Targeting BACE with small inhibitory nucleic acids - a future for Alzheimer's disease therapy?

• Autorzy: Nawrot B.
• Języki publikacji: EN

Abstrakty

EN

ß-Secretase, a ß-site amyloid precursor protein (APP) cleaving enzyme (BACE), par­ticipates in the secretion of ß-amyloid peptides (Aß), the major components of the toxic amyloid plaques found in the brains of patients with Alzheimer's disease (AD). According to the amyloid hypothesis, accumulation of Aß is the primary influence driving AD pathogenesis. Lowering of Aß secretion can be achieved by decreasing BACE activity rather than by down-regulation of the APP substrate protein. There­fore, ß-secretase is a primary target for anti-amyloid therapeutic drug design. Se­veral approaches have been undertaken to find an effective inhibitor of human ß-secretase activity, mostly in the field of peptidomimetic, non-cleavable substrate analogues. This review describes strategies targeting BACE mRNA recognition and its down-regulation based on the antisense action of small inhibitory nucleic acids (siNAs). These include antisense oligonucleotides, catalytic nucleic acids — ribo­zymes and deoxyribozymes — as well as small interfering RNAs (siRNAs). While antisense oligonucleotides were first used to identify an aspartyl protease with S-secretase activity, all the strategies now demonstrate that siNAs are able to inhibit BACE gene expression in a sequence-specific manner, measured both at the level of its mRNA and at the level of protein. Moreover, knock-down of BACE reduces the intra- and extracellular population of Aß40 and Aß42 peptides. An anti-amyloid effect of siNAs is observed in a wide spectrum of cell lines as well as in primary cortical neurons. Thus targeting BACE with small inhibitory nucleic acids may be beneficial for the treatment of Alzheimer’s disease and for future drug design.

Słowa kluczowe

EN

beta-amyloid peptide; Alzheimer's disease; beta-secretase; deoxyribozyme; nucleic acid; therapy; hammerhead ribozyme

• Wydawca: -
• Czasopismo: Acta Biochimica Polonica
• Rocznik: 2004
• Tom: 51
• Numer: 2
• Opis fizyczny: p.431-444,fig.,ref.

Twórcy

autor

Nawrot B.

• Polish Academy of Sciences, Sienkiewicza 112, 90-363 Lodz, Poland

Bibliografia

• Banks WA, Farr SA, Butt W, Kumar VB, Franko MW, Morley JE. (2001) Delivery across the blood-brain barrier of antisense directed against amyloid beta: reversal of learning and memory deficits in mice overexpressing amyloid precursor protein. J Pharmacol Exp Ther.; 297: 1113-21.
• Barger SW, Fiscus RR, Ruth P, Hofmann F, Mattson MP. (1995) Role of cyclic GMP in the regulation of neuronal calcium and survival by secreted forms of beta-amyloid precursor. JNeurochem.; 64: 2087-96.
• Basi G, Frigon N, Barbour R, Doan T, Gordon G, McConlogue L, Sinha S, Zeller M. (2003) Antagonistic effects of BACE1 and BACE2 on Abeta production in cells. J Biol Chem.; 278: 31512-20.
• Bernstein E, Caudy AA, Hammond SM, Hannon GJ. (2001) Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature.; 409: 363-6.
• Bhisetti GR, Saunders JO, Murcko MA, Lepre CA, Britt SD, Come JH, Deninger DD, Wang T. (2002) Inhibitors of BACE. Patent WO 02/88101.
• Brady SF, Singh S, Crouthamel MC, Holloway MK, Coburn CA, Garsky VM, Bogusky M, Pennington MW, Vacca JP, Hazuda D, Lai MT. (2004) Rational design and synthesis of selective BACE-1 inhibitors. Bioorg Med Chem Lett.; 14: 601-4.
• Bridge AJ, Pebernard S, Ducraux A, Nicoulaz AL, Iggo R. (2003) Induction of an interferon response by RNAi vectors in mammalian cells. Nat Genet.; 34: 263-4.
• Brummelkamp TR, Bernards R, Agami R. (2002) A system for stable expression of short interfering RNAs in mammalian cells. Science.; 296: 550-3.
• Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, Wong PC. (2001) BACE1 is the major beta- secretase for generation of Ab peptides by neurons. NatNeurosci.; 4: 233-4.
• Christoffersen RE, Marr JJ. (1995) Ribozymes as human therapeutic agents. J Med Chem.; 38: 2023-37.
• Citron M. (2002a) Beta-secretase as a target for the treatment of Alzheimer's disease. J Neurosci Res.; 70: 373-9.
• Citron M. (2002b) Emerging Alzheimer's disease therapies: inhibition of beta-secretase. Neurobiol Aging.; 23: 1017-22.
• Davidson BL, Breakefield XO. (2003) Viral vectors for gene delivery to the nervous system. Nat Rev Neurosci.; 4: 353-64.
• Dorsett Y, Tuschl T. (2004) siRNAs: applications in functional genomics and potential as therapeutics. Nat Rev Drug Discov.; 3: 318-29.
• Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. (2001a) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature.; 411: 494-8.
• Elbashir SM, Martinez J, Patkaniowska A, Lendeckel W, Tuschl T. (2001b) Functional anatomy of siRNAs for mediating efficient RNAi in Drosophila melanogasterembryo lysate. EMBO J.; 20: 6877-88.
• Emilsson GM, Nakamura S, Roth A, Breaker RR. (2003) Ribozyme speed limits. RNA.; 9: 907-18.
• Evans J. (2001) New paths to Alzheimer's drugs. Chemistry in Britain.; April, 47-51.
• Farzan M, Schnitzler CE, Vasilieva N, Leung D, Choe H. (2000) BACE2, a beta-secretase homolog, cleaves at the beta site and within the amyloid-betaeta region of the amyloid-beta precursor protein. Proc Natl Acad Sci USA.; 97: 9712-7.
• Ghosh AK, Shin D, Downs D, Koelsch G, Lin X, Ermolieff J, Tang J. (2000) Design of potent inhibitors for human brain memapsin 2 (beta-secretase). J Am Chem Soc.; 122: 3522-3.
• Ghosh AK, Bilcer G, Harwood C, Kawahama R, Shin D, Hussain KA, Hong L, Loy JA, Nguyen C, Koelsch G, Ermolieff J, Tang J. (2001) Structure-based design: potent inhibitors of human brain memapsin 2 (beta- secretase). J Med Chem.; 44: 2865-8.
• Ghosh AK, Hong L, Tang J. (2002) Beta-secretase as a therapeutic target for inhibitor drugs. Curr Med Chem.; 9: 1135-44.
• Haass C, Selkoe DJ. (1993) Cellular processing of beta-amyloid precursor protein and the genesis of amyloid beta-peptide. Cell.; 75: 1039-42.
• Hardy J, Allsop D. (1991) Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol Sci.; 12: 383-8.
• Hardy J, Selkoe DJ. (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science.; 297: 353-6.
• Helmut L. (2000) Antibiotic to treat Alzheimer's? Science.; 290: 1273-4.
• Hendriks L, Van Broeckhoven Ch. (1996) A beta A4 amyloid precursor protein gene and Alzheimer's disease. Eur J Biochem.; 237: 6-15.
• Highleyman L. (1998) FDA approves fomivirsen, famciclovir, and Thalidomide. Food and Drug Administration. BETA. Oct.; 5.
• Hong L, Koelsch G, Lin X, Wu S, Terzyan S, Ghosh AK, Zhang XC, Tang J. (2000) Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science.; 290: 150-3.
• Hong L, Turner RT 3rd, Koelsch G, Shin D, Ghosh AK, Tang J. (2002) Crystal structure of memapsin 2 (beta- secretase) in complex with an inhibitor 0M00-3. Biochemistry.; 41: 10963-7.
• Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, Gloger IS, Murphy KE, Southan CD, Ryan DM, Smith TS, Simmons DL, Walsh FS, Dingwall C, Christie G. (1999) Identification of a novel aspartyl protease (Asp 2) as beta-secretase. Mol Cell Neurosci.; 14: 419-27.
• Jackson AL, Bartz SR, Schelter J, Kobayashi SV, Burchard J, Mao M, Li B, Cavet G, Linsley PS. (2003)
• Expression profiling reveals off-target gene regulation by RNAi. NatBiotechnol.; 21: 635-7.
• Jarrett JT, Berger EP, Lansbury PT Jr. (1993) The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease. Biochemistry.-, 32: 4693-7.
• John V, Beck JP, Bienkowski MJ, Sinha S, Heinrikson RL. (2003) Human beta-secretase (BACE) and BACE inhibitors. J Med Chem.; 46: 4625-30.
• Kao SC, Krichevsky AM, Kosik KS, Tsai LH. (2004) BACE1 suppression by RNA interference in primary cortical neurons. J Biol Chem.; 279: 1942-9.
• Kawasaki H, Warashina M, Kuwabara T, Taira K. (2004) Helicase-attached novel hybrid ribozymes. Methods Mol Biol.; 252: 237-44.
• Kitazume S, Tachida Y, Oka R, Kotani N, Ogawa K, Suzuki M, Dohmae N, Takio K, Saido TC, Hashimoto Y. (2003) Characterization of alpha 2,6-sialyltransferase cleavage by Alzheimer's beta-secretase (BACE1). J Biol Chem.; 278: 14865-71.
• Kitazume S, Tachida Y, Oka R, Shirotani K, Saido TC, Hashimoto Y. (2001) Alzheimer's beta-secretase, beta­site amyloid precursor protein-cleaving enzyme, is responsible for cleavage of a Golgi-resident sialyltransferase. Proc Natl Acad Sci USA.; 98: 13554-9.
• Koseki S, Tanabe T, Tani K, Asano S, Shioda T, Nagai Y, Shimada T, Ohkawa J, Taira K. (1999) Factors governing the activity in vivo of ribozymes transcribed by RNA polymerase III. J Virology.; 73: 1868-77.
• Kummer C, Wehner S, Quast T, Werner S, Herzog V. (2002) Expression and potential function of beta- amyloid precursor proteins during cutaneous wound repair. Exp Cell Res.; 280: 222-32.
• Kurreck J. (2003) Antisense technologies, improvement through novel chemical modifications. Eur J Biochem.; 270: 1628-44.
• Kuwabara T, Warashina M, Sano M, Tang H, Wong-Staal F, Munekata E, Taira K. (2001) Recognition of engineered tRNAs with an extended 3' end by exportin-t (Xpo-t) and transport of tRNA-attached ribozymes to the cytoplasm in somatic cells. Biomacromolecules.; 2: 1229-42.
• Lewin AS, Hauswirth WW. (2001) Ribozyme gene therapy: applications for molecular medicine. Trends Mol Med.; 7: 221-8.
• Li Q, Sudhof TC. (2004) Cleavage of amyloid-beta precursor protein and amyloid-beta precursor-like protein by BACE 1. J Biol Chem.; 279: 10542-50.
• Li R, Lindholm K, Yang LB, Yue X, Citron M, Yan R, Beach T, Sue L, Sabbagh M, Cai H, Wong P, Price D, Shen Y. (2004) Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer's disease patients. Proc Natl Acad Sci USA.; 101: 3632-7.
• Lichtenthaler SF, Dominguez DI, Westmeyer GG, Reiss K, Haass C, Saftig P, De Strooper B, Seed B. (2003) The cell adhesion protein P-selectin glycoprotein ligand-1 is a substrate for the aspartyl protease BACE1. J Biol Chem.; 278: 48713-9.
• Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. (2000) Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci USA.; 97: 1456-60.
• Luo Y, Bolon B, Kahn S, Bennett BD, Babu-Khan S, Denis P, Fan W, Kha H, Zhang J, Gong Y, Martin L, Louis JC, Yan Q, Richards WG, Citron M, Vassar R. (2001) Mice deficient in BACE1, the Alzheimer's beta- secretase, have normal phenotype and abolished beta-amyloid generation. Nat Neurosci.; 4: 231-2.
• Mattson MP, Cheng B, Culwell AR, Esch FS, Lieberburg I, Rydel RE. (1993) Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the beta-amyloid precursor protein. Neuron.; 10: 243-54.
• Mattson MP, Furukawa K. (1997) Alzheimer's disease. Short precursor shortens memory. Nature.; 387: 457-8.
• McSwinggen J, Beigelman L. (2003) RNA interference mediated treatment of Alzheimer's disease using short interfering nucleic acids (siNA). Patent WO 03/070895.
• Miyagishi M, Taira K. (2002) U6 promoter-driven siRNAs with four uridine 3' overhangs efficiently suppress targeted gene expression in mammalian cells. NatBiotechnol.; 20: 497-500.
• Miyamoto M, Matsui J, Fukumoto H, Tarui N. (2001) b-Secretase inhibitors. Patent WO 01/187293.
• Nawrot B, Antoszczyk S, Maszewska M, Kuwabara T, Warashina M, Taira K, Stec WJ. (2003) Efficient inhibition of beta-secretase (BACE) gene expression in HEK293T cells by tRNAVal/CTE-driven hammerhead ribozymes. Eur J Biochem.; 270: 3962-70.
• Nawrot B, Antoszczyk S, Maszewska M, Rebowski G, Kuwabara T, Warashina M, Taira K, Stec WJ. (2002) Modulation of beta-secretase gene expression by action of catalytic nucleic acids. Nucleic Acids Res Suppl.; 2: 105-6.
• Omi K, Tokunaga K, Hohjoh H. (2004) Long-lasting RNAi activity in mammalian neurons. FEBSLett.; 558: 89-95.
• Opalinska JB, Gewirtz AM. (2002) Nucleic acid therapeutics: a work in progress. Curr Opin InvestigDrugs.; 3: 928-33.
• Paddison PJ, Caudy AA, Bernstein E, Hannon GJ, Conklin DS. (2002) Short hairpin RNAs (shRNAs) induce sequence-specific silencing in mammalian cells. Genes Dev.; 16: 948-58.
• Paddison PJ, Caudy AA, Hannon GJ. (2002) Stable suppression of gene expression by RNAi in mammalian cells. Proc Natl Acad Sci USA.; 99: 1443-8.
• Pardridge WM. (2002) Drug and gene targeting to the brain with molecular trojan horses. Nat Rev Drug Discov.; 1: 131-9.
• Paul CP, Good PD, Winer I, Engelke DR. (2002) Effective expression of small interfering RNA in human cells. Nat Biotechnol.; 20: 505-8.
• Persengiev SP, Zhu X, Green MR. (2004) Nonspecific, concentration-dependent stimulation and repression of mammalian gene expression by small interfering RNAs (siRNAs). RNA.; 10: 12-8.
• Qiao L, Etcheberrigaray R. (2002) Phosphinylmethyl and phosphorylmethyl succinic and glutaric acid analogs as beta-secretase inhibitors. Patent WO 02/96897.
• Roberds SL, Anderson J, Basi G, Bienkowski MJ, Branstetter DG, Chen KS, Freedman SB, Frigon NL, Games D, Hu K, Johnson-Wood K, Kappenman KE, Kawabe TT, Kola I, Kuehn R, Lee M, Liu W, Motter R, Nichols NF, Power M, Robertson DW, Schenk D, Schoor M, Shopp GM, Shuck ME, Sinha S, Svensson KA, Tatsuno G, Tintrup H, Wijsman J, Wright S, McConlogue L. (2001) BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics. Hum Mol Genet.; 10: 1317-24.
• Roggo S. (2002) Inhibition of BACE, a promising approach to Alzheimer's disease therapy. Curr Top Med Chem.; 2: 359-70.
• Schmidt B. (2003) Aspartic proteases involved in Alzheimer's disease. ChemBioChem.; 4: 366-78.
• Schwarz D, Hutvagner G, Du T, Xu Z, Aronin N, Zamore PD. (2003) Assymetry in the assembly of the RNAi enzyme complex. Cell.; 115: 199-208.
• Selkoe DJ. (1991) The molecular pathology of Alzheimer's disease. Neuron.; 6: 487-98.
• Simons K, Ehehalt R. (2002) Cholesterol, lipid rafts, and disease. J Clin Invest.; 110: 597-603.
• Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, Frigon N, Hong J, Jacobson-Croak K, Jewett N, Keim P, Knops J, Lieberburg I, Power M, Tan H, Tatsuno G, Tung J, Schenk D, Seubert P, Suomensaari SM, Wang S, Walker D, John V., et al. (1999) Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature.; 402: 537-40.
• Stein CA, Cheng YC. (1993) Antisense oligonucleotides as therapeutic agents — is the bullet really magical? Science.; 261: 1004-12.
• Sullenger BA, Gilboa E. (2002) Emerging clinical applications of RNA. Nature.; 418: 252-8.
• Trulzsch B, Wood M. (2004) Application of nucleic acid technology in the CNS. JNeurochem.; 88: 257-65.
• Turner RT 3ed, Koelsch G, Hong L, Castanheira P, Ermolieff J, Ghosh AK, Tang J. (2001) Subsite specificity of memapsin 2 (beta-secretase): implications for inhibitor design. Biochemistry.; 40: 10001-6.
• Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Bier AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M. (1999) beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science.; 286: 735-41.
• Vinogradov SV, Batrakova EV, Kabanov AV. (2004) Nanogels for oligonucleotide delivery to the brain. Bioconjug Chem.; 15: 50-60.
• Warashina M, Kuwabara T, Kato Y, Sano M, Taira K. (2001) RNA-protein hybrid ribozymes that efficiently cleave any mRNA independently of the structure of the target RNA. Proc Natl Acad Sci USA.; 98: 5572-7.
• Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE, Carter DB, Tomasselli AG, Parodi LA, Heinrikson RL, Gurney ME. (1999) Membrane- anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature.; 402: 533-7.
• Zuker M. (2003) Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res.; 31: 3406-15.