Intravenous adeno-associated virus serotype 8 encoding urocortin-2 provides sustained augmentation of left ventricular function in mice

• Published in: Human gene therapy Vol. 24; no. 9; p. 777
• Main Authors: Gao, Mei Hua, Lai, N Chin, Miyanohara, Atsushi, Schilling, Jan M, Suarez, Jorge, Tang, Tong, Guo, Tracy, Tang, Ruoying, Parikh, Jay, Giamouridis, Dimosthenis, Dillmann, Wolfgang H, Patel, Hemal H, Roth, David M, Dalton, Nancy D, Hammond, H Kirk
• Format: Journal Article
• Language: English
• Published: United States 01-09-2013
• Subjects: Animals; Calcium; Corticotropin-Releasing Hormone - blood; Corticotropin-Releasing Hormone - genetics; Corticotropin-Releasing Hormone - metabolism; Dependovirus - genetics; Gene Transfer Techniques; Genetic Therapy - methods; Genetic Vectors - genetics; Heart Failure - therapy; Heart Ventricles - metabolism; Liver - metabolism; Male; Mice; Mice, Inbred C57BL; Myocytes, Cardiac - metabolism; RNA, Messenger - biosynthesis; Sarcoplasmic Reticulum Calcium-Transporting ATPases - biosynthesis; Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics; Urocortins - blood; Urocortins - genetics; Urocortins - metabolism; Ventricular Function, Left - genetics
• ISSN: 1557-7422
• DOI: 10.1089/hum.2013.088

Urocortin-2 (UCn2) peptide infusion increases cardiac function in patients with heart failure, but chronic peptide infusion is cumbersome, costly, and provides only short-term benefits. Gene transfer would circumvent these shortcomings. Here we ask whether a single intravenous injection of adeno-associated virus type 8 encoding murine urocortin-2 (AAV8.UCn2) could provide long-term elevation in plasma UCn2 levels and increased left ventricular (LV) function. Normal mice received AAV8.UCn2 (5×10¹¹ genome copies, intravenous). Plasma UCn2 increased 15-fold 6 weeks and >11-fold 7 months after delivery. AAV8 DNA and UCn2 mRNA expression was persistent in LV and liver up to 7 months after a single intravenous injection of AAV8.UCn2. Physiological studies conducted both in situ and ex vivo showed increases in LV +dP/dt and in LV -dP/dt, findings that endured unchanged for 7 months. SERCA2a mRNA and protein expression was increased in LV samples and Ca²⁺ transient studies showed an increased rate of Ca²⁺ decline in cardiac myocytes from mice that had received UCn2 gene transfer. We conclude that a single intravenous injection of AAV8.UCn2 increases plasma UCn2 and increases LV systolic and diastolic function for at least 7 months. The simplicity of intravenous injection of a long-term expression vector encoding a gene with paracrine activity to increase cardiac function is a potentially attractive strategy in clinical settings. Future studies will determine the usefulness of this approach in the treatment of heart failure.