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Regenerative Therapy In Cardiac Failure And Pacing: CUPID’s Role 29 May 2013BCS Editorial By: Claire Brough As the population ages, cardiomyocyte and/or pacemaker cell failure is an increasing reality, with consequential growth in the prevalence of cardiac failure and conduction disorders. Through basic science research, our understanding of the cellular and molecular mechanisms involved has exposed targets for potential novel biological, cellular and genetic therapies. Cellular analysis of hearts post cardiac resynchronisation therapy has confirmed reversal in the heterogeneous regional action potential durations and mechano-energetics but also modification in b-adrenergic signalling, neuro-hormones, cytokines, and sarcoplasmic reticulum ATPase cardiac isoform expression (SERCA2a).1 This editorial will discuss the current status of regenerative gene therapy for heart failure, concentrating on SERCA2a gene replacement and conclude with the exciting potential for pacemaker cell restoration. Genetic Targets Cardiovascular gene therapy aims to modify gene function in a consistent dose-dependent manner, without arrhythmia development.2 In heart failure, multiple calcium handling defects produce impaired excitation-contraction-relaxation coupling and thus dominate the focus for treatment.3,4,5,6 Other targets are subject to on-going studies (Table 1).
Table 1: Gene targets6,7,8 Depolarisation opens L-type calcium channels on T-tubules and ryanodine linked SERCA2a channels, enabling calcium influx into the cytosol (Figure 1).8 SERCA2a extrudes 75% of cytoplasmic calcium into the sarcoplasmic reticulum during diastole but the reduced expression and activity in heart failure impedes sarcoplasmic reticulum calcium cycling, elevating end diastolic cytosolic calcium levels and delaying myocardial relaxation.2, 5 Figure 1: Cellular Ca2+ handling8 Animal models having confirmed overexpression of SERCA2a normalises intracellular calcium homeostasis, cellular energetics, lusitropic action, inotropic function and decreases ventricular arrhythmias, thus improving overall survival.9 This contrasts with the potential ventricular arrhythmia burden, energy wasting and poor survival associated with pharmacological inotropes.7, 9 Transferring Cardiovascular Genes To Cells i. Vectors Viral and non-viral agents have been utilised as the vehicles for gene transfer. Although non-viral vectors display exemplary safety and low immunogenicity profiles, the superior efficiency of gene transfer by viral vectors has led to their dominance in pre-clinical models (Table 2).6, 7, 8
Table 2: Common vectors in cardiovascular gene transfer2,7, 8 Neutralising antibodies to the adeno-associated viruses (AAV) however are prevalent, with titres >1 in 20 in 20% - 40% of the population (80% seropositive for AAV2, 50% AAV1, 40% AAV5, 30% AAV6).7, 10 The potential limitations for translating therapy into clinical practice was highlighted by pre-trial screening in CUPID phase 1, with nearly 50% of patients excluded secondary to antibody titres <1 in 4.11, 12 ii. Delivery Methods The simplest and least invasive method for gene delivery would be peripheral intravenous infusion, however until highly cardiotropic vectors are discovered, intravascular dilution and potential extracardiac tissue uptake precludes this. Site specific delivery methods involve intracoronary (antegrade or retrograde), intrapericardial and intramyocardial approaches (Table 3).8
Table 3: Delivery method advantages and disadvantages2, 7, 8 Intracoronary antegrade delivery is the safest method, but rapid coronary artery flow and short endothelial exposure times yield low myocardial transduction (Figure 2).8 Permeability agents to assist gene transfer across the endothelium have been considered (nitroglycerine, serotonin, bradykinin, histamine, substance P, vascular endothelial growth factor) and slow intracoronary infusion of the gene-vector mix, rather than bolus administration.
Method A - Balloon inflation blocking the coronary artery, viral injection downstream (poorly tolerated with flow limiting stenoses) Method B - No balloon inflation Method C - Closed loop perfusion (coronary artery – sinus)
Figure 2: Intracoronary antegrade delivery approaches8 Clinical Trials Calcium Up-regulation by Percutaneous administration of gene therapy in Cardiac Disease (CUPID) was the first in man trial confirming the safety and biological effect of SERCA2a transfer by AAV1 vector.11, 12 Phase 1 recruited 9 patients with NYHA class III or IV heart failure, on stable outpatient therapy, with an ejection fraction <30%, VO2 max <16ml/kg/min and an ICD in situ. A single, antegrade epicardial intracoronary infusion over 10 minutes without balloon occlusion was performed, with three patients in each of the following dose cohorts; cohort 1 dose 1.4x1011, cohort 2 dose 6x1011 or cohort 3 dose 3x1012. Some centres routinely administered nitroglycerine to prevent vasospasm.11, 12 Routine heart failure outcome measures were evaluated at 6 months. 5 patients demonstrated symptomatic improvement (NYHA, Minnesota Living with Heart Failure Questionnaire) and left ventricular remodelling (ejection fraction, end systolic volume). 4 patients gained functional benefit (6 minute walk, VO2 max). 2 patients failed to demonstrate improvement but they had developed neutralising antibodies to AAV1.11, 12 Phase 2 involved a randomised double-blind, placebo-controlled, dose ranging, feasibility study, randomising 39 patients (Figure 3). Minor inclusion criteria modifications were made following phase 1 (ejection fraction <35%, VO2 max <20ml/mg/min, neutralising AAV1 antibody titre <1:2) and nitroglycerine administration prior to vector delivery was standardised, after ovine models demonstrated improved gene transduction. 11 Figure 3: Phase 2 study protocol11 Follow-up occurred over 12 months, with telephone consultations to 2 years. The high dose group (1x1013) demonstrated individual and group success (Figure 4), with an 88% major cardiovascular event risk reduction and mean hospitalised duration reduction (0.4 days v. 4.5 days), compared to placebo. 11 Figure 4: Outcome results11 Following CUPID, further trials received ethical approval and are currently recruiting (Table 4).
Table 4: Current enrolling trials7 Proof of concept models with gene therapy have also been established for the creation of cells with pacing capabilities.13, 14, 15 The hyperpolarisation activated cyclic nucleotide gated pacemaker gene family (HCN) have held the principal attention, meeting optimal outcome measures defined to reflect normal physiology (basal heart rate 60-90bpm, autonomic responsiveness, low/absent back-up pacing). 70% biological pacing, with catecholamine responsiveness, has been confirmed following adenovirus-HCN2 injection into a canine model with complete heart block.15 However, evidence regarding the longevity of their pacing ability and absence of both pro-arrhythmia and cell migration, will determine the future trajectory.15 Conclusion The prospect of regenerative therapy application to cardiovascular disease can be contemplated with optimism; SERCA2a gene therapy demonstrating reversal of cardiac failure in human trials and proof of concept models established for biological pacemakers. However, contemporary trials are small and only when large clinical trials with longitudinal assessment demonstrate sustained and consistent transgene expression, will gene therapy be amiably embraced among the armament against failing cardiac physiology. 1. Cho H, Barth AS, Tomaselli GF. Basic Science for the Clinical Electrophysiologist Basic Science of Cardiac Resynchronization Therapy Molecular and Electrophysiological Mechanisms. Circulation: Arrhythmia and Electrophysiology 2012;5:594-603. 2. Lipskaia L, Chemaly ER, Hadri L, Lompre A-M, Hajjar RJ. Sarcoplasmic reticulum Ca2+ ATPase as a therapeutic target for heart failure. Expert Opin Biol Ther 2010 January;10(1):29–41. 3. Lipskaia L, Ly H, Kawase Y, Hajjar RJ, Lompre A-M. Treatment of heart failure by calcium cycling gene therapy. Future Cardiology 2007;3(4):413–23. 4. Del Monte F, Hajjar RJ. Intracellular devastation in heart failure. Heart Fail Rev 2008 Jun;13(2):151–62. 5. Kawase Y, Hajjar RJ. The cardiac sarcoplasmic/endoplasmic reticulum calcium ATPase: a potent target for cardiovascular diseases. Nat Clin Pract Cardiovasc Med 2008 Sep;5(9):554–65. 6. Kairouz V, Lipskaia L, Hajjar RJ, Chemaly ER. Molecular targets in heart failure gene therapy: current controversies and translational perspectives. Ann N Y Acad Sci 2012 April:1254:42-50. 7. Kawase Y, Ladage D, Hajjar RJ. Rescuing the Failing Heart by Targeted Gene Transfer. JACC 2011 March 8;57(10):1169-1180. 8. Tilemann L, Ishikawa K, Weber T, Hajjar RJ. Gene Therapy for Heart Failure. Circulation Research 2012;110:777-793. 9. Lyon AR, Bannister ML, Collins T, Pearce E, Sepehripour AH, Dubb SS et al. SERCA2a gene transfer decreases SR calcium leak and reduces ventricular arrhythmias in a model of chronic heart failure. Circ Arrhythm Electrophysiol 2011 June1;4(3):362-372. 10. Calcedo R, Vandenberghe LH, Gao G, Lin J, Wilson JM. Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J Infect Dis 2009;199:381–390. 11. Jessup M, Greenberg B, Mancini D, Cappola T, Pauly DF, Jaski B et al. Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) A Phase 2 Trial of Intracoronary Gene Therapy of Sarcoplasmic Reticulum Ca2+-ATPase in Patients With Advanced Heart Failure. Circ 2011:124;304-313. 12. Jaski BE, Jessup ML, Mancini DM, Cappola TP, Pauly DF, Greenberg B et al. Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID Trial), a First-in-Human Phase ˝ Clinical Trial. J Card Fail 2009 April;15(3):171-181. 13. Rosen MR, Brink PR, Cohen IS, Robinson RB. Cardiac Pacing From Biological to Electronic…..to Biological? Circ Arrhythmia Electrophysiol 2008:1;54-61. 14. Li RA. Gene- and cell-based bio-artifical pacemaker: what basic and translational lessons have we learnt? Gene ther 2012 June:19(6):588-595. 15. Boink GJJ, Duan L, Nearing BD, Shlapakova IN, Sosunov EA, Anyukhovsky EA et al. HCN2/SkM1 Gene transfer Into Canine Left Bundle Branch Induces Stable, Autonomically Responsive Biological Pacing at Physiological Heart Rates. JACC 2013;61:1192-201. Number of hits: 12403 Add Comments |
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