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A - Viral Vector Development -> AAV Vectors – Preclinical and Proof-of-Concept Studies

7: Temporary Mechanical Support Improves Cardiac AAV Gene Transfer Efficacy in a Pig HF Model

Type: Oral Abstract Session

Presentation Details
Session Title: AAV Gene Therapy in Large Animal Models
Location: Room 204
Start Time: 5/16/2022 11:30
End Time: 5/16/2022 11:45

Purpose: Gene therapy using adeno-associated virus (AAV) is increasingly promising as a potential breakthrough therapy for heart failure (HF) as evidenced in animal studies. However, challenges remain in achieving successful gene transduction for human heart. Using a catheter-based approach, we hypothesized that compared to conventional delivery by slow continuous infusion, AAV exposure to the heart can be prolonged using temporary coronary balloon occlusions aided by a mechanical cardiac support device for hemodynamic maintenance. We predicted that this novel technique would lead to increased gene expression in the heart in a pig model of HF. Methods: Yorkshire pigs received AAV-6 encoding luciferase gene (5.0 x 1013 vg) by antegrade injection into the coronary artery one week after myocardial infarction (MI). Pigs were allocated to one of the following groups: conventional delivery (n=3), delivery with coronary artery occlusion (CAO, n=3), and delivery with coronary artery and coronary sinus occlusions (CAO + CSO, n=3). A catheter-based cardiac support device was inserted to preserve hemodynamics during coronary balloon occlusion. Four weeks later, tissues were harvested from various heart regions and other organs to assess luciferase expression. Two other animals underwent MI creation and were injected one week later with 20 nm gold nanoparticles (the size of AAV) by either CAO + CSO or conventional delivery with mechanical support in order to visualize distribution by electron microscopy (EM). Infarct and remote regions from explanted hearts were further processed and analyzed for the presence of injected gold nanoparticles between delivery methods. Results: Catheter-based support offered safe vector delivery during 1-1.5 minutes of CA and CS occlusions in preventing hemodynamic instability and arrhythmia. CAO delivery enhanced luciferase expression up to 20-fold globally in the heart, but not in non-cardiac tissues, compared to conventional delivery. CAO + CSO delivery further increased luciferase expression, also noted by increased vector genome in the tissues detected by PCR. At infarct border and remote regions, CAO + CSO delivery led to a more than 300-fold increase. EM data demonstrated a greater presence of gold nanoparticles after CAO + CSO delivery in contrast to conventional delivery. The majority of gold nanoparticles seen were at the interface of the vessel lumen and endothelium, with some observed within vesicles in remote areas in the CAO + CSO delivery group, as well as occasional incidence in infarct area. Conclusion: Coronary artery and sinus occlusion with catheter-based cardiac support dramatically improved AAV gene expression in the heart without compromising hemodynamics or increasing off-target expression. Furthermore, this delivery approach leads to higher vector uptake into cardiac tissue. Higher detection of gold nanoparticles beyond the arterial lumen with this technique suggests greater opportunity for AAV transduction by optimizing the time of vector exposure to tissue. This method offers clinically applicable and efficient cardiac gene delivery as a new therapeutic option for patients with heart failure.



Renata Mazurek, Tomoki Sakata, Spyros Mavropoulos, Anjali J. Ravichandran, Francisco Romeo, Kiyotake Ishikawa

Mount Sinai, New York, NY
  R. Mazurek: 1; Commercial Interest i.e. Company X; Abiomed, Inc.. 1; What was received? i.e. Honorarium; Research awards (abstract competitions). 1; For what role? i.e. Speaker; Recipient as Postdoctoral Fellow.

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