Cycle adenosine monophosphate-incompetent adenylyl cyclase and compositions and methods for treating heart failure and increasing cardiac function

A method for:

• (1) treating a subject having or at risk of having a heart disease or a heart failure;
• (2) treating, ameliorating, reversing the effects of, protecting or preventing an individual or a patient against:
• a heart disease,
• a heart failure,
• a decrease in heart function or cardiac output,
• a decrease in heart function or cardiac output due to a heart infection or a heart condition,
• (3) enhancing calcium handling in intact cardiac myocytes by increasing sarcoplasmic reticulum (SR) Ca2+ uptake and/or increased Ca2+ transients with reduced time of relaxation in intact cardiac myocytes,
• (4) inhibiting the generation of intracellular cAMP levels in cardiac myocytes,
• (5) protecting a cardiac myocyte from a programmed cell death (apoptosis) signal, or decreasing the number of cardiac myocytes signaled to programmed cell death (apoptosis) subsequent to an apoptotic signal, or
• (6) in heart failure patients or in individuals having a heart infection or a heart condition resulting in a decrease in heart function or cardiac output:
• increasing heart function or cardiac output, reducing symptom and/or decreasing mortality;
• or reducing the frequency of hospitalizations for heart failure,
• comprising:
• (a) providing:
• (i) a cyclic adenosine monophosphate-incompetent (cAMP-incompetent) adenylyl cyclase type 6 (AC6) protein or polypeptide (also called “an AC6mut”),
• wherein optionally the AC6mut is a recombinant, a synthetic, a peptidomimetic or an isolated AC6mut polypeptide or peptide;
• or
• (ii) a AC6mut-encoding nucleic acid or gene:
• wherein optionally the AC6mut-encoding nucleic acid or gene is operatively linked to a transcriptional regulatory sequence, wherein optionally the transcriptional regulatory sequence is a promoter and/or an enhancer, or a cardiac cell-specific promoter or a myocyte-specific promoter;
• or
• wherein optionally the AC6mut-encoding nucleic acid or gene is operatively linked to a transcriptional regulatory sequence, and optionally the AC6mut-encoding nucleic acid or gene is contained in a delivery vehicle, a vector, an expression vector, a recombinant virus, or an equivalent, and the delivery vehicle, expression vehicle, vector, recombinant virus, or equivalent can express the AC6mut-encoding nucleic acid or gene in a cell or in vivo,
• wherein optionally the cell is a cardiac cell or a myocyte;
• wherein the AC6mut does not catalyze the breakdown of ATP to cAMP, or has impaired ability to catalyze the breakdown of ATP to cAMP, and optionally the impaired ability to catalyze the breakdown of ATP to cAMP is defined as the AC6mut having only about 1%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% of the ATP to cAMP catalytic activity of wild type AC6,
• and when the AC6mut is expressed in a cardiac myocyte in vivo left ventricular (LV) function is not affected or does not decrease or LV function is substantially not affected or decreased,
• and optionally AC6mut expression in a cardiac myocyte increases sarcoplasmic reticulum Ca2+ uptake,
• and optionally AC6mut expression in a cardiac myocyte reduces the EC50 for SERCA2a activation,
• and optionally AC6mut expression in a cardiac myocyte reduces expression of a phospholamban protein,
• optionally the substitution inhibits Mg2+ binding and alters the efficiency of Gsα-mediated activation of the catalytic core;
• (b) delivering or administering the AC6mut, or the AC6mut-encoding nucleic acid or gene, to a cardiac cell or a cardiac myocyte, or expressing the AC6mut in a cardiac cell or a cardiac myocyte, or expressing the AC6mut-encoding nucleic acid or gene in a cardiac cell or a cardiac myocyte,
• wherein optionally the AC6mut-encoding nucleic acid is operatively linked to a transcriptional regulatory sequence, or optionally the delivery vehicle, vector, expression vector, recombinant virus, or equivalent, is delivered or administered to a cardiac myocyte cell, or to an individual or a patient in need thereof,
• and optionally the delivering or administering of the AC6mut-encoding nucleic acid or gene to the cardiac cell or myocyte in vivo is a targeted delivery to a heart muscle or a cardiac myocyte, or comprises direct delivery or administration to a heart, or comprises an intracardiac injection or an infusion,
• thereby:
• treating the subject having or at risk of having a heart disease or a heart failure,
• treating, ameliorating or protecting (preventing) an individual or a patient against a heart disease, a heart failure, a decrease in heart function or cardiac output, a decrease in heart function or cardiac output due to a heart infection or a heart condition,
• enhancing calcium handling in intact cardiac myocytes by increasing sarcoplasmic reticulum (SR) Ca2+ uptake and/or increased Ca2+ transients with reduced time of relaxation in intact cardiac myocytes,
• inhibiting the generation of intracellular cAMP levels in cardiac myocytes,
• protecting a cardiac myocyte from a programmed cell death (apoptosis) signal, or decreasing the number of cardiac myocytes signaled to programmed cell death (apoptosis) subsequent to an apoptotic signal, or
• in heart failure patients or in individuals having a heart infection or a heart condition resulting in a decrease in heart function or cardiac output:
• increasing heart function or cardiac output, reducing symptom and/or decreasing mortality.