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Nonviral siRNA Delivery for Gene Silencing in Neurodegenerative Diseases

  • Satya Prakash
  • Meenakshi Malhotra
  • Venkatesh Rengaswamy
Part of the Methods in Molecular Biology book series (MIMB, volume 623)

Abstract

Linking genes with the underlying mechanisms of diseases is one of the biggest challenges of genomics-driven drug discovery research. Designing an inhibitor for any neurodegenerative disease that effectively halts the pathogenicity of the disease is yet to be achieved. The challenge lies in crossing the blood-brain barrier (BBB)/blood-cerebrospinal fluid barrier (BCSFB) to reach the catalytic pockets of the enzyme/protein involved in the molecular mechanism of the disease process. Designing siRNA with exquisite specificity may result in selective suppression of the disease-linked gene. Although siRNA is the most promising method, it loses its potency in downregulating the gene due to its inherent instability, off-target effects, and lack of on-target effective delivery systems. Viral as well as nonviral delivery methods have been effectively tested in vivo for silencing of molecular targets and have resulted in significant efficacy in animal models of Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), anxiety, depression, encephalitis, glioblastoma, Huntington’s disease, neuropathic pain, and spinocerebellar ataxia. To realize the full therapeutic potential of siRNA for neurodegenerative diseases, we need to overcome many hurdles and challenges such as selecting suitable tissue-specific delivery vectors, minimizing the off-target effects, and achieving distribution in sufficient concentrations at the target tissue without any side effects. Cationic nanoparticle-mediated targeted siRNA delivery for therapeutic purposes has gained considerable clinical importance as a result of its promising efficacy.

Key words

Cationic nanoparticles Targeted delivery siRNA Biotherapeutics Gene silencing Neurodegenerative diseases 

Notes

Acknowledgments

We gratefully acknowledge the research grant received from Canadian Institute of Health Research (CIHR) to Dr. S. Prakash. We also acknowledge support of McGill Faculty of Medicine Internal Scholarship to M. Malhotra.

References

  1. 1.
    Sah, W. Y. (2006) Therapeutic potential of RNA interference for neurological disorders. Life Sci. 79, 1773–1780.CrossRefPubMedGoogle Scholar
  2. 2.
    Behlke, M. A. (2006) Progress towards in-vivo use of siRNAs. Mol. Ther. 13, 644–670.CrossRefPubMedGoogle Scholar
  3. 3.
    Gonzalez-Alegre, P. (2007) Therapeutic RNA interference for neurodegenerative diseases: from promise to progress. Pharmacol. Ther. 114, 34–55.CrossRefPubMedGoogle Scholar
  4. 4.
    Brown, R. C., Lockwood, A. H., and Sonawane, B. R. (2005) Neurodegenerative diseases: an overview of environmental risk factors. Environ. Health Perspect. 113, 1250–1256.CrossRefPubMedGoogle Scholar
  5. 5.
    Elbashir, S. M., Harborth, J., Lendeckel,W., Yalcin, A.,Weber, K., and Tuschl, T. (2001) Duplexes of 21-nucleotide RNA mediate RNA interference in cultured mammalian cells. Nature 411, 494–498.CrossRefPubMedGoogle Scholar
  6. 6.
    Dorn, G., Patel, S., Wotherspoon, G., Hemmings-Mieszczak, M., Barclay, J., Natt, F. J., et al. (2004) siRNA relieves chronic neuropathic pain. Nucleic Acids Res. 32, e49.CrossRefPubMedGoogle Scholar
  7. 7.
    Guan, H., Zhou, Z., Wang, H., Jia, S.F., Liu, W., and Kleinerman, E. S. (2005) A small interfering RNA targeting vascular endothelial growth factor inhibits Ewing’s sarcoma growth in a xenograft mouse model. Clin. Cancer Res. 11, 2662–2669.CrossRefPubMedGoogle Scholar
  8. 8.
    Takei, Y., Kadomatsu, K., Yuzawa, Y., Matsuo, S., and Muramatsu, T. (2004) A small interfering RNA targeting vascular endothelial growth factor as cancer therapeutics. Cancer Res. 64, 3365–3370.CrossRefPubMedGoogle Scholar
  9. 9.
    Shen, J., Samul, R., Silva, R. L., Akiyama, H., Liu, H., Saishin, Y., et al. (2006) Suppression of ocular neovascularization with siRNA targeting VEGF receptor 1. Gene Ther. 13, 225–234.CrossRefPubMedGoogle Scholar
  10. 10.
    Zhang, Y., Zhang, Y. F., Bryant, J., Charles, A., Boado, R. J., and Pardridge, W. M. (2004) Intravenous RNA interference gene therapy targeting the human epidermal growth factor receptor prolongs survival in intracranial brain cancer. Clin. Cancer Res. 10, 3667–3677.CrossRefPubMedGoogle Scholar
  11. 11.
    Luo, M., Ge, P., Hadwiger, P., Meyers, R., Sah, D. W. Y., Porreca, F., and Lai, J. (2005) RNAi of neuropeptide Y (NPY) for neuropathic pain. Soc Neurosci Abstr.Google Scholar
  12. 12.
    Bhoumik, A., Huang, T. G., Ivanov, V., Gangi, L., Qiao, R. F., Woo, S. L., Chen, S. H., and Ronai, Z. (2002) An ATF2-derived peptide sensitizes melanomas to apoptosis and inhibits their growth and metastasis. J. Clin. Invest. 110, 643–650.PubMedGoogle Scholar
  13. 13.
    Gaudilliere, B., Shi, Y., and Bonni, A. (2002) RNA interference reveals a requirement for MEF2A in activity-dependent neuronal survival. J. Biol. Chem. 277, 46442–46446.CrossRefPubMedGoogle Scholar
  14. 14.
    Qiu, S., Adema, C. M., and Lane, T. (2005) A computational study of off-target effects of RNA interference. Nucleic Acids Res. 33, 1834–1847.CrossRefPubMedGoogle Scholar
  15. 15.
    Soutschek, J., Akinc, A., Bramlage, B., Charisse, K., Constien, R., Donoghue, M., et al. (2004) Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432, 173–178.CrossRefPubMedGoogle Scholar
  16. 16.
    Song, E., Lee, S. K., Wang, J., Ince, N., Ouyang, N., Min, J., et al. (2003) RNA interference targeting Fas protects mice from fulminant hepatitis. Nat. Med. 9, 347–351.CrossRefPubMedGoogle Scholar
  17. 17.
    Stark, G. R., Kerr, I. M., Williams, B. R., Silverman, R. H., and Schreiber, R. D. (1998) How cells respond to interferons. Annu. Rev. Biochem. 67, 227−264.CrossRefPubMedGoogle Scholar
  18. 18.
    Wheeler, G., Ntounia-Fousara, S., Granda, B., Rathjen, T., and Dalmay, T. (2006) Identification of new central nervous system specific mouse microRNA. FEBS Lett. 580, 2195–2200.CrossRefPubMedGoogle Scholar
  19. 19.
    Davis, M. E., Pun, S. H., Bellocq, N. C., Reineke, T. M., Popielarski, S. R., Mishra, S. Heidel, J. D. (2004) Self-assembling nucleic acid delivery vehicles via linear, water-soluble, cyclodextrin containing polymers. Curr. Med. Chem. 11, 179–197.CrossRefPubMedGoogle Scholar
  20. 20.
    Lu, P. Y., Xie, F. and Woodle, M. C. (2005) In vivo application of RNA interference: from functional genomics to therapeutics. Adv. Genet. 54, 117–42.PubMedGoogle Scholar
  21. 21.
    Tan, P. H., Yang, L. C., Shih, H. C., Lan, K. C., and Cheng, J. T. (2005) Gene knockdown with intrathecal siRNA of NMDA receptor NR2B subunit reduces formalin-induced nociception in the rat. Gene Ther. 12, 59–66.CrossRefPubMedGoogle Scholar
  22. 22.
    Thakker, D. R., Hoyer, D., and Cryan, J. F. (2006) Interfering with the brain: use of RNA interference for understanding the pathophysiology of psychiatric and neurological disorders. Pharmacol. Ther. 109, 413–438.CrossRefPubMedGoogle Scholar
  23. 23.
    Thakker, D. R., Natt, F., Husken, D., van der Putten, H., Maier, R., Hoyer, D., and Cryan, J. F. (2005) siRNA-mediated knockdown of the serotonin transporter in the adult mouse brain. Mol. Psychiatry 10, 782-789CrossRefPubMedGoogle Scholar
  24. 24.
    Wang, Y. L., Liu, W., Wada, E., Murata, M., Wada, K., and Kanazawa, I. (2005) Clinico-pathological rescue of a model mouse of Huntington’s disease by siRNA. Neurosci. Res. 53, 241–249.CrossRefPubMedGoogle Scholar
  25. 25.
    Kumar, P., Lee, S. K., Shankar, P., and Manjunath, N. (2006) A single siRNA suppresses fatal encephalitis induced by two different flaviviruses. PLoS Med. 3, e96.CrossRefPubMedGoogle Scholar
  26. 26.
    Hassani, Z., Lemkine, G. F., Erbacher, P., Palmier, K., Alfama, G., Behr, C., and Demeneix, J.-P. (2005) Lipid-mediated siRNA delivery down-regulates exogenous gene expression in the mouse brain at picomolar levels. J. Gene Med. 7, 198–207.CrossRefPubMedGoogle Scholar
  27. 27.
    Katas, H., and Alpar, H.O. (2006) Development and characterisation of chitosan nanoparticles for siRNA delivery. Mol. Ther. 115, 216–225.Google Scholar
  28. 28.
    Howard, K. A., Rahbek, U. L., Liu, X., Damgaard, C. K., Glud, S. Z., Andersen, M. Ø., et al. (2006) RNA interference in-vitro and in-vivo using a novel chitosan/siRNA nanoparticle system. Mol. Ther. 14, 476–484.CrossRefPubMedGoogle Scholar
  29. 29.
    Bartlett, D. W., Su, H., Hildebrandt, I. J., Weber, W. A., and Davis, M. E. (2007) Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in-vivo imaging. Proc. Natl. Acad. Sci. U.S.A. 104, 5549–5554.CrossRefGoogle Scholar
  30. 30.
    Inoue, Y., Kurihara, R., Tsuchida, A., Hasegawa, M., Nagashima, T., Mori, T., et al. (2008) Efficient delivery of siRNA using dendritic poly(l-lysine) for loss-of-function analysis. J. Control. Release 126, 59–66.CrossRefPubMedGoogle Scholar
  31. 31.
    Patil, M. L., Zhang, M., Betigeri, S., Taratula, O., He, H., and Minko, T. (2008) Surface-modified and internally cationic polyamidoamine dendrimers for efficient siRNA delivery. Bioconjug. Chem. 19, 1396–1403.CrossRefPubMedGoogle Scholar
  32. 32.
    Park, Y., Kwok, K. Y., Boukarim, C., and Rice, K. G. (2002) Synthesis of sulfhydryl cross-linking poly(ethylene glycol)-peptides and glycopeptides as carriers for gene delivery. Bioconjug. Chem. 13, 232–239.CrossRefPubMedGoogle Scholar
  33. 33.
    Oupicky, D., Ogris, M., Howard, K. A. Dash, P. R., Ulbrich, K., and Seymour L. W. (2002) Importance of lateral and steric stabilization of polyelectrolyte gene delivery vectors for extended systemic circulation. Mol. Ther. 5, 463–472.CrossRefPubMedGoogle Scholar
  34. 34.
    Sun, Y. X., Zeng, X., Meng, Q. F., Zhang, X. Z., Cheng, S. X., and Zhuo, R. X. (2008) The influence of RGD addition on the gene transfer characteristics of disulfide-containing polyethyleneimine/DNA complexes. Biomaterials 29, 4356–4365.CrossRefPubMedGoogle Scholar
  35. 35.
    Kumar, P., Wu, H., McBride, J. L., Jung, K. E., Kim, M. H., Davidson, B.L., et al. (2007) Transvascular delivery of small interfering RNA to the central nervous system. Nature 448, 39–43.CrossRefPubMedGoogle Scholar
  36. 36.
    Pang, Z., Lu, W., Gao, H., Hu, K., Chen, J., Zhang, C., et al. (2008) Preparation and brain delivery property of biodegradable polymersomes conjugated with OX26. J. Control. Release 128, 120–127.CrossRefPubMedGoogle Scholar
  37. 37.
    Urban-Klein, B., Werth, S., Abuharbeid, S., Czubayko, F., Aigner, A. (2005) RNA-mediated gene-targeting through systemic application of polyethyleneimine (PEI)-complexes siRNA in-vivo. Gene Ther. 12, 461–466.CrossRefPubMedGoogle Scholar
  38. 38.
    Murata, N., Takashima, Y., Toyoshima, K., Yamamoto, M., and Okada, H. (2008) Anti-tumor effects of anti-VEGF siRNA encapsulated with PLGA microspheres in mice. J. Control. Release 126, 246–254.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Satya Prakash
    • 1
  • Meenakshi Malhotra
    • 1
  • Venkatesh Rengaswamy
    • 2
  1. 1.Biomedical Technology and Cell Therapy Research Laboratory, Departments of Biomedical Engineering and Physiology, Faculty of Medicine, Artificial Cells and Organs Research CenterMcGill UniversityMontrealCanada
  2. 2.Advance Microscopy and Imaging Facility, Molecular Virology and Cell Biology LabIndian Institute of Technology (IIT)ChennaiIndia

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