expression were achieved in swine and therapeutic levels of FVIII expression was detected in canine0
using the clinically feasible protocol. Only transient tissue damages were observed and repaired quickly and
returned to normal within short time. However, in order to translate this novel technology to clinics, we recognize
that several major problems need to be solved, (i) higher FVIII expression levels are needed to achieve a long-
term therapeutic effect, (ii) persistence of therapeutic FVIII expression needs to be evaluated and maintained,
(iii) consistently high efficiency of US treatment on targeted liver tissue is needed to achieve reproducible and
efficient transfection. (iv) Better functional FVIII expression and reduced liver damage are desired. This may be
achieved by targeting FVIII transfection in liver sinusoidal endothelial cells (LSECs), the native site of FVIII
synthesis or by using newly synthesized nanobubbles (NBs). Thus, we propose to continue improving the
transcutaneous UMGD instrument, transducers, US protocols, FVIII plasmid constructs, and MBs/NBs in mice
and swine. Furthermore, we will deliver FVIII gene using the best transcutaneous UMGD protocol combined with
optim...

## Key facts

- **NIH application ID:** 10128318
- **Project number:** 5R01HL151077-02
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Carol H Miao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $774,401
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128318

## Citation

> US National Institutes of Health, RePORTER application 10128318, Ultrasound-mediated gene delivery to achieve therapeutic correction of hemophilia A (5R01HL151077-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10128318. Licensed CC0.

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