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Additional treatments are urgently needed to help improve survival and quality of life in patients with advanced heart failure since polypharmacy is reaching a natural limit. Cell therapy is an attractive proposition, but present autologous therapies such as bone marrow-derived stem cells do not appear to create new myocardial muscle in appreciable quantities. An alternative is to produce more power from the remaining myocytes. Early studies in the laboratories of Harding and Hajjar showed that even the apparently undamaged myocardium/myocytes from failing human heart were performing sub-optimally, implying that stimulation could potentially retrieve useful power. World-wide efforts identified the underlying mechanism as a defect in Ca2+ handling in the myocyte, with changes in the sarcoplasmic reticulum (SR) stores and loss of SERCA2a (the SR Ca2+-ATPase) among the key factors. Inotropic support was attempted, but the use of beta-agonists or phosphodiesterase inhibitors gave short term improvement at the price of accelerated mortality. Inotropes fell from favour for heart failure, until we and others showed that it was possible to restore the integrity of the SR Ca2+ storage and so reverse the deterioration of contractility, without long-term damage. One important piece of evidence that recovery of function is possible in heart failure patients is that resting the ventricular myocardium results in improvement in myocyte function; a subset of patients can be weaned from LVAD support because of marked improvement in muscle performance and those patients in which recovery is observed are the ones with improved SR calcium stores. This implies that contractile dysfunction is reversible to a functionally relevant degree. The UK SERCA2a Gene therapy trial is a randomised placebo controlled trial to investigate the safety and feasibility of raising myocardial SERCA2a levels, using an adeno-associated viral vector, in heart failure patients that have undergone left ventricular device implantation (LVAD). The ultimate clinical goal is to treat all heart failure patients (not only those receiving LVAD support), in order to improve cardiac contraction and relaxation and so provide symptomatic benefit and extension of life. The choice of gene therapy over small molecule stimulation of SERCA2a or inhibition of phospholamban has been driven by the lack of success of drug discovery programmes to identify a suitable candidate. The vector will be rAAV, which has been shown to produce long term stable expression, from months to years, in large animals. AAV vectors of various serotypes have been used in studies of >400 patients, and are agents in more than 50 currently registered clinical trials: AAV2 is most commonly used. AAV6-CMV-SERCA2a will be infused percutaneously into the right and left coronary arteries in patients with advanced heart failure who are clinically stable after implantation of LVADs. The advantage of this patient population is that they are protected from the major potential cardiac risks, arrhythmias and deterioration of function, by the presence of the LVAD. Additionally, there is the potential to obtain some surrogate measures of efficacy even from a small patient population. Tissue is routinely taken during the LVAD implantation procedures, and comparative samples can be obtained either when the patient receives a heart transplant, or when the pump is explanted. This gives the potential for determining efficacy of viral transfection and other functional parameters. A parallel US Trial, CUPID, is being run by Celladon at a number of hospitals within the US. It uses AAV1 instead of AAV6 to deliver CMV-SERCA2a, again using the percutaneous route. Patients have a similar demographic to the UK trial, but are not being supported on LVADs. It has reported 6-12 month follow-up for 9 patients in 3 out of 4 sections of the Phase 1 dose-ranging study. On the basis of the results from this, the Phase 2 placebo controlled arm has been allowed to proceed, and 50 patients treated in total. Results from the US trial will be known in late 2010, and from the UK trial in 2011. |