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Systemic AAV-9 transduction in mice is influenced by animal age but not by the route of administration

Abstract

Adeno-associated virus (AAV) serotype-9 (AAV-9) has attracted great attention as an optimal vehicle for body-wide gene delivery. Here we examined the effect of animal age (newborn vs adult) and the route of administration (intravenous vs intra-arterial) on systemic AAV-9 transduction. We delivered an alkaline phosphatase (AP) reporter gene AAV vector (AV.RSV.AP) to either newborn (via either the facial vein or the left ventricular cavity) or adult (via tail vein) C57Bl/10 mice. At 12 weeks’ postinfection, we examined the AP expression. We observed efficient transduction in multiple skeletal muscles and the heart, irrespective of the age or delivery route. However, the soleus muscle, which consists mainly of slow-twitch myofibers, was poorly transduced. Besides striated muscle, we also found consistent high-level transduction in the lung. Abundant AP-positive cells were seen in alveolar cells and vasculature, but not in bronchioles. Interestingly, several organs demonstrated an age-dependent profile. In particular, the aorta, liver and kidney were preferentially transduced in adult mice while the inner layer of retina was strongly transduced only following the neonatal administration. Taken together, our results demonstrate the robustness of intravascular AAV-9 delivery for muscle and lung gene therapy applications. The unique expression patterns in the aorta, liver, kidney and retina call for special attention when designing AAV-9 gene therapy applications for these organs.

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References

  1. Inagaki K, Fuess S, Storm TA, Gibson GA, McTiernan CF, Kay MA et al. Robust systemic transduction with AAV9 vectors in mice: efficient global cardiac gene transfer superior to that of AAV8. Mol Ther 2006; 14: 45–53.

    Article  CAS  PubMed Central  Google Scholar 

  2. Pacak CA, Mah CS, Thattaliyath BD, Conlon TJ, Lewis MA, Cloutier DE et al. Recombinant adeno-associated virus serotype 9 leads to preferential cardiac transduction in vivo. Circ Res 2006; 99: e3–9.

    Article  CAS  Google Scholar 

  3. Ghosh A, Yue Y, Long C, Bostick B, Duan D . Efficient whole-body transduction with trans-splicing adeno-associated viral vectors. Mol Ther 2007; 15: 750–755.

    Article  CAS  PubMed Central  Google Scholar 

  4. Yue Y, Li Z, Harper SQ, Davisson RL, Chamberlain JS, Duan D . Microdystrophin gene therapy of cardiomyopathy restores dystrophin–glycoprotein complex and improves sarcolemma integrity in the mdx mouse heart. Circulation 2003; 108: 1626–1632.

    Article  CAS  PubMed Central  Google Scholar 

  5. Gregorevic P, Blankinship MJ, Allen JM, Crawford RW, Meuse L, Miller DG et al. Systemic delivery of genes to striated muscles using adeno-associated viral vectors. Nat Med 2004; 10: 828–834.

    Article  CAS  PubMed Central  Google Scholar 

  6. Wang Z, Zhu T, Qiao C, Zhou L, Wang B, Zhang J et al. Adeno-associated virus serotype-8 efficiently delivers genes to muscle and heart. Nat Biotechnol 2005; 23: 321–328.

    Article  CAS  PubMed Central  Google Scholar 

  7. Mah C, Cresawn KO, Fraites Jr TJ, Pacak CA, Lewis MA, Zolotukhin I et al. Sustained correction of glycogen storage disease type II using adeno-associated virus serotype 1 vectors. Gene Therapy 2005; 12: 1405–1409.

    Article  CAS  PubMed Central  Google Scholar 

  8. Pruchnic R, Cao B, Peterson ZQ, Xiao X, Li J, Samulski RJ et al. The use of adeno-associated virus to circumvent the maturation-dependent viral transduction of muscle fibers. Hum Gene Ther 2000; 11: 521–536.

    Article  CAS  PubMed Central  Google Scholar 

  9. Blankinship MJ, Gregorevic P, Allen JM, Harper SQ, Harper H, Halbert CL et al. Efficient transduction of skeletal muscle using vectors based on adeno-associated virus serotype-6. Mol Ther 2004; 10: 671–678.

    Article  CAS  PubMed Central  Google Scholar 

  10. Lai Y, Yue Y, Liu M, Ghosh A, Engelhardt JF, Chamberlain JS et al. Efficient in vivo gene expression by trans-splicing adeno-associated viral vectors. Nat Biotechnol 2005; 23: 1435–1439.

    Article  CAS  PubMed Central  Google Scholar 

  11. Baker AH, Kritz A, Work LM, Nicklin SA . Cell-selective viral gene delivery vectors for the vasculature. Exp Physiol 2005; 90: 27–31.

    Article  PubMed Central  Google Scholar 

  12. Xiao WD, Chirmule N, Schnell MA, Tazelaar J, Hughes JV, Wilson JM . Route of administration determines induction of T-cell-independent humoral responses to adeno-associated virus vectors. Mol Ther 2000; 1: 323–329.

    Article  CAS  PubMed Central  Google Scholar 

  13. Ohashi K, Nakai H, Couto LB, Kay MA . Modified infusion procedures affect recombinant adeno-associated virus vector type-2 transduction in the liver. Hum Gene Ther 2005; 16: 299–306.

    Article  CAS  PubMed Central  Google Scholar 

  14. Berraondo P, Crettaz J, Ochoa L, Paneda A, Prieto J, Troconiz IF et al. Intrahepatic injection of recombinant adeno-associated virus serotype 2 overcomes gender-related differences in liver transduction. Hum Gene Ther 2006; 17: 601–610.

    Article  CAS  PubMed Central  Google Scholar 

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Acknowledgements

We thank Drs Guangping Gao and Jim Wilson for providing the AAV-9 packaging plasmid pRep2/Cap9 We thank Drs Lixing Reneker and Bo Lei for the help with retinal embedding and retinal morphology data interpretation. This work is supported by grants from the National Institutes of Health (AR-49419, DD; DK-76522, DD), the Muscular Dystrophy Association (DD) and the Cystic Fibrosis Foundation (DD). BB was partially supported by a training grant from the National Institutes of Health (GM 008396).

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Correspondence to D Duan.

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Supplementary Information accompanies the paper on Gene Therapy website (http://www.nature.com/gt)

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Bostick, B., Ghosh, A., Yue, Y. et al. Systemic AAV-9 transduction in mice is influenced by animal age but not by the route of administration. Gene Ther 14, 1605–1609 (2007). https://doi.org/10.1038/sj.gt.3303029

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