title: Prolonged regulatable expression of EPO from an HSV vector using the LAP2 promoter element.
abstract: We previously reported regulated expression of erythropoietin (EPO) over 4 weeks in the peripheral nerve in vivo, using a herpes simplex virus (HSV)-based vector containing a Tet-on regulatable gene expression cassette. To create a vector that would be appropriate for the treatment of chronic neuropathy, we constructed a HSV vector with expression of EPO under the control of the Tet-on system in which the HSV latency-associated promoter 2 element was used to drive the expression of the Tet-on transactivator. EPO expression from the vector was tightly controlled by administration of doxycycline (DOX) in vitro. One month after inoculation of the vector to transduce dorsal root ganglion (DRG) in vivo, administration of DOX-containing chow-induced expression of EPO. Mice with streptozotocin-induced diabetes, inoculated with the vector, were protected against the development of neuropathy by continuous administration of DOX-containing chow over the course of 3 months. Identical results were achieved when DOX was administered every other week over 3 months of diabetes, but administration of DOX, 1 week out of 3, provided only partial protection against the development of neuropathy. Taken together, these results suggest such a vector is well suited for clinical trial for the treatment of chronic or subacutely developing neuropathy.
authors.affiliation: Department of Neurology, University of Michigan and VA Ann Arbor Healthcare System, Ann Arbor, MI 48109, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Wu
authors.forename: M
authors.initials: M
authors.lastname: Mata
authors.forename: D J
authors.initials: DJ
authors.lastname: Fink
mesh_terms: D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics*; D003929:Diabetic Neuropathies / Q000235:genetics / Q000628:therapy; D018450:Disease Progression; D004318:Doxycycline / Q000494:pharmacology; D004921:Erythropoietin / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D023061:Gene Order; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D011401:Promoter Regions, Genetic; D018139:Simplexvirus / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D008565:Membrane Proteins; C093413:lamina-associated polypeptide 2; D004921:Erythropoietin; D004318:Doxycycline
references.citation: Ann Neurol. 2002 Jan;51(1):8-11
references.pmid: 11782976
references.citation: Eur J Cancer. 2009 Jan;45(1):154-63
references.pmid: 19027286
references.citation: Mol Ther. 2008 Feb;16(2):343-51
references.pmid: 18180781
references.citation: Eur J Cancer. 2007 Mar;43(4):710-7
references.pmid: 17251006
references.citation: Hum Gene Ther. 2011 Sep;22(9):1143-53
references.pmid: 21476867
references.citation: Diabetologia. 2007 Jul;50(7):1550-8
references.pmid: 17508196
references.citation: Exp Neurol. 2008 Jan;209(1):161-70
references.pmid: 17967455
references.citation: Ann Neurol. 2011 Aug;70(2):207-12
references.pmid: 21796661
references.citation: Mol Ther. 2011 Feb;19(2):310-7
references.pmid: 20924361
references.citation: Life Sci. 1994;55(7):519-25
references.pmid: 7913736
references.citation: Brain. 2009 Apr;132(Pt 4):879-88
references.pmid: 19244253
references.citation: Brain. 2004 Apr;127(Pt 4):929-39
references.pmid: 14749293
references.citation: Brain Res. 1998 Jun 1;794(2):313-9
references.pmid: 9622663
references.citation: Nat Neurosci. 2002 Nov;5 Suppl:1046-50
references.pmid: 12403983
references.citation: Antimicrob Agents Chemother. 1982 Jul;22(1):71-7
references.pmid: 6289742
references.citation: Mol Ther. 2004 Jul;10(1):67-75
references.pmid: 15233943
references.citation: Gene Ther. 2005 Sep;12(18):1377-84
references.pmid: 15843809
references.citation: Clin Chem Lab Med. 2001 Apr;39(4):351-5
references.pmid: 11388661
references.citation: J Virol. 1994 Apr;68(4):2239-52
references.pmid: 8139009
references.citation: Ann Neurol. 1994 Aug;36(2):244-6
references.pmid: 8053664
references.citation: Neurosci Lett. 2004 Nov 23;371(2-3):102-5
references.pmid: 15519737
references.citation: Adv Drug Deliv Rev. 2009 Jul 2;61(7-8):527-41
references.pmid: 19394373
references.citation: Hum Gene Ther. 1998 Sep 1;9(13):1939-50
references.pmid: 9741432
references.citation: Biomed Pharmacother. 2010 Dec;64(10):681-5
references.pmid: 20685070
references.citation: Ann Neurol. 2010 Nov;68(5):629-38
references.pmid: 21031578
references.citation: Neurobiol Dis. 2006 Dec;24(3):525-30
references.pmid: 17010629
references.citation: Brain Res Mol Brain Res. 1996 Mar;36(2):280-6
references.pmid: 8965648
references.citation: Mol Ther. 2005 Aug;12(2):307-13
references.pmid: 15927533
references.citation: Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5547-51
references.pmid: 1319065
references.citation: Microbiol Rev. 1989 Sep;53(3):318-32
references.pmid: 2552271
references.citation: Science. 1995 Jun 23;268(5218):1766-9
references.pmid: 7792603
references.citation: Mol Ther. 2006 May;13(5):967-75
references.pmid: 16442848
references.citation: Endocr Res. 2011;36(1):25-34
references.pmid: 21226565
references.citation: Gene Ther. 2007 Dec;14(23):1668-73
references.pmid: 17914405
references.citation: Cell Mol Neurobiol. 2011 Nov;31(8):1229-43
references.pmid: 21681558
references.citation: Neurotox Res. 2010 Aug;18(2):151-60
references.pmid: 19876698
references.citation: Mol Ther. 2006 Nov;14(5):710-5
references.pmid: 16949343
references.citation: Mol Ther. 2001 May;3(5 Pt 1):688-96
references.pmid: 11356074
references.citation: Clin Pharmacol Ther. 2010 Aug;88(2):204-13
references.pmid: 20164833