Design of a phase 1/2 trial of intracoronary administration of AAV1/SERCA2a in patients with heart failure.
BACKGROUND
Heart failure (HF) remains a major cause of morbidity and mortality in North America. With an aging population and an unmet clinical need by current pharmacologic and device-related therapeutic strategies, novel treatment options for HF are being explored. One such promising strategy is gene therapy to target underlying molecular anomalies in the dysfunctional cardiomyocyte. Prior animal and human studies have documented decreased expression of SERCA2a, a major cardiac calcium cycling protein, as a major defect found in HF.


RESULTS
We hypothesize that increasing the activity of SERCA2a in patients with moderate to severe HF will improve their cardiac function, disease status, and quality of life. Gene transfer of SERCA2a will be performed via an adeno-associated viral (AAV) vector, derived from a nonpathogenic virus with long-term transgene expression as well as a clinically established favorable safety profile.


CONCLUSIONS
We describe the design of a phase 1 clinical trial of antegrade epicardial coronary artery infusion (AECAI) administration of AAVI/SERCA2a (MYDICAR) to subjects with HF divided into 2 stages: in Stage 1, subjects will be assigned open-label MYDICAR in one of up to 4 sequential dose escalation cohorts; in Stage 2, subjects will be randomized in parallel to 2 or 3 doses of MYDICAR or placebo in a double-blinded manner.
Mount Sinai School of Medicine, New York, New York 10029, USA.
Roger J
RJ
Hajjar
Krisztina
K
Zsebo
Lawrence
L
Deckelbaum
Craig
C
Thompson
Jeff
J
Rudy
Alex
A
Yaroshinsky
Hung
H
Ly
Yoshiaki
Y
Kawase
Kim
K
Wagner
Kenneth
K
Borow
Brian
B
Jaski
Barry
B
London
Barry
B
Greenberg
Daniel F
DF
Pauly
Richard
R
Patten
Randall
R
Starling
Donna
D
Mancini
Mariell
M
Jessup
D000293:Adolescent; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D003131:Combined Modality Therapy; D003331:Coronary Vessels; D000229:Dependovirus; D004232:Diuretics / Q000627:therapeutic use; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D006333:Heart Failure / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011945:Receptors, Angiotensin / Q000819:agonists; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D014161:Transduction, Genetic / Q000379:methods*; D019076:Transgenes
D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D004232:Diuretics; D011945:Receptors, Angiotensin; D049452:Green Fluorescent Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases