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Open Access 01-12-2010 | Research

Differential adeno-associated virus mediated gene transfer to sensory neurons following intrathecal delivery by direct lumbar puncture

Authors: Lucy Vulchanova, Daniel J Schuster, Lalitha R Belur, Maureen S Riedl, Kelly M Podetz-Pedersen, Kelley F Kitto, George L Wilcox, R Scott McIvor, Carolyn A Fairbanks

Published in: Molecular Pain | Issue 1/2010

Abstract

Background

Neuronal transduction by adeno-associated viral (AAV) vectors has been demonstrated in cortex, brainstem, cerebellum, and sensory ganglia. Intrathecal delivery of AAV serotypes that transduce neurons in dorsal root ganglia (DRG) and spinal cord offers substantial opportunities to 1) further study mechanisms underlying chronic pain, and 2) develop novel gene-based therapies for the treatment and management of chronic pain using a non-invasive delivery route with established safety margins. In this study we have compared expression patterns of AAV serotype 5 (AAV5)- and AAV serotype 8 (AAV8)-mediated gene transfer to sensory neurons following intrathecal delivery by direct lumbar puncture.

Results

Intravenous mannitol pre-treatment significantly enhanced transduction of primary sensory neurons after direct lumbar puncture injection of AAV5 (rAAV5-GFP) or AAV8 (rAAV8-GFP) carrying the green fluorescent protein (GFP) gene. The presence of GFP in DRG neurons was consistent with the following evidence for primary afferent origin of the majority of GFP-positive fibers in spinal cord: 1) GFP-positive axons were evident in both dorsal roots and dorsal columns; and 2) dorsal rhizotomy, which severs the primary afferent input to spinal cord, abolished the majority of GFP labeling in dorsal horn. We found that both rAAV5-GFP and rAAV8-GFP appear to preferentially target large-diameter DRG neurons, while excluding the isolectin-B4 (IB4) -binding population of small diameter neurons. In addition, a larger proportion of CGRP-positive cells was transduced by rAAV5-GFP, compared to rAAV8-GFP.

Conclusions

The present study demonstrates the feasibility of minimally invasive gene transfer to sensory neurons using direct lumbar puncture and provides evidence for differential targeting of subtypes of DRG neurons by AAV vectors.

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Kaemmerer WF, Reddy RG, Warlick CA, Hartung SD, McIvor RS, Low WC: In vivo transduction of cerebellar Purkinje cells using adeno-associated virus vectors. Mol Ther 2000, 2: 446–457. 10.1006/mthe.2000.0134PubMedCrossRef

Beutler AS, Banck MS, Walsh CE, Milligan ED: Intrathecal gene transfer by adeno-associated virus for pain. Curr Opin Mol Ther 2005, 7: 431–439.PubMed

Lin D, Fantz CR, Levy B, Rafi MA, Vogler C, Wenger DA, Sands MS: AAV2/5 vector expressing galactocerebrosidase ameliorates CNS disease in the murine model of globoid-cell leukodystrophy more efficiently than AAV2. Mol Ther 2005, 12: 422–430. 10.1016/j.ymthe.2005.04.019PubMedCrossRef

Broekman ML, Comer LA, Hyman BT, Sena-Esteves M: Adeno-associated virus vectors serotyped with AAV8 capsid are more efficient than AAV-1 or -2 serotypes for widespread gene delivery to the neonatal mouse brain. Neuroscience 2006, 138: 501–510. 10.1016/j.neuroscience.2005.11.057PubMedCrossRef

Storek B, Reinhardt M, Wang C, Janssen WG, Harder NM, Banck MS, Morrison JH, Beutler AS: Sensory neuron targeting by self-complementary AAV8 via lumbar puncture for chronic pain. Proc Natl Acad Sci USA 2008, 105: 1055–1060. 10.1073/pnas.0708003105PubMedCentralPubMedCrossRef

Xu Y, Gu Y, Xu GY, Wu P, Li GW, Huang LY: Adeno-associated viral transfer of opioid receptor gene to primary sensory neurons: a strategy to increase opioid antinociception. Proc Natl Acad Sci USA 2003, 100: 6204–6209. 10.1073/pnas.0930324100PubMedCentralPubMedCrossRef

Finegold AA, Perez FM, Iadarola MJ: In vivo control of NMDA receptor transcript level in motoneurons by viral transduction of a short antisense gene. Brain Res Mol Brain Res 2001, 90: 17–25. 10.1016/S0169-328X(01)00062-6PubMedCrossRef

Yaksh TL, Jessell TM, Gamse R, Mudge AW, Leeman SE: Intrathecal morphine inhibits substance P release from mammalian spinal cord in vivo. Nature 1980, 286: 155–157. 10.1038/286155a0PubMedCrossRef

Finegold AA, Mannes AJ, Iadarola MJ: A paracrine paradigm for in vivo gene therapy in the central nervous system: treatment of chronic pain. Hum Gene Ther 1999, 10: 1251–1257. 10.1089/10430349950018238PubMedCrossRef

10.

Towne C, Pertin M, Beggah AT, Aebischer P, Decosterd I: Recombinant adeno-associated virus serotype 6 (rAAV2/6)-mediated gene transfer to nociceptive neurons through different routes of delivery. Mol Pain 2009, 5: 52. 10.1186/1744-8069-5-52PubMedCentralPubMedCrossRef

11.

Pogatzki EM, Zahn PK, Brennan TJ: Lumbar catheterization of the subarachnoid space with a 32-gauge polyurethane catheter in the rat. Eur J Pain 2000, 4: 111–113. 10.1053/eujp.1999.0157PubMedCrossRef

12.

Xu JJ, Walla BC, Diaz MF, Fuller GN, Gutstein HB: Intermittent lumbar puncture in rats: a novel method for the experimental study of opioid tolerance. Anesth Analg 2006, 103: 714–720. 10.1213/01.ane.0000226100.46866.eaPubMedCrossRef

13.

Storkson RV, Kjorsvik A, Tjolsen A, Hole K: Lumbar catheterization of the spinal subarachnoid space in the rat. Journal of Neuroscience Methods 1996, 65: 167–172. 10.1016/0165-0270(95)00164-6PubMedCrossRef

14.

Sakura S, Hashimoto K, Bollen AW, Ciriales R, Drasner K: Intrathecal catheterization in the rat. Improved technique for morphologic analysis of drug-induced injury. Anesthesiology 1996, 85: 1184–1189. 10.1097/00000542-199611000-00028PubMedCrossRef

15.

Jones LL, Tuszynski MH: Chronic intrathecal infusions after spinal cord injury cause scarring and compression. Microsc Res Tech 2001, 54: 317–324. 10.1002/jemt.1144PubMedCrossRef

16.

Tsang BK, He Z, Ma T, Ho IK, Eichhorn JH: Decreased paralysis and better motor coordination with microspinal versus PE10 intrathecal catheters in pain study rats. Anesth Analg 1997, 84: 591–594. 10.1097/00000539-199703000-00023PubMed

17.

Fairbanks CA: Spinal delivery of analgesics in experimental models of pain and analgesia. Adv Drug Deliv Rev 2003, 55: 1007–1041. 10.1016/S0169-409X(03)00101-7PubMedCrossRef

18.

Levin AB, Duff TA, Javid MJ: Treatment of increased intracranial pressure: a comparison of different hyperosmotic agents and the use of thiopental. Neurosurgery 1979, 5: 570–575. 10.1227/00006123-197911000-00005PubMedCrossRef

19.

Kroll RA, Neuwelt EA: Outwitting the blood-brain barrier for therapeutic purposes: osmotic opening and other means. Neurosurgery 1998, 42: 1083–1099. discussion 1099–1100 10.1097/00006123-199805000-00082PubMedCrossRef

20.

Fu H, Muenzer J, Samulski RJ, Breese G, Sifford J, Zeng X, McCarty DM: Self-complementary adeno-associated virus serotype 2 vector: global distribution and broad dispersion of AAV-mediated transgene expression in mouse brain. Mol Ther 2003, 8: 911–917. 10.1016/j.ymthe.2003.08.021PubMedCrossRef

21.

Mastakov MY, Baer K, Symes CW, Leichtlein CB, Kotin RM, During MJ: Immunological aspects of recombinant adeno-associated virus delivery to the mammalian brain. J Virol 2002, 76: 8446–8454. 10.1128/JVI.76.16.8446-8454.2002PubMedCentralPubMedCrossRef

22.

Akache B, Grimm D, Pandey K, Yant SR, Xu H, Kay MA: The 37/67-kilodalton laminin receptor is a receptor for adeno-associated virus serotypes 8, 2, 3, and 9. J Virol 2006, 80: 9831–9836. 10.1128/JVI.00878-06PubMedCentralPubMedCrossRef

23.

Asokan A, Hamra JB, Govindasamy L, Agbandje-McKenna M, Samulski RJ: Adeno-associated virus type 2 contains an integrin alpha5beta1 binding domain essential for viral cell entry. J Virol 2006, 80: 8961–8969. 10.1128/JVI.00843-06PubMedCentralPubMedCrossRef

24.

Kashiwakura Y, Tamayose K, Iwabuchi K, Hirai Y, Shimada T, Matsumoto K, Nakamura T, Watanabe M, Oshimi K, Daida H: Hepatocyte growth factor receptor is a coreceptor for adeno-associated virus type 2 infection. J Virol 2005, 79: 609–614. 10.1128/JVI.79.1.609-614.2005PubMedCentralPubMedCrossRef

25.

Qing K, Mah C, Hansen J, Zhou S, Dwarki V, Srivastava A: Human fibroblast growth factor receptor 1 is a co-receptor for infection by adeno-associated virus 2. Nat Med 1999, 5: 71–77. 10.1038/8526PubMedCrossRef

26.

Summerford C, Samulski RJ: Membrane-associated heparan sulfate proteoglycan is a receptor for adeno-associated virus type 2 virions. J Virol 1998, 72: 1438–1445.PubMedCentralPubMed

27.

Di Pasquale G, Davidson BL, Stein CS, Martins I, Scudiero D, Monks A, Chiorini JA: Identification of PDGFR as a receptor for AAV-5 transduction. Nat Med 2003, 9: 1306–1312. 10.1038/nm929PubMedCrossRef

28.

Walters RW, Yi SM, Keshavjee S, Brown KE, Welsh MJ, Chiorini JA, Zabner J: Binding of adeno-associated virus type 5 to 2,3-linked sialic acid is required for gene transfer. J Biol Chem 2001, 276: 20610–20616. 10.1074/jbc.M101559200PubMedCrossRef

29.

Baiou D, Santha P, Avelino A, Charrua A, Bacskai T, Matesz K, Cruz F, Nagy I: Neurochemical characterization of insulin receptor-expressing primary sensory neurons in wild-type and vanilloid type 1 transient receptor potential receptor knockout mice. J Comp Neurol 2007, 503: 334–347. 10.1002/cne.21389PubMedCrossRef

30.

Zwick M, Davis BM, Woodbury CJ, Burkett JN, Koerber HR, Simpson JF, Albers KM: Glial cell line-derived neurotrophic factor is a survival factor for isolectin B4-positive, but not vanilloid receptor 1-positive, neurons in the mouse. J Neurosci 2002, 22: 4057–4065.PubMed

31.

Price TJ, Flores CM: Critical evaluation of the colocalization between calcitonin gene-related peptide, substance P, transient receptor potential vanilloid subfamily type 1 immunoreactivities, and isolectin B4 binding in primary afferent neurons of the rat and mouse. J Pain 2007, 8: 263–272. 10.1016/j.jpain.2006.09.005PubMedCentralPubMedCrossRef

32.

Sun H, Ren K, Zhong CM, Ossipov MH, Malan TP, Lai J, Porreca F: Nerve injury-induced tactile allodynia is mediated via ascending spinal dorsal column projections. Pain 2001, 90: 105–111. 10.1016/S0304-3959(00)00392-4PubMedCrossRef

33.

Hylden JL, Wilcox GL: Intrathecal morphine in mice: a new technique. Eur J Pharmacol 1980, 67: 313–316. 10.1016/0014-2999(80)90515-4PubMedCrossRef

34.

Mestre C, Pelissier T, Fialip J, Wilcox G, Eschalier A: A method to perform direct transcutaneous intrathecal injection in rats. J Pharmacol Toxicol Methods 1994, 32: 197–200. 10.1016/1056-8719(94)90087-6PubMedCrossRef

35.

Vulchanova L, Riedl MS, Shuster SJ, Stone LS, Hargreaves KM, Buell G, Surprenant A, North RA, Elde R: P _{2 × 3} is expressed by DRG neurons that terminate in inner lamina II. Eur J Neurosci 1998, 10: 3470–3478. 10.1046/j.1460-9568.1998.00355.xPubMedCrossRef

36.

Fang X, Djouhri L, McMullan S, Berry C, Waxman SG, Okuse K, Lawson SN: Intense isolectin-B4 binding in rat dorsal root ganglion neurons distinguishes C-fiber nociceptors with broad action potentials and high Nav1.9 expression. J Neurosci 2006, 26: 7281–7292. 10.1523/JNEUROSCI.1072-06.2006PubMedCrossRef

Title: Differential adeno-associated virus mediated gene transfer to sensory neurons following intrathecal delivery by direct lumbar puncture
Authors: Lucy Vulchanova
Daniel J Schuster
Lalitha R Belur
Maureen S Riedl
Kelly M Podetz-Pedersen
Kelley F Kitto
George L Wilcox
R Scott McIvor
Carolyn A Fairbanks
Publication date: 01-12-2010
Publisher: BioMed Central
Published in: Molecular Pain / Issue 1/2010
Electronic ISSN: 1744-8069
DOI: https://doi.org/10.1186/1744-8069-6-31

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Differential adeno-associated virus mediated gene transfer to sensory neurons following intrathecal delivery by direct lumbar puncture

Abstract

Background

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Results

Conclusions

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