AAV8-H1-sh-tPA

AAV8-H1-sh-tPA is a preclinical gene therapy construct designed to silence the expression of tissue-type plasminogen activator (tPA) specifically in hepatocytes. It utilizes an adeno-associated virus serotype 8 (AAV8) vector to deliver a short hairpin RNA (shRNA) under the control of the H1 promoter. Research presented at the AHA 2022 meeting indicates that hepatocyte-derived tPA plays a critical non-fibrinolytic role in lipid metabolism by limiting the production of very-low-density lipoprotein (VLDL). Mechanistically, tPA appears to inhibit the interaction between apolipoprotein B (ApoB) and microsomal triglyceride transfer protein (MTP), thereby reducing ApoB lipidation and VLDL secretion. Silencing tPA with this vector in mouse models leads to increased plasma cholesterol and triglycerides and exacerbates atherosclerosis, making it a valuable tool for studying the link between fibrinolytic enzymes and atherogenic lipid profiles.