Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

The MRI contrast agent gadoteridol enhances distribution of rAAV1 in the rat hippocampus

Gene Therapy volume 20, pages 1172–1177 (2013)Cite this article

Subjects

Abstract

Contrast agents are commonly used in combination with magnetic resonance imaging (MRI) to monitor the distribution of molecules in the brain. Recent experiments conducted in our laboratory have shown that co-infusion of recombinant Adeno-associated virus serotype 5 (rAAV5) and the MRI contrast agent gadoteridol (Gd) enhances vector transduction in the rat striatum. The goal of this study was to determine whether gadoteridol may also be used as a tool to enhance transduction efficiency of rAAV1 and rAAV5 within the rat hippocampus. We show that Gd/rAAV1-GFP but not Gd/rAAV5-GFP co-infusion results in significantly higher distribution of the transgene both in the injected hemisphere as well as in the contralateral side and adjacent areas of cortex along the injection track. We also show that Gd/rAAV1-GFP co-infusion has no deleterious effect on hippocampal function as assessed by two tests of spatial memory formation. This work indicates that Gd can be exploited as a method to increase transduction efficiency of AAV1 in the hippocampus for animal studies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Bartel MA, Weinstein JR, Schaffer DV . Directed evolution of novel adeno-associated viruses for therapeutic gene delivery. Gene Therapy 2012; 19: 694–700.

    Article  CAS  PubMed  Google Scholar 

  2. Mandel R, Burger C . Clinical trials in neurological disorders using AAV vectors: promises and challenges. Curr Op Mol Therapeutics 2004; 6: 482–490.

    CAS  Google Scholar 

  3. McCown TJ, Xiao X, Li J, Breese GR, Samulski RJ . Differential and persistent expression patterns of CNS gene transfer by an adeno-associated virus (AAV) vector. Brain Res 1996; 713: 99–107.

    Article  CAS  PubMed  Google Scholar 

  4. Sanlioglu S, Monick MM, Luleci G, Hunninghake GW, Engelhardt JF . Rate limiting steps of AAV transduction and implications for human gene therapy. Curr Gene Ther 2001; 1: 137–147.

    Article  CAS  PubMed  Google Scholar 

  5. Zolotukhin S, Potter M, Zolotukhin I, Sakai Y, Loiler S, Fraites TJ Jr. et al. Production and purification of serotype 1, 2, and 5 recombinant adeno-associated viral vectors. Methods 2002; 28: 158–167.

    Article  CAS  PubMed  Google Scholar 

  6. Gao G, Vandenberghe LH, Wilson JM . New recombinant serotypes of AAV vectors. Curr Gene Ther 2005; 5: 285–297.

    Article  CAS  PubMed  Google Scholar 

  7. Foust KD, Nurre E, Montgomery CL, Hernandez A, Chan CM, Kaspar BK . Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol 2008; 27: 59–65.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Ghodsi A, Stein C, Derksen T, Martins I, Anderson RD, Davidson BL . Systemic hyperosmolality improves beta-glucuronidase distribution and pathology in murine MPS VII brain following intraventricular gene transfer. Exp Neurol 1999; 160: 109–116.

    Article  CAS  PubMed  Google Scholar 

  9. Burger C, Nguyen FN, Deng J, Mandel RJ . Systemic mannitol-induced hyperosmolality amplifies rAAV2-mediated striatal transduction to a greater extent than local co-infusion. Mol Ther 2005; 11: 327–331.

    Article  CAS  PubMed  Google Scholar 

  10. Carty N, Lee D, Dickey C, Ceballos-Diaz C, Jansen-West K, Golde TE et al. Convection-enhanced delivery and systemic mannitol increase gene product distribution of AAV vectors 5, 8, and 9 and increase gene product in the adult mouse brain. J Neurosci Methods 2010; 194: 144–153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Su X, Kells AP, Salegio EA, Richardson RM, Hadaczek P, Beyer J et al. Real-time MR imaging with gadoteridol predicts distribution of transgenes after convection-enhanced delivery of AAV2 vectors. Mol Ther 2010; 18: 1490–1495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Fiandaca MS, Varenika V, Eberling J, McKnight T, Bringas J, Pivirotto P et al. Real-time MR imaging of adeno-associated viral vector delivery to the primate brain. Neuroimage 2009; 47 (Suppl 2): T27–T35.

    Article  PubMed  Google Scholar 

  13. Abujudeh HH, Kaewlai R, Kagan A, Chibnik LB, Nazarian RM, High WA et al. Nephrogenic systemic fibrosis after gadopentetate dimeglumine exposure: case series of 36 patients. Radiology 2009; 253: 81–89.

    Article  PubMed  Google Scholar 

  14. Ding D, Kanaly CW, Cummings TJ, Herndon JE 2nd, Raghavan R, Sampson JH . Long-term safety of combined intracerebral delivery of free gadolinium and targeted chemotherapeutic agent PRX321. Neurol Res 2010; 32: 810–815.

    Article  CAS  PubMed  Google Scholar 

  15. Burger C, Gorbatyuk OS, Velardo MJ, Peden CS, Williams P, Zolotukhin S et al. Recombinant AAV viral vectors pseudotyped with viral capsids from serotypes 1, 2, and 5 display differential efficiency and cell tropism after delivery to different regions of the central nervous system. Mol Ther 2004; 10: 302–317.

    Article  CAS  PubMed  Google Scholar 

  16. Gerstein H, O'Riordan K, Osting S, Schwarz M, Burger C . Rescue of synaptic plasticity and spatial learning deficits in the hippocampus of Homer1 knockout mice by recombinant Adeno-associated viral gene delivery of Homer1c. Neurobiol Learn Mem 2012; 97: 17–29.

    Article  CAS  PubMed  Google Scholar 

  17. Astary GW, Kantorovich S, Carney PR, Mareci TH, Sarntinoranont M . Regional convection-enhanced delivery of gadolinium-labeled albumin in the rat hippocampus in vivo. J Neurosci Methods 2010; 187: 129–137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nguyen JB, Sanchez-Pernaute R, Cunningham J, Bankiewicz KS . Convection-enhanced delivery of AAV-2 combined with heparin increases TK gene transfer in the rat brain. Neuroreport 2001; 12: 1961–1964.

    Article  CAS  PubMed  Google Scholar 

  19. Mastakov MY, Baer K, Xu R, Fitzsimons H, During MJ . Combined injection of rAAV with mannitol enhances gene expression in the rat brain. Mol Ther 2001; 3: 225–232.

    Article  CAS  PubMed  Google Scholar 

  20. Bankiewicz KS, Eberling JL, Kohutnicka M, Jagust W, Pivirotto P, Bringas J et al. Convection-enhanced delivery of AAV vector in parkinsonian monkeys; in vivo detection of gene expression and restoration of dopaminergic function using pro-drug approach. Exp Neurol 2000; 164: 2–14.

    Article  CAS  PubMed  Google Scholar 

  21. Hadaczek P, Kohutnicka M, Krauze MT, Bringas J, Pivirotto P, Cunningham J et al. Convection-enhanced delivery of adeno-associated virus type 2 (AAV2) into the striatum and transport of AAV2 within monkey brain. Hum Gene Ther 2006; 17: 291–302.

    Article  CAS  PubMed  Google Scholar 

  22. Gerstein H, Lindstrom MJ, Burger C . Gene delivery of Homer1c rescues spatial learning in a rodent model of cognitive aging. Neurobiol Aging 2013; 34: 1963–1970.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Brown RH . A transgenic-mouse model of amyotrophic lateral sclerosis. N Engl J Med 1994; 331: 1091–1092.

    Article  CAS  PubMed  Google Scholar 

  24. Matalon R, Rady PL, Platt KA, Skinner HB, Quast MJ, Campbell GA et al. Knock-out mouse for Canavan disease: a model for gene transfer to the central nervous system. J Gene Med 2000; 2: 165–175.

    Article  CAS  PubMed  Google Scholar 

  25. Gerstein H, Hullinger R, Lindstrom MJ, Burger C . A behavioral paradigm to evaluate hippocampal performance in aged rodents for pharmacological and genetic target validation. PLoS One 2013; 8: e62360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Schneider CA, Rasband WS, Eliceiri KW . NIH Image to ImageJ: 25 years of image analysis. Nature Methods 2012; 9: 671–675.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Burger C, Cecilia Lopez M, Feller JA, Baker HV, Muzyczka N, Mandel RJ . Changes in transcription within the CA1 field of the hippocampus are associated with age-related spatial learning impairments. Neurobiol Learn Mem 2007; 87: 21–41.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Jordan Wackett for technical assistance. This research was supported by funds from Kinetics Foundation and the Department of Neurology, University of Wisconsin-Madison to CB. RH was supported by the University of Wisconsin Neuroscience Training Program Grant NIH/NIGMS T32GM007507 and an NSF Graduate Research Fellowship. LPS was supported by Universidad Nacional Autónoma de Mexico (UNAM), Doctorado en Ciencias Biomedicas and program UNAM CONACYT, Beca Mixta No. 208245 scholarship program. We would also like to acknowledge the rat subjects who participated in this study.

Author information

Authors and Affiliations

  1. Department of Neurology, University of Wisconsin-Madison, Medical Sciences Center, 1300 University Ave, Room 73 Bardeen, Madison, WI, USA

    R Hullinger, J Ugalde, S Osting & C Burger

  2. Neuroscience Training Program, University of Wisconsin-Madison, Madison, USA

    R Hullinger

  3. Departamento de Neurobiología Conductual y Cognitiva, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Campus Juriquilla, Boulevard Juriquilla No. 3001 Juriquilla, Querétaro, Qro, Mexico

    L Purón-Sierra

Authors
  1. R Hullinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Ugalde
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L Purón-Sierra
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Osting
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C Burger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C Burger.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hullinger, R., Ugalde, J., Purón-Sierra, L. et al. The MRI contrast agent gadoteridol enhances distribution of rAAV1 in the rat hippocampus. Gene Ther 20, 1172–1177 (2013). https://doi.org/10.1038/gt.2013.47

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2013.47

Keywords

This article is cited by

Search

Advanced search

Quick links