Liquid jet delivery method featuring S100A1 gene therapy in the rodent model following acute myocardial infarction

Abstract

The S100A1 gene is a promising target enhancing contractility and survival post myocardial infarction (MI). Achieving sufficient gene delivery within safety limits is a major translational problem. This proof of concept study evaluates viral-mediated S100A1 overexpression featuring a novel liquid jet delivery (LJ) method. 24 rats after successful MI were divided into 3 groups (n=8 ea.): saline control (SA), ssAAV9.S100A1 (SS) delivery, and scAAV9.S100A1 (SC) delivery (both 1.2×1011 viral particles). For each post MI rat, the LJ device fired three separate 100 μL injections into the myocardium. Following 10 weeks, all rats were evaluated with echocardiography, quantitative polymerase chain reaction (qPCR), and overall S100A1 and CD38 immune protein. At 10 weeks all groups demonstrated a functional decline from baseline, but the S100A1 therapy groups displayed preserved LV function with significantly higher ejection fraction %; SS group [60±3] and SC group [57±4] versus saline [46±3], p<0.05. Heart qPCR testing showed robust S100A1 in the SS [10,147±3993] and SC [35,155±5808] copies per 100 ng DNA, while off target liver detection was lower in both SS [40±40], SC [34,841±3164] respectively. Cardiac S100A1 protein expression was [4.3±0.2] and [6.1±0.3] fold higher than controls in the SS and SC groups respectively, p<0.05.

Hydrodynamic gene delivery in human skin using a hollow microneedle device

“…6), with increased transfection evident when the naked pDNA was applied to cell monolayers using the MicronJet device compared to a pipette tip, although absolute gene expression levels remain low. Direct cell transfection by a high velocity liquid is also supported by a significant body of literature related to jet injections [10,[18][19][20]65,74,75]. However, although a jet injection mechanism may contribute to the heightened gene expression observed in this study, the limited number of jets and the extensive distribution of gene expression suggest that it is unlikely to be the sole or major reason for the enhancement.…”

Commentary: Doubling up on gene therapy for heart failure

“…In animal models of myocardial ischemia-reperfusion, myocardial infarction, and heart failure, S100A1 overexpression improves calcium handling, myocardial contractility, and cardiac function. [3][4][5][6][7] S100A1 is a therefore a target of interest for human heart failure treatment.…”

S100A1 as a potential biomarker for the diagnosis of patients with acute aortic dissection

“… 12 Calcium-binding protein S100A1, a member of the S100 protein family, is one of the most important regulators of myocardial systolic and diastolic functions. 13 S100A1 can serve as an early diagnostic marker of ischemic coronary artery disease in patients with acute myocardial infarction. 14 However, few studies have evaluated S100A1 as a biomarker in patients with AAD.…”