Early or late-stage anti-N-terminal huntingtin intrabody gene therapy reduces pathological features in B6.HDR6/1 mice

Journal of Neuropathology and Experimental Neurology

Volumn 69, Issue 10, 2010, Pages 1078-1085

  Snyder Keller, Abigail ^a,b,c   McLear, Julie A ^a,d   Hathorn, Tyisha ^c   Messer, Anne ^a,b,c  

^a WADSWORTH CENTER   (United States)

^b STATE UNIVERSITY OF NEW YORK   (United States)

^c ALBANY MEDICAL COLLEGE   (United States)

^d UTICA COLLEGE   (United States)

Author keywords

AAV; Aggregates; Gene therapy; Huntington disease; Intrabody; R6 1 mice; scFv

Indexed keywords

HUNTINGTIN; SINGLE CHAIN FRAGMENT VARIABLE ANTIBODY; VIRUS VECTOR; 4',6 DIAMIDINO 2 PHENYLINDOLE; ANTIBODY; DIAGNOSTIC AGENT; HUNTINGTON PROTEIN, MOUSE; INDOLE DERIVATIVE; NERVE PROTEIN; NUCLEAR PROTEIN; PEPTIDE; POLYGLUTAMINE;

ADENO ASSOCIATED VIRUS; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CORPUS STRIATUM; FEMALE; GENE THERAPY; GLIA CELL; HUNTINGTON CHOREA; MALE; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; AGE; ANIMAL; C57BL MOUSE; CHEMISTRY; DISEASE MODEL; GENE VECTOR; GENETICS; IMMUNOLOGY; METHODOLOGY; MUTATION; PATHOLOGY; TIME; TRANSGENIC MOUSE;

AGE FACTORS; ANIMALS; ANTIBODIES; DISEASE MODELS, ANIMAL; GENE THERAPY; GENETIC VECTORS; HUNTINGTON DISEASE; INDOLES; MICE; MICE, INBRED C57BL; MICE, TRANSGENIC; MUTATION; NERVE TISSUE PROTEINS; NUCLEAR PROTEINS; PEPTIDES; TIME FACTORS;

EID: 77957930942     PISSN: 00223069     EISSN: None     Source Type: Journal    
DOI: 10.1097/NEN.0b013e3181f530ec     Document Type: Article

References (34)

1. La Spada AR, Taylor JP. Repeat expansion disease: Progress and puzzles in disease pathogenesis. Nat Rev Genet 2010;11:247-58
2. Group THsDCR. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Hun-tington's Disease Collaborative Research Group. Cell 1993;72:971-83
3. DiFiglia M, Sapp E, Chase KO, et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 1997;277:1990-93
4. Gutekunst CA, Li SH, Yi H, et al. Nuclear and neuropil aggregates in Huntington's disease: Relationship to neuropathology. J Neurosci 1999; 19:2522-34
5. Dai Y, Dudek NL, Li Q, et al. Striatal expression of a calmodulin fragment improved motor function, weight loss, and neuropathology in the R6/2 mouse model of Huntington's disease. J Neurosci 2009;29:11550-59
6. DiFiglia M, Sena-Esteves M, Chase K, et al. Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuro-pathology and behavioral deficits. Proc Natl Acad Sci U S A 2007;104: 17204-9
7. Rodriguez-Lebron E, Denovan-Wright EM, Nash K, et al. Intrastriatal rAAV-mediated delivery of anti-huntingtin shRNAs induces partial reversal of disease progression in R6/1 Huntington's disease transgenic mice. Mol Ther 2005;12:618-33
8. Davies SW, Turmaine M, Cozens BA, et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 1997;90:537-48
9. Mangiarini L, Sathasivam K, Seller M, et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 1996;87:493-506
10. Miller TW, Messer A. Intrabody applications in neurological disorders: Progress and future prospects. Mol Ther 2005;12:394-401
11. Naver B, Stub C, Moller M, et al. Molecular and behavioral analysis of the R6/1 Huntington's disease transgenic mouse. Neuroscience 2003; 122:1049-57
12. Messer A, McLear J. The therapeutic potential of intrabodies in neurologic disorders: Focus on Huntington and Parkinson diseases. BioDrugs 2006;20:327-33
13. Lecerf JM, Shirley TL, Zhu Q, et al. Human single-chain Fv intrabodies counteract in situ huntingtin aggregation in cellular models of Hunting-ton's disease. Proc Natl Acad Sci U S A 2001;98:4764-69
14. Miller TW, Zhou C, Gines S, et al. A human single-chain Fv intrabody preferentially targets amino-terminal Huntingtin's fragments in striatal models of Huntington's disease. Neurobiol Dis 2005;19:47-56
15. Murphy RC, Messer A. A single-chain Fv intrabody provides functional protection against the effects of mutant protein in an organotypic slice culture model of Huntington's disease. Brain Res Mol Brain Res 2004; 121:141-45
16. Wolfgang WJ, Miller TW, Webster JM, et al. Suppression of Hunting-ton's disease pathology in Drosophila by human single-chain Fv antibodies. Proc Natl Acad Sci U S A 2005;102:11563-68
17. Kvam E, Nannenga BL, Wang MS, et al. Conformational targeting of fibrillar polyglutamine proteins in live cells escalates aggregation and cytotoxicity. PLoS One 2009;4:5727
18. Li H, Li SH, Cheng AL, et al. Ultrastructural localization and progressive formation of neuropil aggregates in Huntington's disease transgenic mice. Hum Mol Genet 1999;8:1227-36
19. Morton AJ, Lagan MA, Skepper JN, et al. Progressive formation of inclusions in the striatum and hippocampus of mice transgenic for the human Huntington's disease mutation. J Neurocytol 2000;29:679-702
20. Ehrnhoefer DE, Butland SL, Pouladi MA, et al. Mouse models of Huntington disease: Variations on a theme. Dis Model Mech 2009;2: 123-29
21. Saudou F, Finkbeiner S, Devys D, et al. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 1998;95:55-66
22. Arrasate M, Mitra S, Schweitzer ES, et al. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 2004;431:805-10
23. Yamamoto A, Lucas JJ, Hen R. Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease. Cell 2000; 101:57-66
24. Wang CE, Tydlacka S, Orr AL, et al. Accumulation of N-terminal mutant huntingtin in mouse and monkey models implicated as a pathogenic mechanism in Huntington's disease. Hum Mol Genet 2008; 17:2738-51
25. Southwell AL, Ko J, Patterson PH. Intrabody gene therapy ameliorates motor, cognitive, and neuropathological symptoms in multiple mouse models of Huntington's disease. J Neurosci 2009;29:13589-602
26. Gu X, Greiner ER, Mishra R, et al. Serines 13 and 16 are critical determinants of full-length human mutant huntingtin induced disease patho-genesis in HD mice. Neuron 2009;64:828-40
27. Davidson BL, Breakefield XO. Viral vectors for gene delivery to the nervous system. Nat Rev Neurosci 2003;4:353-64
28. Reimsnider S, Manfredsson FP, Muzyczka N, et al. Time course of transgene expression after intrastriatal pseudotyped rAAV2/1, rAAV2/2, rAAV2/5, and rAAV2/8 transduction in the rat. Mol Ther 2007;15: 1504-11
29. Dodiya HB, Bjorklund T, Stansell J 3rd, et al. Differential transduction following basal ganglia administration of distinct pseudotyped AAV capsid serotypes in nonhuman primates. Mol Ther 2010;18:579-87
30. Wang C, Wang CM, Clark KR, et al. Recombinant AAV serotype 1 transduction efficiency and tropism in the murine brain. Gene Ther 2003; 10:1528-34
31. Burger C, Gorbatyuk OS, Velardo MJ, 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;10:302-17
32. Giampa C, Patassini S, Borreca A, et al. Phosphodiesterase 10 inhibition reduces striatal excitotoxicity in the quinolinic acid model of Hunting-ton's disease. Neurobiol Dis 2009;34:450-56
33. Ferrante RJ, Kowall NW, Beal MF, et al. Selective sparing of a class of striatal neurons in Huntington's disease. Science 1985;230:561-63
34. Bortvedt SF, McLear JA, Messer A, et al. Cystamine and intrabody co-treatment confers additional benefits in a fly model of Huntington's disease. Neurobiol Dis 2010;40:130-34