title: Differential myofiber-type transduction preference of adeno-associated virus serotypes 6 and 9.
abstract: BACKGROUND
  Gene therapy strategies are promising therapeutic options for monogenic muscular dystrophies, with several currently underways. The adeno-associated viral (AAV) vector is among the most effective gene delivery systems. However, transduction efficiency in skeletal muscles varies between AAV serotypes, with the underlying factors poorly understood. We hypothesized that myofiber-specific tropism differs between AAV serotypes.
  
  
  METHODS
  We developed a quantitative histology procedure and generated myofiber pattern maps for four myosin heavy chain (MyHC) isotypes. We compared myofiber pattern maps between AAV6 or AAV9 injected tibialis anterior muscle in mice. We correlated MyHC expression with AAV-derived green fluorescence protein (GFP) expression using statistical models.
  
  
  RESULTS
  We found that MyHC-2x expressing myofibers display a significantly higher preference for AAV transduction, whereas MyHC-2b expressing myofibers negatively correlated with AAV transduction. In addition, we show that AAV9-mediated transduction is enriched in myofibers expressing MyHC-1 and MyHC-1/2a. Moreover, AAV9-mediated transduction can predominantly be predicted by the expression of MyHC isotypes. In contrast, AAV6 transduction can be predicted by myofiber size but not by myofiber types.
  
  
  CONCLUSIONS
  Our findings identify differences between AAV6 and AAV9 for myofiber-type preferences, which could be an underlying factor for mosaic transduction of skeletal muscle. Adjusting AAV serotype for specific muscle conditions can therefore improve transduction efficacy in clinical applications.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Building 2, Room R3-17, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Riaz
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Building 2, Room R3-17, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.
authors.forename: Yotam
authors.initials: Y
authors.lastname: Raz
authors.affiliation: Department of Regeneration of Sensorimotor Systems, Netherlands Institute for Neuroscience, Royal Dutch Academy of Sciences, Amsterdam, The Netherlands.
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Moloney
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Building 2, Room R3-17, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.
authors.forename: Maaike
authors.initials: M
authors.lastname: van Putten
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Building 2, Room R3-17, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.
authors.forename: Yvonne D
authors.initials: YD
authors.lastname: Krom
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Building 2, Room R3-17, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.
authors.forename: Silvere M
authors.initials: SM
authors.lastname: van der Maarel
authors.affiliation: Department of Regeneration of Sensorimotor Systems, Netherlands Institute for Neuroscience, Royal Dutch Academy of Sciences, Amsterdam, The Netherlands ; Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognition Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Verhaagen
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Building 2, Room R3-17, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.
authors.forename: Vered
authors.initials: V
authors.lastname: Raz
keywords: AAV serotypes; Adeno-associated viral vectors; Gene therapy; Myofiber types; Skeletal muscle