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Commentary: A synthetic adeno-associated viral vector as a means of future precision treatment

      Figure thumbnail fx1
      One needs to target the heart only with an AAV vector.
      Rather than like shooting flies with a cannon, gene therapy affords a targeted means of bringing a specific healing gene molecule to the exact site of treatment.
      See Article page e429.
      Treating acute myocardial infarction should not be like shooting flies with a cannon; the target is the ischemic heart only, and a specifically targeted local treatment decreases risks of systematic side effects. The key is to bring the treatment to the specific tissue area intended to heal without influencing unnecessarily the whole of the body.
      Gene therapy could serve as an adjunct treatment of myocardial infarction. A healing gene molecule is incorporated within a transporting adeno-associated viral (AAV) 9 vector vehicle and specifically smuggled to a local area while minimizing overall viral infection and toxicity.
      • Lai C.M.
      • Lai Y.K.Y.
      • Rakoczy P.E.
      Adenovirus and adeno-associated virus vectors.
      Unfortunately, delayed gene expression, poor sustainability, and any systematic immune response caused by the injection of AAV9 vector may restrict the wide adaption of gene therapy clinically.
      A novel synthetic AAV vector, Anc80L65, enters the scene.
      • 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.
      Anc80L65 was created using a reverse genetic approach and ancestral AAV sequence reconstruction; Anc80L65 may rule out some of the challenges presented by AAV vectors.
      • Carvalho L.S.
      • Xiao R.
      • Wassmer S.J.
      • Langsdof A.
      • Zinn E.
      • Pacouret S.
      • et al.
      Synthetic adeno-associated viral vector efficiently targets mouse and nonhuman primate retina in vivo.
      ,
      • Hudry E.
      • Andres-Mateos E.
      • Lerner E.P.
      • Volak A.
      • Cohen O.
      • Hyman B.T.
      • et al.
      Efficient gene transfer to the central nervous system by single-stranded Anc80L65.
      The capsid structure of the Anc80L65 vector may ensure transduction capabilities. The aim of the experimental rat study by 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.
      was to investigate the efficacy of Anc80L65 as a vector vehicle for cardiac gene therapy. The transduction efficiency of Anc80L65 and AAV9 in neonatal rat cardiomyocytes in vitro and rat hearts in vivo after intramyocardial and intracoronary administration were compared using fluorescence and bioluminescence techniques.
      Three arguments were explored.
      • 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.
      First, the efficacy of the delivery means to bring a molecule to the sick tissue area was investigated; the heart uptake of Anc80L65 was increased compared with AAV9 vector. As observed by fluorescence imaging, Anc80L65-mediated transgene expression increased in rat cardiomyocytes in vitro and in vivo in a time-dependent manner using intramyocardial or intracoronary rat heart administrations. Bioluminescence imaging confirmed the time-dependent increase of rat heart Anc80L65 vector. Second, Anc80L65 distribution adhered well to the heart, whereas AAV9 distribution was relatively dispersed in other organs as well, as detected by quantified polymerase analysis of the vectors. Finally, minimized systematic side effects could be anticipated as some pro- and anti-inflammatory cytokine responses were negligible after Anc80L65 administration.
      The functional efficacy of a therapeutic molecule after the gene vector transport was not investigated and remains to be proven. Paradoxically, if the nonimmunogenic synthetic vector does not induce any systematic effect such as inflammation, is there a possibility that the synthetic vector has no meaningful auxiliary effect locally either? Rapid therapeutic gene induction may be important in treating the acute myocardial ischemia, but for chronic phases such as angiogenesis, could a constant foreign gene activation even be detrimental? Besides the cardiomyocytes, are other cardiac cells influenced by the induction of Anc80L65 vector?
      The study by 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.
      includes empiric observations on a synthetic AAV gene transport; the rat hearts with Anc80L65 were aptly compared with another optional heart delivery means including AAV9 vector. The study reveals limitations of accepting the technology clinically, but it suggests that a sustainable gene therapy using Anc80L65 may replace the less precise AAV9 vector.

      References

        • Lai C.M.
        • Lai Y.K.Y.
        • Rakoczy P.E.
        Adenovirus and adeno-associated virus vectors.
        DNA Cell Biol. 2002; 21: 895-913
        • 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.
        J Thorac Cardiovasc Surg. 2022; 164: e429-e443
        • Carvalho L.S.
        • Xiao R.
        • Wassmer S.J.
        • Langsdof A.
        • Zinn E.
        • Pacouret S.
        • et al.
        Synthetic adeno-associated viral vector efficiently targets mouse and nonhuman primate retina in vivo.
        Hum Gene Ther. 2018; 29: 771-784
        • Hudry E.
        • Andres-Mateos E.
        • Lerner E.P.
        • Volak A.
        • Cohen O.
        • Hyman B.T.
        • et al.
        Efficient gene transfer to the central nervous system by single-stranded Anc80L65.
        Mol Ther Methods Clin Dev. 2018; 23: 197-209

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