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Distinct transduction of muscle tissue in mice after systemic delivery of AAVpo1 vectors

Gene Therapy volume 27, pages 170–179 (2020)Cite this article

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Abstract

The human musculature is a promising and pivotal target for human gene therapy, owing to numerous diseases that affect this tissue and that are often monogenic, making them amenable to treatment and potentially cure on the genetic level. Particularly attractive would be the possibility to deliver clinically relevant DNA to muscle tissue from a minimally invasive, intravenous vector delivery. To date, this aim has been approximated by the use of Adeno-associated viruses (AAV) of different serotypes (rh.74, 8, 9) that are effective, but unfortunately not specific to the muscle and hence not ideal for use in patients. Here, we have thus studied the muscle tropism and activity of another AAV serotype, AAVpo1, that was previously isolated from pigs and found to efficiently transduce muscle following direct intramuscular injection in mice. The new data reported here substantiate the usefulness of AAVpo1 for muscle gene therapies by showing, for the first time, its ability to robustly transduce all major muscle tissues, including heart and diaphragm, from peripheral infusion. Importantly, in stark contrast to AAV9 that forms the basis for ongoing clinical gene therapy trials in the muscle, AAVpo1 is nearly completely detargeted from the liver, making it a very attractive and potentially safer option.

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Acknowledgements

WT, QHP, JEA, TV, MKC, and DG are very grateful for funding and other support from the MYOCURE project. MYOCURE has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 667751. DG is thankful for support by the German Center for Infection Research (DZIF, BMBF; TTU-HIV 04.803 and TTU-HIV 04.815). DG acknowledges additional funding by the German Research Foundation (DFG) through the Cluster of Excellence CellNetworks (EXC81) and the Collaborative Research Centers SFB1129 (Projektnummer 240245660) and TRR179 (Projektnummer 272983813). TV and MKC obtained funding from the Fonds Wetenschappelijk Onderzoek (FWO), VUB Industrieel Onderzoeksfonds (IOF), Koning Boudewijn Stichting (Creemers-Opdebeek) and Association Belge contre les Maladies Neuromusculaires (ABMM). We are grateful to Alexander Bello and Gary Kobinger for initially supplying the po1 sequence. The authors thank Julia Fakhiri for critical reading of the manuscript as well as Ermira Samara for her help with AAV vector production.

Author information

Author notes

  1. Warut Tulalamba

    Present address: Research Division, Faculty of Medicine Siriraj Hospital, Mahidol University, 10700, Bangkok, Thailand

  2. Jonas Weinmann

    Present address: Boehringer Ingelheim Pharma GmbH & Co. KG, Drug Discovery Sciences, Birkendorfer Straße 65, 88400, Biberach an der Riß, Germany

  3. These authors contributed equally: Warut Tulalamba, Jonas Weinmann, Quang Hong Pham

Authors and Affiliations

  1. Department of Gene Therapy & Regenerative Medicine, Vrije Universiteit Brussel (VUB), B-1050, Brussels, Belgium

    Warut Tulalamba, Quang Hong Pham, Thierry VandenDriessche & Marinee K. Chuah

  2. Department of Infectious Diseases/Virology, BioQuant Center, Heidelberg University Hospital, University of Heidelberg, 69120, Heidelberg, Germany

    Jonas Weinmann, Jihad El Andari & Dirk Grimm

  3. Department of Cardiovascular Sciences, Center for Molecular & Vascular Biology, University of Leuven, 3000, Leuven, Belgium

    Thierry VandenDriessche & Marinee K. Chuah

  4. German Center for Infection Research (DZIF) and German Center for Cardiovascular Research (DZHK), Partner site Heidelberg, Heidelberg, Germany

    Dirk Grimm

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Contributions

TV, MKC, and DG conceived and designed the experiments. WT, JW, QHP, and JEA generated constructs and performed experiments. WT, JEA, TV, MKC, and DG wrote the manuscript. All authors read the manuscript and approved the final version.

Corresponding authors

Correspondence to Thierry VandenDriessche, Marinee K. Chuah or Dirk Grimm.

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Conflict of interest

DG is a co-founder and shareholder of AaviGen GmbH. JW is currently an employee of Boehringer Ingelheim Pharma GmbH & Co. KG. All other authors declare that they have no conflict of interest.

Ethical approval

All animal procedures were approved by the institutional animal ethics committee of the Free University of Brussels (VUB) (Brussels, Belgium). Husbandry was carried out in individually ventilated Thoren cages that contained Hygienic Animal Bedding (Lignocel). Temperature was maintained at ~21 °C with 50–60% humidity. Animals were fed SsniFF laboratory animal food (ABEDD Vertriebs GmbH, Vienna, Austria) ad libitum.

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Tulalamba, W., Weinmann, J., Pham, Q.H. et al. Distinct transduction of muscle tissue in mice after systemic delivery of AAVpo1 vectors. Gene Ther 27, 170–179 (2020). https://doi.org/10.1038/s41434-019-0106-3

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