Preventing formation of toxic N-terminal huntingtin fragments through antisense oligonucleotide-mediated protein modification

Nucleic Acid Therapeutics

Volumn 24, Issue 1, 2014, Pages 4-12

  Evers, Melvin M ^a   Tran, Hoang Dai ^a   Zalachoras, Ioannis ^a   Meijer, Onno C ^a   Den Dunnen, Johan T ^a   Van Ommen, Gert Jan B ^a   Aartsma Rus, Annemieke ^a   Van Roon Mom, Willeke M C ^a  

^a LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

ANTISENSE OLIGONUCLEOTIDE; CASPASE 3; CASPASE 6; COMPLEMENTARY DNA; HUNTINGTIN; MESSENGER RNA PRECURSOR; N TERMINAL HUNTINGTIN FRAGMENT; UNCLASSIFIED DRUG;

AMINO ACID SEQUENCE; AMINO TERMINAL SEQUENCE; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CAG REPEAT; CELL CULTURE; CELL VIABILITY; CONTROLLED STUDY; CORPUS STRIATUM; EXON; EXON SKIPPING; FIBROBLAST; GENETIC TRANSFECTION; HUMAN; HUMAN CELL; HUNTINGTON CHOREA; IN VITRO STUDY; IN VIVO STUDY; MALE; MOUSE; NERVE DEGENERATION; NEUROTOXICITY; NONHUMAN; PRIORITY JOURNAL; PROTEIN ISOLATION; PROTEIN MODIFICATION; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; SINGLE DRUG DOSE; WESTERN BLOTTING;

ANIMALS; CASPASE 6; CELL LINE; EXONS; HUMANS; HUNTINGTON DISEASE; MALE; MICE; MICE, INBRED C57BL; MUTANT PROTEINS; MUTATION; NERVE TISSUE PROTEINS; OLIGONUCLEOTIDES, ANTISENSE; PEPTIDE FRAGMENTS; PROTEIN MODIFICATION, TRANSLATIONAL; SEROTONIN PLASMA MEMBRANE TRANSPORT PROTEINS; TARGETED GENE REPAIR; TRINUCLEOTIDE REPEAT EXPANSION;

EID: 84893555011     PISSN: 21593337     EISSN: None     Source Type: Journal    
DOI: 10.1089/nat.2013.0452     Document Type: Article

References (56)

1. AARTSMA-RUS, A. (2012). Overview on AON design. Methods Mol. Biol. 867, 117-129.
2. AARTSMA-RUS, A., BREMMER-BOUT, M., JANSON, A.A.M., DEN DUNNEN, J.T., VAN OMMEN, G.J.B., and VAN DEUTEKOM, J.C.T. (2002). Targeted exon skipping as a potential gene correction therapy for Duchenne muscular dystrophy. Neuromuscular Disord. 12, S71-S77.
3. AARTSMA-RUS, A., DE WINTER, C.L., JANSON, A.A., KAMAN, W.E., VAN OMMEN, G.J., DEN DUNNEN, J.T., and VAN DEUTEKOM, J.C. (2005). Functional analysis of 114 exon-internal AONs for targeted DMD exon skipping: indication for steric hindrance of SR protein binding sites. Oligonucleotides 15, 284-297.
4. AARTSMA-RUS, A., VAN, V.L., HIRSCHI, M., JANSON, A.A., HEEMSKERK, H., DE WINTER, C.L., DE, K.S., VAN DEUTEKOM, J.C., 'T HOEN, P.A., and VAN OMMEN, G.J. (2009). Guidelines for antisense oligonucleotide design and insight into splice-modulating mechanisms. Mol. Ther. 17, 548-553.
5. ANDREW, S.E., GOLDBERG, Y.P., KREMER, B., TELENIUS, H., THEILMANN, J., ADAM, S., STARR, E., SQUITIERI, F., LIN, B., KALCHMAN, M.A., et al. (1993). The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington disease. Am. J. Hum. Gen. 53, 1118.
6. BAUER, S., KIRSCHNING, C.J., HACKER, H., REDECKE, V., HAUSMANN, S., AKIRA, S., WAGNER, H., and LIPFORD, G.B. (2001). Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc. Natl. Acad. Sci. U. S. A 98, 9237-9242.
7. BOUDREAU, R.L., MCBRIDE, J.L., MARTINS, I., SHEN, S., XING, Y., CARTER, B.J., and DAVIDSON, B.L. (2009). Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington's disease mice. Mol Ther. 17, 1053-1063.
8. CARROLL, J.B., WARBY, S.C., SOUTHWELL, A.L., DOTY, C.N., GREENLEE, S., SKOTTE, N., HUNG, G., BENNETT, C.F., FREIER, S.M., and HAYDEN, M.R. (2011). Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the Huntington disease gene/allele-specific silencing of mutant huntingtin. Mol. Ther. 19, 2178-2185.
9. CIRAK, S., ARECHAVALA-GOMEZA, V., GUGLIERI, M., FENG, L., TORELLI, S., ANTHONY, K., ABBS, S., GARRALDA, M.E., BOURKE, J., WELLS, D.J., et al. (2011). Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study. Lancet 378, 595-605.
10. CROOK, Z.R., and HOUSMAN, D. (2011). Huntington's disease: can mice lead the way to treatment? Neuron 69, 423-435.
11. DESMET, F.O., HAMROUN, D., LALANDE, M., COLLODBEROUD, G., CLAUSTRES, M., and BEROUD, C. (2009). Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res. 37, e67.
12. DRAGATSIS, I., LEVINE, M.S., and ZEITLIN, S. (2000). Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nat. Genet. 26, 300-306.
13. DROUET, V., PERRIN, V., HASSIG, R., DUFOUR, N., AUREGAN, G., ALVES, S., BONVENTO, G., BROUILLET, E., LUTHI-CARTER, R., HANTRAYE, P., et al. (2009). Sustained Effects of Nonallele-Specific Huntingtin Silencing. Ann. Neurol. 65, 276-285.
14. EHRNHOEFER, D.E., SUTTON, L., and HAYDEN, M.R. (2011). Small changes, big impact: posttranslational modifications and function of huntingtin in Huntington disease. Neuroscientist 17, 475-492.
15. EVERS, M.M., PEPERS, B.A., VAN DEUTEKOM, J.C., MULDERS, S.A., DEN DUNNEN, J.T., AARTSMA-RUS, A., VAN OMMEN, G.J., and VAN ROON-MOM, W.M. (2011). Targeting several CAG expansion diseases by a single antisense oligonucleotide. PLoS One. 6, e24308.
16. GAFNI, J., PAPANIKOLAOU, T., DEGIACOMO, F., HOLCOMB, J., CHEN, S., MENALLED, L., KUDWA, A., FITZPATRICK, J., MILLER, S., RAMBOZ, S., et al. (2012). Caspase-6 activity in a BACHD mouse modulates steadystate levels of mutant huntingtin protein but is not necessary for production of a 586 amino acid proteolytic fragment. J. Neurosci. 32, 7454-7465.
17. GAGNON, K.T., PENDERGRAFF, H.M., DELEAVEY, G.F., SWAYZE, E.E., POTIER, P., RANDOLPH, J., ROESCH, E.B., CHATTOPADHYAYA, J., DAMHA, M.J., BENNETT, C.F., et al. (2010). Allele-selective inhibition of mutant huntingtin expression with antisense oligonucleotides targeting the expanded CAG repeat. Biochemistry 49, 10166-10178.
18. GOLDBERG, Y.P., NICHOLSON, D.W., RASPER, D.M., KALCHMAN, M.A., KOIDE, H.B., GRAHAM, R.K., BROMM, M., KAZEMI-ESFARJANI, P., THORNBERRY, N.A., VAILLANCOURT, J.P., et al. (1996). Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. Nat. Genet. 13, 442-449.
19. GRAHAM, R.K., DENG, Y., CARROLL, J., VAID, K., COWAN, C., POULADI, M.A., METZLER, M., BISSADA, N., WANG, L., FAULL, R.L., et al. (2010). Cleavage at the 586 amino acid caspase-6 site in mutant huntingtin influences caspase-6 activation in vivo. J. Neurosci. 30, 15019-15029.
20. GRAHAM, R.K., DENG, Y., SLOW, E.J., HAIGH, B., BISSADA, N., LU, G., PEARSON, J., SHEHADEH, J., BERTRAM, L., MURPHY, Z., et al. (2006). Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell 125, 1179-1191.
21. HU, J.X., MATSUI, M., GAGNON, K.T., SCHWARTZ, J.C., GABILLET, S., ARAR, K., WU, J., BEZPROZVANNY, I., and COREY, D.R. (2009). Allele-specific silencing of mutant huntingtin and ataxin-3 genes by targeting expanded CAG repeats in mRNAs. Nat. Biotechnol. 27, 478-484.
22. KORDASIEWICZ, H.B., STANEK, L.M., WANCEWICZ, E.V., MAZUR, C., MCALONIS, M.M., PYTEL, K.A., ARTATES, J.W., WEISS, A., CHENG, S.H., SHIHABUDDIN, L.S., et al. (2012). Sustained therapeutic reversal of Huntington's disease by transient repression of huntingtin synthesis. Neuron 74, 1031-1044.
23. KROL, J., FISZER, A., MYKOWSKA, A., SOBCZAK, K., DE MEZER, M., and KRZYZOSIAK, W.J. (2007). Ribonuclease dicer cleaves triplet repeat hairpins into shorter repeats that silence specific targets. Mol. Cell 25, 575-586.
24. LENTZ, J.J., JODELKA, F.M., HINRICH, A.J., MCCAFFREY, K.E., FARRIS, H.E., SPALITTA, M.J., BAZAN, N.G., DUELLI, D.M., RIGO, F., and HASTINGS, M.L. (2013). Rescue of hearing and vestibular function by antisense oligonucleotides in a mouse model of human deafness. Nat. Med. 19, 345-350.
25. LOMBARDI, M.S., JASPERS, L., SPRONKMANS, C., GELLERA, C., TARONI, F., DI MARIA, E., DI DONATO, S., and KAEMMERER, W.F. (2009). A majority of Huntington's disease patients may be treatable by individualized allele-specific RNA interference. Exp. Neurol. 217, 312-319.
26. LUNKES, A., LINDENBERG, K.S., BEN-HAIEM, L.,WEBER, C., DEVYS, D., LANDWEHRMEYER, G.B., MANDEL, J.L., and TROTTIER, Y. (2002). Proteases acting on mutant huntingtin generate cleaved products that differentially build up cytoplasmic and nuclear inclusions. Mol. Cell 10, 259-269.
27. MANGIARINI, L., SATHASIVAM, K., SELLER, M., COZENS, B., HARPER, A., HETHERINGTON, C., LAWTON, M., TROTTIER, Y., LEHRACH, H., DAVIES, S.W., et al. (1996). Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87, 493-506.
28. MCBRIDE, J.L., PITZER, M.R., BOUDREAU, R.L., DUFOUR, B., HOBBS, T., OJEDA, S.R., and DAVIDSON, B.L. (2011). Preclinical safety of RNAi-mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington's disease. Mol. Ther. 19, 2152-2162.
29. MCNEIL, S.M., NOVELLETTO, A., SRINIDHI, J., BARNES, G., KORNBLUTH, I., ALTHERR, M.R., WASMUTH, J.J., GUSELLA, J.F., MACDONALD, M.E., and MYERS, R.H. (1997). Reduced penetrance of the Huntington's disease mutation. Hum. Mol. Genet. 6, 775-779.
30. MILLER, T.M., PESTRONK, A., DAVID, W., ROTHSTEIN, J., SIMPSON, E., APPEL, S.H., ANDRES, P.L., MAHONEY, K., ALLRED, P., ALEXANDER, K., et al. (2013). An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol. 12, 435-442.
31. PFISTER, E.L., KENNINGTON, L., STRAUBHAAR, J., WAGH, S., LIU, W.Z., DIFIGLIA, M., LANDWEHRMEYER, B., VONSATTEL, J.P., ZAMORE, P.D., and ARONIN, N. (2009). Five siRNAs targeting three SNPs may provide therapy for three-quarters of Huntington's disease patients. Curr. Biol. 19, 774-778.
32. POULADI, M.A., GRAHAM, R.K., KARASINSKA, J.M., XIE, Y., SANTOS, R.D., PETERSEN, A., and HAYDEN, M.R. (2009). Prevention of depressive behaviour in the YAC128 mouse model of Huntington disease by mutation at residue 586 of huntingtin. Brain 132, 919-932.
33. RIGAMONTI, D., BAUER, J.H., DE FRAJA, C., CONTI, L., SIPIONE, S., SCIORATI, C., CLEMENTI, E., HACKAM, A., HAYDEN, M.R., LI, Y. et al. (2000). Wild-type Huntingtin protects from apoptosis upstream of caspase-3. J. Neurosci. 20, 3705-3713.
34. ROSS, C.A., and TABRIZI, S.J. (2011). Huntington's disease: from molecular pathogenesis to clinical treatment. Lancet Neurol. 10, 83-98.
35. ROZEN, S., and SKALETSKY, H. (2000). Primer3 on the WWW for general users and for biologist programmers. Methods Mol. Biol. 132, 365-386.
36. RUIJTER, J.M., RAMAKERS, C., HOOGAARS, W.M.H., KARLEN, Y., BAKKER, O., VAN DEN HOFF, M.J.B., and MOORMAN, A.F.M. (2009). Amplification efficiency: linking baseline and bias in the analysis of quantitative PCR data. Nucleic Acids Res. 37, e45.
37. SAH, D.W., and ARONIN, N. (2011). Oligonucleotide therapeutic approaches for Huntington disease. J. Clin. Invest. 121, 500-507.
38. SATHASIVAM, K., NEUEDER, A., GIPSON, T.A., LANDLES, C., BENJAMIN, A.C., BONDULICH, M.K., SMITH, D.L., FAULL, R.L., ROOS, R.A., HOWLAND, D., et al. (2013). Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease. Proc. Natl. Acad. Sci. U. S. A 110, 2366-2370.
39. SPITALI, P., and AARTSMA-RUS, A. (2012). Splice modulating therapies for human disease. Cell 148, 1085-1088.
40. TANGANYIKA-DE WINTER, C.L., HEEMSKERK, H., KARNAOUKH, T.G., VAN, P.M., DE KIMPE, S.J., VAN, D.J., and AARTSMA-RUS, A. (2012). Long-term exon skipping studies with 2'-O-Methyl phosphorothioate antisense oligonucleotides in dystrophic mouse models. Mol. Ther. Nucleic Acids 1, e44.
41. TEBBENKAMP, A.T., GREEN, C., XU, G., DENOVANWRIGHT, E.M., RISING, A.C., FROMHOLT, S.E., BROWN, H.H., SWING, D., MANDEL, R.J., TESSAROLLO, L., et al. (2011). Transgenic mice expressing caspase-6-derived N-terminal fragments of mutant huntingtin develop neurologic abnormalities with predominant cytoplasmic inclusion pathology composed largely of a smaller proteolytic derivative. Hum. Mol. Genet. 20, 2770-2782.
42. VAN BILSEN, P.H.J., JASPERS, L., LOMBARDI, M.S., ODEKERKEN, J.C.E., BURRIGHT, E.N., and KAEMMERER, W.F. (2008). Identification and allele-specific silencing of the mutant huntingtin allele in Huntington's disease patient-derived fibroblasts. Hum. Gene Ther. 19, 710-718.
43. VAN PUTTEN, M., and AARTSMA-RUS, A. (2011). Opportunities and challenges for the development of antisense treatment in neuromuscular disorders. Expert. Opin. Biol. Ther. 11, 1025-1037.
44. VONSATTEL, J.P., and DIFIGLIA, M. (1998). Huntington disease. J. Neuropathol. Exp. Neurol. 57, 369-384.
45. WALDRON-ROBY, E., RATOVITSKI, T., WANG, X., JIANG, M., WATKIN, E., ARBEZ, N., GRAHAM, R.K., HAYDEN, M.R., HOU, Z., MORI, S., et al. (2012). Transgenic mouse model expressing the caspase 6 fragment of mutant huntingtin. J. Neurosci. 32, 183-193.
46. WARBY, S.C., DOTY, C.N., GRAHAM, R.K., CARROLL, J.B., YANG, Y.Z., SINGARAJA, R.R., OVERALL, C.M., and HAYDEN, M.R. (2008). Activated caspase-6 and caspase-6-cleaved fragments of huntingtin specifically colocalize in the nucleus. Hum. Mol. Genet. 17, 2390-2404.
47. WARBY, S.C., MONTPETIT, A., HAYDEN, A.R., CARROLL, J.B., BUTLAND, S.L., VISSCHER, H., COLLINS, J.A., SEMAKA, A., HUDSON, T.J., and HAYDEN, M.R. (2009). CAG expansion in the Huntington disease gene is associated with a specific and targetable predisposing haplogroup. Am. J. Hum. Genet. 84, 351-366.
48. WELLINGTON, C.L., ELLERBY, L.M., HACKAM, A.S., MARGOLIS, R.L., TRIFIRO, M.A., SINGARAJA, R., MCCUTCHEON, K., SALVESEN, G.S., PROPP, S.S., BROMM, M., et al. (1998). Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J. Biol. Chem. 273, 9158-9167.
49. WELLINGTON, C.L., SINGARAJA, R., ELLERBY, L., SAVILL, J., ROY, S., LEAVITT, B., CATTANEO, E., HACKAM, A., SHARP, A., THORNBERRY, N., et al. (2000). Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells. J. Biol. Chem. 275, 19831-19838.
50. WILTON, S.D., FALL, A.M., HARDING, P.L., MCCLOREY, G., COLEMAN, C., and FLETCHER, S. (2007). Antisense oligonucleotide-induced exon skipping across the human dystrophin gene transcript. Mol. Ther. 15, 1288-1296.
51. YU, D., PENDERGRAFF, H., LIU, J., KORDASIEWICZ, H.B., CLEVELAND, D.W., SWAYZE, E.E., LIMA, W.F., CROOKE, S.T., PRAKASH, T.P., and COREY, D.R. (2012). Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression. Cell 150, 895-908.
52. ZALACHORAS, I., EVERS, M.M., VAN ROON-MOM, W.M., AARTSMA-RUS, A.M., and MEIJER, O.C. (2011). Antisense-mediated RNA targeting: versatile and expedient genetic manipulation in the brain. Front. Mol. Neurosci. 4, 10.
53. ZEITLIN, S., LIU, J.P., CHAPMAN, D.L., PAPAIOANNOU, V.E., and EFSTRATIADIS, A. (1995). Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue. Nat. Genet. 11, 155-163.
54. ZHANG, M.Q. (1998). Statistical features of human exons and their flanking regions. Hum. Mol. Genet. 7, 919-932.
55. ZHANG, Y., ENGELMAN, J., and FRIEDLANDER, R.M. (2009). Allele-specific silencing of mutant Huntington's disease gene. J. Neurochem. 108, 82-90.
56. ZUKER, M. (2003). Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res. 31, 3406-3415.