Gene therapy for heart failure Barry Greenberg, MD  Journal of Cardiology  Volume 66, Issue 3, Pages 195-200 (September 2015) DOI: 10.1016/j.jjcc.2015.02.006 Copyright © 2015 Japanese College of Cardiology Terms and Conditions

Fig. 1 Structure of the adeno-associated virus (AAV)1/sarco(endo)plasmic reticulum Ca2+ATPase (SERCA2a) vector used in the Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) studies. The AAV1/SERCA2a vector only incorporates inverted terminal repeats (ITRs) from AAV2 serotype, resulting in <300 nucleotides of the wild-type AAV sequences in the vector genome. The single-stranded DNA is encapsulated in the AAV serotype 1 icosahedral capsid. The SERCA2a expression cassette contains the following components: the cytomegalovirus immediate early enhancer/promoter (CMVie) driving transcription of sequences including a hybrid intron from the commercial plasmid pCI, the huSERCA2a cDNA, and a bovine growth hormone polyadenylation signal (BGHpA). Reproduced with permission from Greenberg et al. [38]. Journal of Cardiology 2015 66, 195-200DOI: (10.1016/j.jjcc.2015.02.006) Copyright © 2015 Japanese College of Cardiology Terms and Conditions

Fig. 2 Summary of the changes in heart failure domains seen after treatment with adeno-associated virus (AAV)1/sarco(endo)plasmic reticulum Ca2+ATPase (SERCA2a) or placebo. Patients treated with placebo demonstrated evidence of worsening over the 12-month follow-up period. In contrast, the clinical course of patients who received high-dose AAV1/SERCA2a therapy appears to have stabilized or improved. NT-proBNP, N-terminal pro-B-type natriuretic peptide. Reproduced with permission from Jessup et al. [35]. Journal of Cardiology 2015 66, 195-200DOI: (10.1016/j.jjcc.2015.02.006) Copyright © 2015 Japanese College of Cardiology Terms and Conditions

Fig. 3 Cardiovascular and Terminal Events in Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease phase 2. This figure represents the clinical course for study patients starting from the date of infusion of AAV1/SERCA2a or placebo; each line represents a single patient. A star at the beginning of a line represents a patient with anti-AAV1 NAb titer that was <1:2 during screening but ≥1:2 at baseline. AAV1/SERCA2a, recombinant adeno-associated viral vector (AAV) containing human sarcoplasmic reticulum Ca2+ATPase 2a (SERCA2a) gene; LVAD, left ventricular assist device; MI, myocardial infarction; NAb+, positive for anti-AAV1 neutralizing antibody (NAb) at baseline; WHF, worsening heart failure. Reproduced with permission from Greenberg et al. [38]. Journal of Cardiology 2015 66, 195-200DOI: (10.1016/j.jjcc.2015.02.006) Copyright © 2015 Japanese College of Cardiology Terms and Conditions