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AAV vector engineering for human aorta transduction: becoming a smooth operator

Gene Therapy volume 32, pages 331–332 (2025)Cite this article

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Vascular smooth muscle cells (VSMCs) are crucially involved in a variety of life-threatening diseases in humans, including abdominal or thoracic aortic aneurysm with the accompanying risk of eventual aortic dissection and rupture [1], peripheral artery disease, or myocardial infarction [1, 2]. The different types of aortic aneurysm share risk factors, such as age, atherosclerosis, hypertension, diabetes and smoking [3]. Moreover, diseases associated with thoracic aortic aneurysm often have a defined genetic component, such as Marfan, Loeys-Dietz or Ehlen-Danlo syndrome that are caused by mutations in fibrillin-1, transforming growth factor beta pathway genes or collagen type III a1, respectively [3, 4]. This knowledge offers potential for gene therapeutic interventions in VSMCs through the overexpression, suppression or editing of disease-related genes, microRNAs or long non-coding RNAs [1,2,3]. Hence, there is a high demand for gene delivery vectors capable of efficiently targeting SMCs in the vasculature while sparing unrelated tissues, especially the liver that acts as a sink for systemically applied agents. A possible and innovative solution is now offered in recent work from Schroeder et al. in Gene Therapy [5].

To date, gene delivery to the human vascular system has mostly been achieved through naked plasmid or adenoviral delivery, yet neither is optimal. While the former is rather inefficient, the latter mediates robust but short-lived gene expression, leading to poor therapeutic outcomes [2]. Recombinant adeno-associated viruses (AAVs) have emerged as potent and safe alternative for in vivo gene delivery, with eight AAV-based drugs approved by the European Medicines Agency and/or the United States Food & Drug Administration [6, 7]. Their main advantages include the moderate immunogenicity, lack of pathogenicity and efficient, long-term gene expression. Still, severe side effects or even human fatalities were observed at high doses [7]. The main reason for these adverse events and a persistent major challenge in AAV gene therapy is insufficient vector specificity and/or efficiency, necessitating the administration of high vector doses. This, in turn, can foster the accumulation of capsids in the liver, which enhances the risk of anti-AAV T-cell activation and hepatotoxicity [8]. Concurrently, it increases the likelihood of inadvertent transgene expression not only in the target cell or tissue, but also in off-targets [7]. This also applies to all natural AAV capsid variants that have already been used to target SMCs and endothelial cells in the vasculature [2, 9, 10]. It also remains a problem for synthetic AAV vectors specifically engineered to target endothelial cells as they typically fail to reach the SMCs [11,12,13]. Nonetheless, there are notable exceptions, such as the mosaic capsid AAV2.5, i.e., AAV2 with a five amino-acid substitution from AAV1. This variant efficiently targeted SMCs after semi-local in vivo delivery in rats and outperformed the AAV1, 2, 5, 8 and 9 benchmarks, although liver detargeting was not established [10]. Another study showed that AAV-PR, i.e., an AAV9 peptide display variant selected in the cerebral vasculature of mice, also targeted SMCs in aortas, but there was no direct comparison to the parental AAV9 capsid [14].

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Authors and Affiliations

  1. Department of Infectious Diseases/Virology, Section Viral Vector Technologies, Medical Faculty, Heidelberg University, BioQuant, Center for Integrative Infectious Diseases (CIID), 69120, Heidelberg, Germany

    Kleopatra Rapti & Dirk Grimm

  2. German Center for Infection Research (DZIF) and German Center for Cardiovascular Research (DZHK), partner site Heidelberg, 69120, Heidelberg, Germany

    Dirk Grimm

  3. Faculty of Engineering Sciences, Heidelberg University, 69120, Heidelberg, Germany

    Dirk Grimm

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  1. Kleopatra Rapti
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  2. Dirk Grimm
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K.R. and D.G. jointly wrote this article.

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Correspondence to Dirk Grimm.

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Rapti, K., Grimm, D. AAV vector engineering for human aorta transduction: becoming a smooth operator. Gene Ther 32, 331–332 (2025). https://doi.org/10.1038/s41434-025-00526-9

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