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:

Imaging gene delivery in a mouse model of congenital neuronal ceroid lipofuscinosis

Gene Therapy volume 18, pages 1173–1178 (2011)Cite this article

Subjects

A Corrigendum to this article was published on 08 November 2012

Abstract

Adeno-associated virus (AAV)-mediated gene replacement for lysosomal disorders have been spurred by the ability of some serotypes to efficiently transduce neurons in the brain and by the ability of lysosomal enzymes to cross-correct among cells. Here, we explored enzyme replacement therapy in a knock-out mouse model of congenital neuronal ceroid lipofuscinosis (NCL), the most severe of the NCLs in humans. The missing protease in this disorder, cathepsin D (CathD) has high levels in the central nervous system. This enzyme has the potential advantage for assessing experimental therapy in that it can be imaged using a near-infrared fluorescence (NIRF) probe activated by CathD. Injections of an AAV2/rh8 vector-encoding mouse CathD (mCathD) into both cerebral ventricles and peritoneum of newborn knock-out mice resulted in a significant increase in lifespan. Successful delivery of active CathD by the AAV2/rh8-mCathD vector was verified by NIRF imaging of mouse embryonic fibroblasts from knock-out mice in culture, as well as by ex vivo NIRF imaging of the brain and liver after gene transfer. These studies support the potential effectiveness and imaging evaluation of enzyme replacement therapy to the brain and other organs in CathD null mice via AAV-mediated gene delivery in neonatal animals.

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
Figure 4

Similar content being viewed by others

References

  1. Hodges BL, Cheng SH . Cell and gene-based therapies for the lysosomal storage diseases. Curr Gene Ther 2006; 6: 227–241.

    Article  CAS  Google Scholar 

  2. Vellodi A . Lysosomal storage disorders. Br J Haematol 2005; 128: 413–431.

    Article  CAS  Google Scholar 

  3. Fernandes Filho JA, Shapiro BE . Tay-Sachs disease. Arch Neurol 2004; 61: 1466–1468.

    Article  Google Scholar 

  4. Mole SE, Williams RE, Goebel HH . Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. Neurogenetics 2005; 6: 107–126.

    Article  Google Scholar 

  5. Siintola E, Partanen S, Stromme P, Haapanen A, Haltia M, Maehlen J et al. Cathepsin D deficiency underlies congenital human neuronal ceroid-lipofuscinosis. Brain 2006; 129: 1438–1445.

    Article  Google Scholar 

  6. Steinfeld R, Reinhardt K, Schreiber K, Hillebrand M, Kraetzner R, Bruck W et al. Cathepsin D deficiency is associated with a human neurodegenerative disorder. Am J Hum Genet 2006; 78: 988–998.

    Article  CAS  Google Scholar 

  7. Whitaker JN, Rhodes RH . The distribution of cathepsin D in rat tissues determined by immunocytochemistry. Am J Anat 1983; 166: 417–428.

    Article  CAS  Google Scholar 

  8. Reid WA, Valler MJ, Kay J . Immunolocalization of cathepsin D in normal and neoplastic human tissues. J Clin Pathol 1986; 39: 1323–1330.

    Article  CAS  Google Scholar 

  9. Palmer DN, Husbands DR, Winter PJ, Blunt JW, Jolly RD . Ceroid lipofuscinosis in sheep. I. Bis(monoacylglycero)phosphate, dolichol, ubiquinone, phospholipids, fatty acids, and fluorescence in liver lipopigment lipids. J Biol Chem 1986; 26: 1766–1772.

    Google Scholar 

  10. Awano T, Katz ML, O’Brien DP, Taylor JF, Evans J, Khan S et al. A mutation in the cathepsin D gene (CTSD) in American bulldogs with neuronal ceroid lipofuscinosis. Mol Genet Metab 2006; 87: 341–348.

    Article  CAS  Google Scholar 

  11. Drogemuller C, Wohlke A, Distl O . Characterization of candidate genes for neuronal ceroid lipofuscinosis in dog. J Hered 2005; 96: 735–738.

    Article  CAS  Google Scholar 

  12. Saftig P, Hetman M, Schmahl W, Weber K, Heine L, Mossmann H et al. Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells. EMBO J 1995; 14: 3599–3608.

    Article  CAS  Google Scholar 

  13. Koike M, Nakanishi H, Saftig P, Ezaki J, Isahara K, Ohsawa Y et al. Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin in mouse CNS neurons. J Neurosci 2000; 20: 6898–6906.

    Article  CAS  Google Scholar 

  14. Koike M, Shibata M, Waguri S, Yoshimura K, Tanida I, Kominami E et al. Participation of autophagy in storage of lysosomes in neurons from mouse models of neuronal ceroid-lipofuscinoses (Batten disease). Am J Pathol 2005; 167: 1713–1728.

    Article  CAS  Google Scholar 

  15. Sands MS, Davidson BL . Gene therapy for lysosomal storage diseases. Mol Ther 2006; 13: 839–849.

    Article  CAS  Google Scholar 

  16. Schiffmann R . Therapeutic approaches for neuronopathic lysosomal storage disorders. J Inherit Metab Dis 2010; 33: 373–379.

    Article  CAS  Google Scholar 

  17. Kroll RA, Neuwald EA . Outwitting the blood-brain barrier for therapeutic purposes: osmotic opening and other means. Neurosurgery 1998; 42: 1082–1099.

    Article  Google Scholar 

  18. Pohlmann R, Boeker MW, von Figura K . The two mannose 6-phosphate receptors transport distinct complements of lysosomal proteins. J Biol Chem 1995; 270: 27311–27318.

    Article  CAS  Google Scholar 

  19. McPhee SW, Janson CG, Li C, Samulski RJ, Camp AS, Francis J et al. Immune responses to AAV in a phase I study for Canavan disease. J Gene Med 2006; 8: 577–588.

    Article  CAS  Google Scholar 

  20. Crystal RG, Sondhi D, Hackett NR, Kaminsky SM, Worgall S, Stieg P et al. Clinical protocol. Administration of a replication-deficient adeno-associated virus gene transfer vector expressing the human CLN2 cDNA to the brain of children with late infantile neuronal ceroid lipofuscinosis. Hum Gene Ther 2004; 15: 1131–1154.

    Article  Google Scholar 

  21. Griffey M, Bible E, Vogler C, Levy B, Gupta P, Cooper J et al. Adeno-associated virus 2-mediated gene therapy decreases autofluorescent storage material and increases brain mass in a murine model of infantile. Neurobiol Dis 2004; 16: 360–369.

    Article  CAS  Google Scholar 

  22. Wong AM, Rahim AA, Waddington SN, Cooper JD . Current therapies for the soluble lysosomal forms of neuronal ceroid lipofuscinosis. Biochem Soc Trans 2010; 38: 1484–1488.

    Article  CAS  Google Scholar 

  23. Shah K, Jacobs A, Breakefield XO, Weissleder R . Molecular imaging of gene therapy for cancer. Gene Therapy 2004; 11: 1175–1187.

    Article  CAS  Google Scholar 

  24. Funovics M, Weissleder R, Tung CH . Protease sensors for bioimaging. Anal Bioanal Chem 2003; 377: 956–963.

    Article  CAS  Google Scholar 

  25. Weissleder R, Tung CH, Mahmood U, Bogdanov AJ . In vivo imaging of tumors with protease-activated near-infrared fluorescent probes. Nat Biotechnol 1999; 17: 375–378.

    Article  CAS  Google Scholar 

  26. Tung CH, Mahmood U, Bredow S, Weissleder R . In vivo imaging of proteolytic enzyme activity using a novel molecular reporter. Cancer Res 2000; 60: 4953–4958.

    CAS  PubMed  Google Scholar 

  27. Shah K, Tung CH, Chang CH, Slootweg E, O’Loughlin T, Breakefield XO et al. In vivo imaging of HIV protease activity in amplicon vector-transduced gliomas. Cancer Res 2004; 64: 273–278.

    Article  CAS  Google Scholar 

  28. Bremer C, Tung CH, Weissleder R . Molecular imaging of MMP expression and therapeutic MMP inhibition. Acad Radiol 2002; 2: S314–S315.

    Article  Google Scholar 

  29. Messerli SM, Prabhakar S, Tang Y, Shah K, Cortes ML, Murthy V et al. A novel method for imaging apoptosis using a caspase-1 near-infrared fluorescent probe. Neoplasia 2004; 6: 95–105.

    Article  CAS  Google Scholar 

  30. Pham W, Weissleder R, Tung CH . An azulene dimer as a near-infrared quencher. Angew Chem Int Ed Engl 2002; 41: 3659–3662.

    Article  CAS  Google Scholar 

  31. Rijinboutt S, Stoorvogel W, Geuze HJ, Strous GJ . Identification of subcellular compartments involved in biosynthetic processing of cathepsin d. J Biol Chem 1992; 267: 15665–15672.

    Google Scholar 

  32. Broekman ML, Comer LA, Hyman BT, Sena-Esteves M . Adeno-associated virus vectors serotyped with AAV8 capsids are more efficient than AAV-1 or -2 serotypes for widespread gene delivery to the neonatal mouse brain. Neuroscience 2006; 138: 501–510.

    Article  CAS  Google Scholar 

  33. Broekman ML, Baek RC, Comer LA, Fernandez JL, Seyfried TN, Sena-Esteves M . Complete correction of enzymatic deficiency and neurochemistry in the GM1-gangliosidosis mouse brain by neonatal adeno-associated virus-mediated gene delivery. Mol Ther 2007; 15: 30–37.

    Article  CAS  Google Scholar 

  34. Mahmood U, Tung CH, Bogdanov AJ, Weissleder R . Near-infrared optical imaging of protease activity for tumor detection. Radiology 1999; 213: 866–870.

    Article  CAS  Google Scholar 

  35. Ntziachristos V, Turner G, Dunham J, Windsor S, Soubret A, Ripoll J et al. Planar fluorescence imaging using normalized data. J Biomed Opt 2005; 10: 064007.

    Article  Google Scholar 

  36. Haller J, Hyde D, Deliolanis N, de Kleine R, Niedre M, Ntziachristos VJ . Visualization of pulmonary inflammation using noninvasive fluorescence molecular imaging. Appl Physiol 2008; 104: 795–802.

    Article  CAS  Google Scholar 

  37. Okamura N, Mori M, Furumoto S, Yoshikawa T, Harada R, Ito S et al. In vivo detection of amyloid plaques in the mouse brain using the near-infrared fluorescence probe THK-265. J Alzherimers Dis 2011; 23: 37–48.

    Article  CAS  Google Scholar 

  38. Klohs J, Baeva N, Steinbrink J, Bourayou R, Boettcher C, Royl G et al. In vivo near-infrared fluorescence imaging of matrix metalloproteinase activity after cerebral ischemia. J Cereb Blood Flow Metab 2009; 29: 1284–1292.

    Article  CAS  Google Scholar 

  39. Passini MA, Lee EB, Heuer GG, Wolfe JH . Distribution of a lysosomal enzyme in the adult brain by axonal transport and by cells of the rostral migratory stream. J Neurosci 2002; 22: 6437–6446.

    Article  CAS  Google Scholar 

  40. Cearley CN, Wolfe JH . A single injection of an adeno-associated virus vector into nuclei with divergent connections results in widespread vector distribution in the brain and global correction of a neurogenetic disease. J Neurosci 2007; 27: 9928–9940.

    Article  CAS  Google Scholar 

  41. Passini MA, Watson DJ, Vite CH, Landsburg DJ, Peigenbaum AL, Wolfe JH . Intraventricular brain injection of adeno-associated virus type 1 (AAV1) in neonatal mice results in complementary patterns of neuronal transduction to AAV2 and total long-term correction of storage lesions in the brains of beta-glucuronidase-deficient mice. J Virol 2003; 77: 7034–7040.

    Article  CAS  Google Scholar 

  42. Passini MA, Wolfe JH . Widespread gene delivery and structure-specific patterns of expression in the brain after intraventricular injections of neonatal mice with an adeno-associated virus vector. J Virol 2001; 25: 12382–12392.

    Article  Google Scholar 

  43. Rudolph D, Sterker I, Graefe G, Till H, Ulrich A, Geyer C . Visual field constriction in children with shunt-treated hydrocephalus. J Neurosurg Pediatr 2010; 6: 481–485.

    Article  Google Scholar 

  44. Watson G, Bastacky J, Belichenko P, Buddhikot M, Jungles S, Vellard M et al. Intrathecal administration of AAV vectors for the treatment of lysosomal storage in the brains of MPS I mice. Gene Therapy 2006; 13: 917–925.

    Article  CAS  Google Scholar 

  45. Muramatsu S, Fujimoto K, Kato S, Mizukami H, Asari S, Ikeguchi K et al. A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinson's disease. Mol Ther 2010; 18: 1731–1735.

    Article  CAS  Google Scholar 

  46. Gray SJ, Woodard KT, Samulski RJ . Viral vectors and delivery strategies for CNS gene therapy. Ther Deliv 2010; 1: 517–534.

    Article  CAS  Google Scholar 

  47. Jaffer FA, Vinegoni C, John MC, Aikawa E, Gold HK, Finn AV et al. Real-time catheter molecular sensing of inflammation in proteolytically active atherosclerosis. Circulation 2008; 118: 1802–1809.

    Article  Google Scholar 

  48. Blum G, von Degenfeld G, Merchant MJ, Blau HM, Bogyo M . Noninvasive optical imaging of cysteine protease activity using fluorescently quenched activity-based probes. Nat Chem Biol 2007; 3: 668–677.

    Article  CAS  Google Scholar 

  49. Maxwell D, Chang Q, Zhang X, Barnett EM, Piwnica-Worms D . An improved cell-penetrating, caspase-activatable, near-infrared fluorescent peptide for apoptosis imaging. Bioconjug Chem 2009; 20: 702–709.

    Article  CAS  Google Scholar 

  50. Hyde D, de Kleine R, MacLaurin SA, Miller E, Brooks DH, Krucker T et al. Hybrid FMT-CT imaging of amyloid-beta plaques in a murine Alzheimer's disease model. Neuroimage 2009; 44: 1304–1311.

    Article  Google Scholar 

  51. Xu L, Daly T, Gao C, Flotte TR, Song S, Byrne BJ et al. CMV-beta-actin promoter directs higher expression from an adeno-associated viral vector in the liver than the cytomegalovirus or elongation factor 1 alpha promoter and results in therapeutic levels of human factor X in mice. Hum Gene Ther 2001; 12: 563–572.

    Article  CAS  Google Scholar 

  52. Saftig P, Peters C, von Figura K, Craessaerts K, Van Leuvan F, De Strooper B . Amyloidogenic processing of human amyloid precursor protein in hippocampal neurons devoid of cathepsin D. J Biol Chem 1996; 271: 27241–27244.

    Article  CAS  Google Scholar 

  53. Bakowska JC, Di Maria MV, Camp SM, Wang Y, Allen PD, Breakefield XO . Targeted transgene integration into transgenic mouse fibroblasts carrying the full-length human AAVS1 locus mediated by HSV/AAV rep(+) hybrid amplicon vector. Gene Therapy 2003; 10: 1691–1702.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by a Howard Hughes Fellowship (GH), NIH/NINDS NS24279 (XOB) and NS045776 (BAT), as well as NIH/NCI CA86355 (XOB and BAT). We thank Suzanne McDavitt for skilled editorial assistance.

Author information

Author notes

  1. L S Pike and B A Tannous: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Massachusetts General Hospital and Neuroscience Program, Harvard Medical School, Boston, MA, USA

    L S Pike, B A Tannous, G Hsich, D Morse, M Sena-Esteves & X O Breakefield

  2. Department of Radiology, Center for Molecular Imaging Research, Massachusetts General Hospital, Boston, MA, USA

    B A Tannous, C-H Tung & X O Breakefield

  3. Institute for Biological and Medical Imaging, Helmholtz Zentrum Muenchen, Ingolstaedter Landstrasse 1-Neuherberg, Neuherberg, Germany

    N C Deliolanis

  4. Center for Pediatric Neurology, Cleveland Clinic, Cleveland, OH, USA

    G Hsich

  5. Department of Radiology, Methodist Hospital Research Institute, Weill Cornell Medical College, Houston, TX, USA

    C-H Tung

  6. Department of Neurology and Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA

    M Sena-Esteves

Authors
  1. L S Pike
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B A Tannous
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N C Deliolanis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G Hsich
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Morse
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C-H Tung
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Sena-Esteves
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. X O Breakefield
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B A Tannous.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pike, L., Tannous, B., Deliolanis, N. et al. Imaging gene delivery in a mouse model of congenital neuronal ceroid lipofuscinosis. Gene Ther 18, 1173–1178 (2011). https://doi.org/10.1038/gt.2011.118

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2011.118

Keywords

This article is cited by

Search

Advanced search

Quick links