Disclosed are methods of treating a subject, such as those having or at risk of cardiomyopathies, with an effective amount of a recombinant adeno-associated virus (rAAV) virion, the rAAV virion comprising an AAV capsid and an expression cassette comprising a polynucleotide encoding a DWORF polypeptide operatively linked to a promoter. Compositions and kits relating to the same are also disclosed.

Bag3 is a multifunctional protein expressed predominantly in the heart, the skeletal muscle, the central nervous system and in many cancers. Although BAG3 was cloned only a decade ago, studies have shown that genetic variants, particularly those that result in haplo-insufficiency, can lead to severe left ventricular dysfunction; however, the full mechanisms responsible have remained obscure. To obviate the influence of heart failure itself on the biology of Bag3, ransgenic mice harboring a single allele knock-out were studied between 8 and 10 weeks of age before any obvious signs of heart failure were evident. The results were surprising and informative. First, it was found that despite a normal phenotype, young Bag3.sup.+/− had marked changes in the proteome that were characterized by changes in proteins associated with metabolism and apoptosis. Consistent with this finding, a decrease in the levels of critical proteins charged with maintaining the mitochondrial membrane potential was observed. It was also found that young mice shifted from a balance between the extrinsic and intrinsic pathways of apoptosis. However, in the presence of stress and the absence of Bag3 there was a shift from a balanced to an extrinsic dominant system (cleaved caspase 8). The diverse array of critical pathways regulated by Bag3 suggests a more important role especially during stress and that this role might include serving as an intracellular glue that holds proteins where they can be most effective rather than having them meet accidentally.

A modality for preventing or treating fibrotic diseases by identifying a marker protein for myofibroblasts is provided.

The present invention relates to prophylactic or therapeutic agents for fibrotic diseases, which contain an inhibitor of GPR176 as an active ingredient.

A pharmaceutical composition suitable for preventing or treating cardiac arrhythmia is disclosed. The pharmaceutical composition contains, as an active ingredient, a CCN5 protein or a nucleotide encoding the CCN5 protein. The pharmaceutical composition inhibits the pathological activity of CaMKII, which induces cardiac electrical abnormalities that is the main cause of atrial arrhythmia and ventricular arrhythmia, so as to restore the electrical functions, and inhibits the activity of myofibroblasts causing structural abnormalities. Therefore, the pharmaceutical composition can be effectively used in the prevention or treatment of cardiac arrhythmia.

In alternative embodiments, provided are compositions, including products of manufacture and kits, and methods, for treating a heart failure in a subject in need thereof comprising administering to the subject an isolated or recombinant nucleic acid, an isolated or recombinant or chimeric polypeptide, or an engineered cell, as provided herein, thereby treating the subject. In alternative embodiments, the administration reduces left ventricular (LV) hypertrophy, increases LV peak pressure development, reduced cAMP production and/or improves LV peak pressure decay in a pressure-overload in the subject. In alternative embodiments, provided are compositions and methods for: treating, ameliorating, or slowing the progress of, or protecting (preventing) an individual or a patient against heart failure; or, reducing LV hypertrophy, increasing LV peak pressure development, and/or improving LV peak pressure decay in a pressure-overload in an individual in need thereof.

The present disclosure provides methods and compositions useful for the treatment or prevention of heart disease. In particular, the present disclosure provides a vector comprising a modified troponin promoter operatively linked to a therapeutic gene product for the treatment or prevention of heart disease, e.g., cardiomyopathy. The gene product may be MYBPC3. The disclosure also provides recombinant adeno-associated virus (rAAV) virions, rAAV viral genomes, and expression cassettes and pharmaceutical compositions thereof. The disclosure further provides methods for treating a disease or disorder, such as heart disease.

The present invention provides NRP1 as a cell surface marker for isolating human cardiomyogenic ventricular progenitor cells (HVPs), in particular progenitor cells that preferentially differentiate into cardiac ventricular muscle cells. Additional HVP cell surface markers identified by single cell sequencing are also provided. The invention provides in vitro methods of the separation of NRP1+ ventricular progenitor cells, and the large scale expansion and propagation thereof. Large clonal populations of isolated NRP1+ ventricular progenitor cells are also provided. Methods of in vivo use of NRP1+ ventricular progenitor cells for cardiac repair or to improve cardiac function are also provided. Methods of using the NRP1+ ventricular progenitor cells for cardiac toxicity screening of test compounds are also provided.

The present invention relates to a polynucleotide comprising an expressible nucleic acid sequence encoding a relaxin family peptide receptor (RXFP) polypeptide for use in treatment and/or prevention of heart failure in a subject. The present invention further relates to a vector comprising the polynucleotide of the present invention for use in treatment and/or prevention of heart failure, as well as to host cells, RXFP agonists, kits and devices related thereto.

The present disclosure provides methods and compositions useful for the treatment or prevention of heart disease. In particular, the present disclosure provides a vector comprising a modified troponin T promoter operatively linked to a therapeutic gene product for the treatment or prevention of heart disease, e.g., cardiomyopathy. The gene product may be MYBPC3. The disclosure also provides recombinant adeno-associated virus (rAAV) virions, rAAV viral genomes, and expression cassettes and pharmaceutical compositions thereof. The disclosure further provides methods for treating a disease or disorder, such as heart disease.

Expression of a phosphatase inhibitor in heart cells can be used to treat cardiac disorders, e.g., heart failure. Decreasing phosphatase activity can improve β-adrenergic responsiveness.