Though numerous advances have been made, heart failure remains one of the leading causes of death in the modern world (Kalyanasundaram & Periasamy, 2008). This struggle to defeat heart failure has made researchers desperate to find a solution that can prolong people’s lives and reverse the myocardial damage that this disease causes. In the past, gene therapy was not a viable candidate for the treatment of heart failure because of the nature of myocardial cells. They rarely divide unless there is substantial tissue damage, and this meant that many older vectors for gene therapy could not target heart cells. However, recent advancements in gene transfer technology and gene therapy vectors have turned cardiovascular gene therapy into a scientific
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A breakdown in the proteins that regulate the concentration of Ca2+ ions in the heart is often seen in patients who suffer from heart failure. In particular, one of the most important regulators of Ca2+ ion concentration in the heart is sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA). The dominant form of this gene in myocardial tissue is SERCA2a, and it is responsible for removing around 75% of the Ca2+ ions from the cytosol of muscle cells in the heart. SERCA2a acts like a pump that sits on the edge of the sarcoplasmic reticulum and protrudes out into the cytoplasm of the cell (Hajjar & Njeim, 2010). The sarcoplasmic reticulum (SR) is an organelle that is unique to muscle cells. Its primary purpose is the storage, release, and reuptake of Ca2+ ions from the cell’s cytosol, and this in turn provides the basis for muscular contraction and relaxation. SERCA2a pumps are responsible for the reuptake of Ca2+ ions from the cytosol back up into the SR (Dirksen & Rossi, 2006). A breakdown in the SERCA2a is a grave problem and a substantial contributor to the onset of heart failure. Once the SERCA2a can no longer function properly, the heart will begin to lose the ability to contract and relax effectively because the concentration of Ca2+ ions in …show more content…
These vectors contain a 4.7 kilobase DNA genome, and they are created by inserting the desired gene along with promoters and helper genes into the virus where the viral DNA would normally be found. Once the AAV reaches a target cell, the virus synthesizes a second strand of DNA to be paired with the first, and it deposits its DNA into the target cell. However, the AAV vector is not capable of site-selective genomic integration. Instead, it creates circles of DNA that exist outside of the chromosome of the target cell, and they are slowly integrated into the genome over time (Chalberg, Kotterman, & Schaffer, 2015). This method of SERCA2a gene therapy has been through a phase I/II clinical trial in patients with advanced heart failure. Thirty-nine patients participated in the trial, and they were randomly given one of three doses of AAV1/SERCA2a particles. The doses were given through an intracoronary infusion, and the effects that the therapy had on the patients were tracked over a three year period. The trial found that negative cardiovascular events occurred the most in the placebo group, often but delayed in the two low dose groups, and much less often in the high dosage group. A negative cardiovascular event was defined as anything that negatively affected the health of the heart including worsening heart failure, cardiac transplantation, and death. Additionally, the
A breakdown in the proteins that regulate the concentration of Ca2+ ions in the heart is often seen in patients who suffer from heart failure. In particular, one of the most important regulators of Ca2+ ion concentration in the heart is sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA). The dominant form of this gene in myocardial tissue is SERCA2a, and it is responsible for removing around 75% of the Ca2+ ions from the cytosol of muscle cells in the heart. SERCA2a acts like a pump that sits on the edge of the sarcoplasmic reticulum and protrudes out into the cytoplasm of the cell (Hajjar & Njeim, 2010). The sarcoplasmic reticulum (SR) is an organelle that is unique to muscle cells. Its primary purpose is the storage, release, and reuptake of Ca2+ ions from the cell’s cytosol, and this in turn provides the basis for muscular contraction and relaxation. SERCA2a pumps are responsible for the reuptake of Ca2+ ions from the cytosol back up into the SR (Dirksen & Rossi, 2006). A breakdown in the SERCA2a is a grave problem and a substantial contributor to the onset of heart failure. Once the SERCA2a can no longer function properly, the heart will begin to lose the ability to contract and relax effectively because the concentration of Ca2+ ions in …show more content…
These vectors contain a 4.7 kilobase DNA genome, and they are created by inserting the desired gene along with promoters and helper genes into the virus where the viral DNA would normally be found. Once the AAV reaches a target cell, the virus synthesizes a second strand of DNA to be paired with the first, and it deposits its DNA into the target cell. However, the AAV vector is not capable of site-selective genomic integration. Instead, it creates circles of DNA that exist outside of the chromosome of the target cell, and they are slowly integrated into the genome over time (Chalberg, Kotterman, & Schaffer, 2015). This method of SERCA2a gene therapy has been through a phase I/II clinical trial in patients with advanced heart failure. Thirty-nine patients participated in the trial, and they were randomly given one of three doses of AAV1/SERCA2a particles. The doses were given through an intracoronary infusion, and the effects that the therapy had on the patients were tracked over a three year period. The trial found that negative cardiovascular events occurred the most in the placebo group, often but delayed in the two low dose groups, and much less often in the high dosage group. A negative cardiovascular event was defined as anything that negatively affected the health of the heart including worsening heart failure, cardiac transplantation, and death. Additionally, the