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Commentary: Can the new synthetic adeno-associated virus vector deliver the promise of cardiac gene therapy?

      Figure thumbnail fx1
      Ming Lau, MBBS, and Michael K. Y. Hsin, MD, FRCS CTh
      The new synthetic adeno-associated virus vector Anc80L65 has superior gene transfer efficiency over the adeno-associated virus 9 vector in rat hearts, but other obstacles remain.
      See Article page e429.
      Katz and colleagues
      • Katz M.G.
      • Hadas Y.
      • Bailey R.A.
      • Fazal S.
      • Vincek A.
      • Madjarova S.J.
      • et al.
      Efficient cardiac gene transfer and early-onset expression of a synthetic adeno-associated viral vector, Anc80L65, after intramyocardial administration.
      have reported the use of a synthetic adeno-associated virus (AAV) lineage clone, Anc80L65, and compared it with AAV9. They showed that transfer of reporter genes with Anc80L65 in rat cardiomyocytes and rat hearts was more efficient and robust than AAV9.
      • Katz M.G.
      • Hadas Y.
      • Bailey R.A.
      • Fazal S.
      • Vincek A.
      • Madjarova S.J.
      • et al.
      Efficient cardiac gene transfer and early-onset expression of a synthetic adeno-associated viral vector, Anc80L65, after intramyocardial administration.
      This was not associated with off-target transfection in other organs, lymphocyte or neutrophil activation, alteration in inflammatory cytokines, or disturbance of cardiac function. These findings are consistent with favorable reports of Anc80 in gene therapy in the retina and the central nervous system.
      • Carvalho L.
      • Xiao R.
      • Wassmer S.
      • Langsdorf A.
      • Zinn E.
      • Pacouret S.
      • et al.
      Synthetic adeno-associated viral vector efficiently targets mouse and nonhuman primate retina in vivo.
      ,
      • Hurdy E.
      • Andres-Mateos E.
      • Lerner E.
      • Volak A.
      • Cohen O.
      • Hyman B.T.
      • et al.
      Efficient gene transfer to the central nervous system by single-stranded Anc80L65.
      However, the optimal route of administration, whether intramyocardial or intracoronary, needs to be determined. Only a single vector dose was studied, and the optimal dosing and timing warrant further investigation.
      In the past 5 years, several gene therapy products received approval for clinical use.
      • High K.A.
      • Roncarolo M.G.
      Gene therapy.
      However, the goal of therapeutic gene therapy in the heart remains elusive. Studies of cardiac gene therapy have focused mostly on 2 areas: therapeutic angiogenesis for coronary artery disease where conventional revascularization is not feasible and heart failure.
      Notable examples of angiogenesis clinical trials include naked DNA plasmid encoding vascular endothelial growth factor A (VEGF-A) (EUROINJECT-1, NOGA Angiogenesis Revascularization Therapy: Assessment by Radiouclide Imaging [NORTHERN trial], Kuopio Angiogenesis Trial [KAT]),
      • Kastrup J.
      • Jørgensen E.
      • Rück A.
      • Tägil K.
      • Glogar D.
      • Ruzyllo W.
      • et al.
      Euroinject One Group
      Direct intramyocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable severe angina pectoris A randomized double-blind placebo-controlled study: the Euroinject One trial.
      • Stewart D.
      • Kutryk M.
      • Fitchett D.
      • Freeman M.
      • Camack N.
      • Su Y.
      • et al.
      VEGF gene therapy fails to improve perfusion of ischemic myocardium in patients with advanced coronary disease: results of the NORTHERN trial.
      • Hedman M.
      • Hartikainen J.
      • Syvänne M.
      • Stjernvall J.
      • Hedman A.
      • Kivelä A.
      • et al.
      Safety and feasibility of catheter-based local intracoronary vascular endothelial growth factor gene transfer in the prevention of postangioplasty and in-stent restenosis and in the treatment of chronic myocardial ischemia: phase II results of the Kuopio Angiogenesis Trial (KAT).
      or encoding both fibroblast growth factor (FGF)-2 and VEGF-A (Intramyocardial Plasmid-Encoding Human Vascular Endothelial Growth Factor A165/Basic Fibroblast Growth Factor Therapy Using Percutaneous Transcatheter Approach in Patients With Refractory Coronary Artery Disease [VIF-CAD])
      • Kukuła K.
      • Chojnowska L.
      • Dąbrowski M.
      • Witkowski A.
      • Chmielak Z.
      • Skwarek M.
      • et al.
      Intramyocardial plasmid-encoding human vascular endothelial growth factor A165/basic fibroblast growth factor therapy using percutaneous transcatheter approach in patients with refractory coronary artery disease (VIF-CAD).
      ; adenoviral vectors with cDNA expressing VEGF-A (Randomized Evaluation of VEGF for Angiogenesis [REVASC], NOGA Delivery of VEGF for Angina [NOVA], KAT),
      • Hedman M.
      • Hartikainen J.
      • Syvänne M.
      • Stjernvall J.
      • Hedman A.
      • Kivelä A.
      • et al.
      Safety and feasibility of catheter-based local intracoronary vascular endothelial growth factor gene transfer in the prevention of postangioplasty and in-stent restenosis and in the treatment of chronic myocardial ischemia: phase II results of the Kuopio Angiogenesis Trial (KAT).
      ,
      • Stewart D.
      • Hilton D.
      • Arnold J.
      • Gregoire J.
      • Rivard A.
      • Archer S.L.
      • et al.
      Angiogenic gene therapy in patients with nonrevascularizable ischemic heart disease: a phase 2 randomized, controlled trial of AdVEGF(121) (AdVEGF121) versus maximum medical treatment.
      ,
      • Kastrup J.
      • Jorgensen E.
      • Fuchs S.
      • Nikol S.
      • Bøtker H.E.
      • Gyöngyösi M.
      • et al.
      A randomised, double-blind, placebo-controlled, multicentre study of the safety and efficacy of BIOBYPASS (AdGVVEGF121.10NH) gene therapy in patients with refractory advanced coronary artery disease: the NOVA trial.
      or FGF4 (Angiogenic Gene Therapy [AGENT]).
      • Grines C.
      The AGENT clinical trials programme.
      None of the plasmid trials showed major influence on clinical outcomes or symptoms, and REVASC failed to show objective improved perfusion; NOVA and AGENT were prematurely terminated.
      In heart failure, the early Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Diseases (CUPID) trials (AAV1 vector to transfer sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) 2a DNA) were promising,
      • Jaski B.
      • Jessup M.
      • Mancini D.
      • Cappola T.P.
      • Pauly D.F.
      • Greenberg B.
      • et al.
      Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1/2 clinical trial.
      but the follow-up Phase 2b CUPID 2 failed to improve clinical outcomes.
      • Greenberg B.
      • Butler J.
      • Felker G.
      • Ponikowski P.
      • Voors A.A.
      • Desai A.S.
      • et al.
      Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial.
      Adenyl cyclase gene transfer improved left ventricular function and remodeling in failing heart in preclinical studies.
      • Lai N.
      • Roth D.
      • Gao M.
      • Tang T.
      • Dalton N.
      • Lai Y.Y.
      • et al.
      Intracoronary adenovirus encoding adenylyl cyclase VI increases left ventricular function in heart failure.
      However, the Phase 3 FLOURISH trial using adenoviral delivery of adenyl cyclase was terminated because of recruitment issues and reevaluation of strategy.
      AC6 gene transfer in patients with reduced left ventricular ejection fraction heart failure (FLOURISH).
      The synthetic AAV Anc80L65 is a vector that shows promise in tackling a key hurdle in gene therapy, namely efficiency in gene delivery. However, gene transfer efficiency alone does not guarantee success of cardiac gene therapy. A limitation is the lack of suitable animal models in preclinical studies. A single intramyocardial injection reaches a much larger area in a rodent heart compared with a human heart.
      • Korpela H.
      • Järveläinen N.
      • Siimes S.
      • Lampela J.
      • Airaksinen J.
      • Valli K.
      • et al.
      Gene therapy for ischaemic heart disease and heart failure.
      Patients being considered for gene therapy trials are in end-stage disease and often have multiple comorbidities, unlike the young healthy laboratory animals used in preclinical studies where the induced pathology is of short duration.
      • Cannatà A.
      • Ali H.
      • Sinagra G.
      • Giacca M.
      Gene therapy for the heart lessons learned and future perspectives.
      Furthermore, with the realization of the complexity of vascularization process, where it is now known that several dozens of factors are involved in vessel formation, targeting 1 or 2 genes may not be the answer to generate functional blood vessels in angiogenesis.
      • Cannatà A.
      • Ali H.
      • Sinagra G.
      • Giacca M.
      Gene therapy for the heart lessons learned and future perspectives.
      Preclinical work in the areas of modulation of gene expression in the heart using noncoding RNA therapeutics and gene editing for inherited cardiac diseases represent exciting new directions that may fulfill the promise of cardiac gene therapy in the future.
      • Cannatà A.
      • Ali H.
      • Sinagra G.
      • Giacca M.
      Gene therapy for the heart lessons learned and future perspectives.

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