Prospect of ultrasound-mediated gene delivery in cardiovascular applications

ABSTRACT

Introduction: The field of regenerative medicine has evolved over the years, investigating gene and stem/progenitor cell therapies to help address the increasing burden of cardiovascular disease (CVD). While the lack of success of gene therapy in clinical trials has dampened enthusiasm, the search continues for a successful and translatable gene therapy strategy for CVD. Ultrasound-mediated gene delivery (UMGD) is a non-invasive technique for gene delivery that utilizes gene-bearing carrier microbubbles and high power ultrasound to facilitate transfection in vivo. Many pre-clinical studies have shown benefit in animal models of CVD, but this has yet to be translated to human applications.

Areas covered: In this review, the basic principles of UMGD will be examined along with an overview of pre-clinical studies to date in CVD, focusing on cardiac and vascular applications and key findings. In addition, the potential path to the clinical translation of UMGD is discussed.

Expert opinion: Ultrasound-mediated gene delivery holds promise as a non-invasive technique for gene delivery in CVD, with the ability to deliver multiple genes with repeated deliveries over time. If the substantial hurdles to clinical translation can be overcome, UMGD may prove to be a key aspect in the success of cardiovascular gene therapy in the future.

KEYWORDS:

• Gene therapy
• ultrasound
• microbubble
• ultrasound-targeted microbubble destruction
• angiogenesis

Article highlights

• Ultrasound-mediated gene delivery (UMGD) or ultrasound-targeted microbubble destruction (UTMD) is a non-invasive technique for gene delivery that utilizes gene-bearing carrier microbubbles and the external application of high power ultrasound to facilitate transfection in vivo.

• This is a physical method (facilitated by microbubble cavitation) of gene transfection, occurring through multiple biologic events at the tissue level, including sonoporation/microporation, microjet formation and shear forces.

• UMGD/UTMD fits many requirements of an ideal gene delivery platform, such as minimal procedural invasiveness, improved target specificity for enhanced localized concentration of gene products without off-target delivery, ability to repeat therapy as required and good safety profile in pre-clinical studies.

• Many pre-clinical studies have shown benefit in animal models of CVD, but this has yet to be translated to human applications. For translation to the clinic, challenges and hurdles to overcome include the need for more efficient vectors given modest transfection efficiency, issues of target cell (vascular versus extravascular targets)/organ and scalability of delivery platforms to humans.

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Declaration of interest

The authors’ work is supported by Operating Grants (MOP 123424, MOP 62,763 and MOP 137109) from the Canadian Institutes of Health Research, Ottawa, Ontario, Canada, and an Equipment Grant from the Canadian Foundation for Innovation, Ottawa, Ontario, Canada. Dr Leong-Poi is supported by the Brazilian Ball Chair in Cardiovascular Research from St. Michael’s Hospital, University of Toronto. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

The authors’ work is supported by Operating Grants (MOP 123424, MOP 62,763 and MOP 137109) from the Canadian Institutes of Health Research, Ottawa, Ontario, Canada, and an Equipment Grant from the Canadian Foundation for Innovation, Ottawa, Ontario, Canada. Dr. Leong-Poi is supported by the Brazilian Ball Chair in Cardiovascular Research from St. Michael’s Hospital, University of Toronto.