Ming Lau, MBBS, and Michael K. Y. Hsin, MD, FRCS CTh
Central Message
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.
Katz and colleagues
1
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 AAV9.1
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.2
,3
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.
4
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]),
5
, - 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.
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.
J Am Coll Cardiol. 2005; 45: 982-988
6
, 7
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])- 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).
Circulation. 2003; 107: 2677-2683
8
; adenoviral vectors with cDNA expressing VEGF-A (Randomized Evaluation of VEGF for Angiogenesis [REVASC], NOGA Delivery of VEGF for Angina [NOVA], KAT),- 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).
Am Heart J. 2011; 161: 581-589
7
,- 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).
Circulation. 2003; 107: 2677-2683
9
,10
or FGF4 (Angiogenic Gene Therapy [AGENT]).- 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.
EuroIntervention. 2011; 6: 813-818
11
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,
12
but the follow-up Phase 2b CUPID 2 failed to improve clinical outcomes.13
Adenyl cyclase gene transfer improved left ventricular function and remodeling in failing heart in preclinical studies.
14
However, the Phase 3 FLOURISH trial using adenoviral delivery of adenyl cyclase was terminated because of recruitment issues and reevaluation of strategy.15
AC6 gene transfer in patients with reduced left ventricular ejection fraction heart failure (FLOURISH).
https://clinicaltrials.gov/ct2/show/NCT03360448
Date accessed: June 14, 2021
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.
16
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.17
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.17
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.
17
References
- Efficient cardiac gene transfer and early-onset expression of a synthetic adeno-associated viral vector, Anc80L65, after intramyocardial administration.J Thorac Cardiovasc Surg. 2022; 164: e429-e443
- Synthetic adeno-associated viral vector efficiently targets mouse and nonhuman primate retina in vivo.Hum Gene Ther. 2018; 29: 771-784
- Efficient gene transfer to the central nervous system by single-stranded Anc80L65.Mol Ther Methods Clin Dev. 2018; 10: 197-209
- Gene therapy.N Engl J Med. 2019; 381: 455-464
- 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.J Am Coll Cardiol. 2005; 45: 982-988
- VEGF gene therapy fails to improve perfusion of ischemic myocardium in patients with advanced coronary disease: results of the NORTHERN trial.Mol Ther. 2009; 17: 1109-1115
- 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).Circulation. 2003; 107: 2677-2683
- 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).Am Heart J. 2011; 161: 581-589
- Angiogenic gene therapy in patients with nonrevascularizable ischemic heart disease: a phase 2 randomized, controlled trial of AdVEGF(121) (AdVEGF121) versus maximum medical treatment.Gene Ther. 2006; 13: 1503-1511
- 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.EuroIntervention. 2011; 6: 813-818
- The AGENT clinical trials programme.Eur Heart J. 2004; 6: E18-E23
- Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1/2 clinical trial.J Card Fail. 2009; 15: 171-181
- 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.Lancet. 2016; 387: 1178-1186
- Intracoronary adenovirus encoding adenylyl cyclase VI increases left ventricular function in heart failure.Circulation. 2004; 110: 330-336
- AC6 gene transfer in patients with reduced left ventricular ejection fraction heart failure (FLOURISH).(Available at:)https://clinicaltrials.gov/ct2/show/NCT03360448Date accessed: June 14, 2021
- Gene therapy for ischaemic heart disease and heart failure.J Intern Med. May 25, 2021; ([Epub ahead of print])
- Gene therapy for the heart lessons learned and future perspectives.Circ Res. 2020; 126: 1394-1414
Article info
Publication history
Published online: June 17, 2021
Accepted:
June 14,
2021
Received in revised form:
June 14,
2021
Received:
June 14,
2021
Footnotes
Disclosures: The authors reported no conflicts of interest.
The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.
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© 2021 by The American Association for Thoracic Surgery
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- Efficient cardiac gene transfer and early-onset expression of a synthetic adeno-associated viral vector, Anc80L65, after intramyocardial administrationThe Journal of Thoracic and Cardiovascular SurgeryVol. 164Issue 6
- PreviewGene therapy is a promising approach in the treatment of cardiovascular diseases. Preclinical and clinical studies have demonstrated that adeno-associated viral vectors are the most attractive vehicles for gene transfer. However, preexisting immunity, delayed gene expression, and postinfection immune response limit the success of this technology. The aim of this study was to investigate the efficacy of the first synthetic adeno-associated viral lineage clone, Anc80L65, for cardiac gene therapy.
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