Mydicar

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Mydicar

Mydicar is a genetically targeted enzyme replacement therapy being studied for use in patients with severe heart failure. It is designed to increase the level of SERCA2a, a sarcoplasmic endoplasmic reticulum calcium (Ca2+) ATPase found in the membrane of the sarcoplasmic reticulum (SR). The SERCA2a gene is delivered to the heart via an adeno-associated viral vector. [1] Using the α-myosin heavy chain gene promoter in the cardiac muscle cells, also called cardiomyocytes, Mydicar is able to direct the gene expression only to the heart muscle. [2] Mydicar is being tested[ when? ] in a phase 2 study, in which has been compared to a placebo in 39 advanced heart failure patients. [3] Thus far, patients treated with Mydicar have shown a 52% reduction in the risk of worsening heart failure compared to patients treated with the placebo. [3]

Contents

The role of SERCA2a in the heart

Normal function of the heart involves proper coordination between the contraction and relaxation of cardiomyocytes. Proper contraction and relaxation depends on the coordinated rise and fall of Ca2+ in the cytosol of the cardiomyocytes. [4] The SERCA2a transporter is found in the membrane of the SR and plays an important role in this cycle by removing cytosolic Ca2+ from the cardiomyocyte and pumping it back into the SR during relaxation of the heart (diastole). SERCA2a restores SR Ca2+ for the next contraction of cardiomyocytes. [5] SERCA2a activity declines in patients experiencing late-stage heart failure. [1] This leads to an above normal amount of cytosolic Ca2+ in the cardiomyocytes during diastole. It also results in less Ca2+ remaining in the SR for the next contraction of the heart. The altered cycling of Ca2+ in cardiomyocytes ultimately leads to improper functioning of the heart, indicating a potentially beneficial effect of gene therapy using Mydicar. [1]

Benefits

Administration of Mydicar occurs via an intracoronary injection of the drug. Mydicar delivers the SERCA2a gene to cardiomyocytes using an adeno-associated viral-vector (AAV). [6] In the cardiomyocytes, the viral vector can insert itself into the genome and increase expression of the SERCA2a protein. Delivering the gene via an AAV is beneficial because it readily infects cardiac tissue and can produce stable, long-term expression of the delivered gene. [7] AAVs also produce less of an immune response than alternative viral vehicles, such as adenoviruses. [7] AAVs have been studied in multiple patients and have not been known to cause human disease. [5]

The importance of calcium reuptake

Proper relaxation of the heart in preparation for the next contraction depends largely on the decline of Ca2+ in the cytosol of cardiomyocytes during diastole. Along with impaired contractility, an increased level of cytosolic Ca2+ increases the risk of arrhythmias and remodeling of the heart. [8] Excess Ca2+ found in the cytosol leads to asynchronous contractions of cardiomyocytes causing tachyarrhythmias. The unusual increase in contraction and faster beating of the heart leads to hypertrophy by increasing the size of the cardiac myocytes in the heart. Excess hypertrophy of the cardiac myocytes leads to further dysfunction of the heart by affecting their ability to relax and contract properly. [5] Administration of Mydicar increasing functioning SERCA2a can assist in lessening these negative effects of an increase in cytosolic Ca2+ during diastole by increasing reuptake into the SR.[ citation needed ]

Related Research Articles

Sarcoplasmic reticulum

The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other cells. The main function of the SR is to store calcium ions (Ca2+). Calcium ion levels are kept relatively constant, with the concentration of calcium ions within a cell being 10,000 times smaller than the concentration of calcium ions outside the cell. This means that small increases in calcium ions within the cell are easily detected and can bring about important cellular changes (the calcium is said to be a second messenger; see calcium in biology for more details). Calcium is used to make calcium carbonate (found in chalk) and calcium phosphate, two compounds that the body uses to make teeth and bones. This means that too much calcium within the cells can lead to hardening (calcification) of certain intracellular structures, including the mitochondria, leading to cell death. Therefore, it is vital that calcium ion levels are controlled tightly, and can be released into the cell when necessary and then removed from the cell.

SERCA, or sarco/endoplasmic reticulum Ca2+-ATPase, or SR Ca2+-ATPase, is a calcium ATPase-type P-ATPase. Its major function is to transport calcium from the cytosol into the sarcoplasmic reticulum.

Muscle contraction Activation of tension-generating sites in muscle

Muscle contraction is the activation of tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in muscle length, such as when holding a heavy book or a dumbbell at the same position. The termination of muscle contraction is followed by muscle relaxation, which is a return of the muscle fibers to their low tension-generating state.

Phospholamban

Phospholamban, also known as PLN or PLB, is a micropeptide protein that in humans is encoded by the PLN gene. Phospholamban is a 52-amino acid integral membrane protein that regulates the calcium (Ca2+) pump in cardiac muscle cells.

Myocardial contractility represents the innate ability of the heart muscle (cardiac muscle or myocardium) to contract. The ability to produce changes in force during contraction result from incremental degrees of binding between different types of tissue, that is, between filaments of myosin (thick) and actin (thin) tissue. The degree of binding depends upon the concentration of calcium ions in the cell. Within an in vivo intact heart, the action/response of the sympathetic nervous system is driven by precisely timed releases of a catecholamine, which is a process that determines the concentration of calcium ions in the cytosol of cardiac muscle cells. The factors causing an increase in contractility work by causing an increase in intracellular calcium ions (Ca++) during contraction.

Amrinone

Amrinone, also known as inamrinone, and sold as Inocor, is a pyridine phosphodiesterase 3 inhibitor. It is a drug that may improve the prognosis in patients with congestive heart failure. Amrinone has been shown to increase the contractions initiated in the heart by high gain calcium induced calcium release (CICR). The positive inotropic effect of amrinone is mediated by the selective enhancement of high gain CICR which contributes to the contraction of myocytes by phosphorylation through cAMP dependent protein kinase A (PKA) and Ca2+ calmodulin kinase pathways.

Calcium ATPase

Ca2+ ATPase is a form of P-ATPase that transfers calcium after a muscle has contracted. The two kinds of calcium ATPase are:

The Bowditch effect, also known as the Treppe phenomenon and the Treppe effect, is an autoregulation method by which myocardial tension increases with an increase in heart rate. It was first observed by Henry Pickering Bowditch in 1871.

ATP2A2 is an ATPase associated with Darier's disease and Acrokeratosis verruciformis.

Lusitropy is the rate of myocardial relaxation. The increase in cytosolic calcium of cardiomyocytes via increased uptake leads to increased myocardial contractility, but the myocardial relaxation, or lusitropy, decreases. This should not be confused, however, with catecholamine-induced calcium uptake into the sarcoplasmic reticulum, which increases lusitropy.

S100A1

S100A1, also known as S100 calcium-binding protein A1 is a protein which in humans is encoded by the S100A1 gene. S100A1 is highly expressed in cardiac and skeletal muscle, and localizes to Z-discs and sarcoplasmic reticulum. S100A1 has shown promise as an effective candidate for gene therapy to treat post-myocardially infarcted cardiac tissue.

ATP2A1

Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 is an enzyme that in humans is encoded by the ATP2A1 gene.

ATP2A3

Sarcoplasmic/endoplasmic reticulum calcium ATPase 3 is an enzyme that in humans is encoded by the ATP2A3 gene.

Sarcolipin

Sarcolipin is a micropeptide protein that in humans is encoded by the SLN gene.

Brody myopathy Medical condition

Brody myopathy is a rare disorder that affects skeletal muscle function. BD was first characterized in 1969 by Dr. Irwin A. Brody at Duke University Medical Center. Individuals with BD have difficulty relaxing their muscles after exercise. This difficulty in relaxation leads to symptoms including cramps, stiffness, and discomfort in the muscles of the limbs and face. Symptoms are heightened by exercise and commonly progress in severity throughout adulthood.

JTV-519 (K201) is a 1,4-benzothiazepine derivative that interacts with many cellular targets. It has many structural similarities to diltiazem, a Ca2+ channel blocker used for treatment of hypertension, angina pectoris and some types of arrhythmias. JTV-519 acts in the sarcoplasmic reticulum (SR) of cardiac myocytes by binding to and stabilizing the ryanodine receptor (RyR2) in its closed state. It can be used in the treatment of cardiac arrhythmias, heart failure, catecholaminergic polymorphic ventricular tachycardia (CPVT) and store overload-induced Ca2+ release (SOICR). Currently, this drug has only been tested on animals and its side effects are still unknown. As research continues, some studies have also found a dose-dependent response; where there is no improvement seen in failing hearts at 0.3 μM and a decline in response at 1 μM.

CXL 1020 is an experimental drug that is being investigated as a treatment for acute decompensated heart failure. CXL 1020 functions as a nitroxyl donor; nitroxyl is the reduced, protonated version of nitric oxide. Nitroxyl is capable of enhancing left ventricular contractility without increasing heart rate by modifying normal Ca2+ cycling through the sarcoplasmic reticulum as well as increasing the sensitivity of cardiac myofilaments to Ca2+.

Istaroxime

Istaroxime is an investigational drug under development for treatment of acute decompensated heart failure

Calcium buffering describes the processes which help stabilise the concentration of free calcium ions within cells, in a similar manner to how pH buffers maintain a stable concentration of hydrogen ions. The majority of calcium ions within the cell are bound to intracellular proteins, leaving a minority freely dissociated. When calcium is added to or removed from the cytoplasm by transport across the cell membrane or sarcoplasmic reticulum, calcium buffers minimise the effect on changes in cytoplasmic free calcium concentration by binding calcium to or releasing calcium from intracellular proteins. As a result, 99% of the calcium added to the cytosol of a cardiomyocyte during each cardiac cycle becomes bound to calcium buffers, creating a relatively small change in free calcium.

ParvE101Q is an experimental modification of parvalbumin, designed to delay calcium sequestration in heart muscles to enhance contraction. The protein parvalbumin has EF hand motifs used for calcium binding. EF hands are structural helix-loop-helix protein subunits that have a high affinity for calcium ions, and a moderate affinity for magnesium ions. In muscle, the binding of Ca2+ by parvalbumin efficiently sequesters it following contraction. This increases the speed of muscle relaxation, allowing the muscle to contract again sooner. Although parvalbumin is classified as a delayed calcium buffer, it quickly sequesters Ca2+, usually before the muscle is done fully contracting. Large amounts of parvalbumin allow rapid contractions of muscles at a high contractile speed with the trade-off of having relatively lower contraction force. This decreased force of contraction is due to the rapid sequestration of Ca2+, preventing prolonged contraction which is required for greater force.

References

  1. 1 2 3 Jaski BE, Jessup ML, Mancini DM, Cappola TP, Pauly DF, Greenberg B, et al. (2010). "Calcium Upregulation by Percutaneous administration of gene therapy In cardiac Disease (CUPID Trial), a first-in-human phase 1/2 clinical trial". Journal of Cardiac Failure. 15(3):171-181.
  2. ↑ Baker DL, Hashimoto K, Grupp IL, Ji Y, Reed T, Loukianov E, et al. (1998). "Targeted overexpression of the sarcoplasmic reticulum Ca2+-ATPase increases cardiac contractility in transgenic mouse hearts". Circulation Research. 83:1205–1214.
  3. 1 2 Greenberg B, Jessup ML, Zsebo KM, Yaroshinsky A and Hajjar RJ. (2010). "CUPID 1: MYDICAR in patients with advanced heart failure continue to demonstrate improvement in clinical outcomes compared to optimal therapy 9 months post-dose". Journal of Cardiac Failure. 16(11): 911.
  4. ↑ del Monte F, Harding SE, Schmidt U, Matsui T, Bin Kang Z, Dec GW, et al. (1999). "Restoration of contractile function in isolated cardiomyocytes from failing human hearts by gene transfer of SERCA2a". Circulation. 100:2308–2311.
  5. 1 2 3 Lipskaia L, Chemaly ER, Hadri L, Lompre A, and Hajjar RJ. (2010). "Sarcoplasmic reticulum Ca2+ ATPase as a therapeutic target for heart failure" Expert Opinion on Biology Therapy. 10(1):29–41.
  6. ↑ Hajjar RJ, Zsebo K, Deckelbaum L, Thompson C, Rudy J, Yaroshinsky A, et al. (2008) "Design of a phase 1/2 trial of intracoronary administration of AAV1/SERCA2a in patients with heart failure". Journal of Cardiac Failure. 14:355–367.
  7. 1 2 Lewis MA, Cloutier DE, Pacak CA, Mah CS, Thattaliyath BD, Conlon TJ, et al. (2006). "Recombinant adeno-associated virus serotype 9 leads to preferential cardiac transduction in vivo". Circulation Research. 99:e3–e9.
  8. ↑ Meyer M, Schillinger W; Pieske B, Holubarsch C, Heilmann C, Posival H, et al. (1995). "Alterations of sarcoplasmic reticulum proteins in failing human dilated cardiomyopathy". Circulation. 92:778–784.
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