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Blood-Brain Barrier Transport for RNAi

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Therapeutic Ribonucleic Acids in Brain Tumors

Abstract

RNAi-based therapeutics represent a new generation of potential drugs for the treatment of disorders of the central nervous system, including brain tumors and neurogenerative diseases like Alzheimer's and Huntington's disease. However, the progress in this field is limited by the poor transport of these molecules across cellular and vascular barriers. A global brain distribution of shRNA expressing genes and siRNA molecules, as well as the targeting of specific regions of the brain, is even more complicated because conventional delivery systems, as in the case of viruses, have poor diffusion in brain when injected in situ and do not cross the blood-brain barrier (BBB), which is only permeable to lipophilic molecules of less than 400 Da. Advances in the “Trojan Horse Liposome” (THL) technology applied to the transvascular non-viral gene therapy of brain disorders presents a promising solution to the shRNA delivery problem. The THL is comprised of immunoliposomes carrying shRNA expression plasmids for RNAi effect. The tissue target specificity of THL is given by conjugation of ∼1% of the PEG residues in the THL surface to peptidomimetic monoclonal antibodies (MAb) that bind to specific endogenous receptors located on both the BBB and on brain cellular membranes, i.e. insulin receptor and transferrin receptor (TfR). These MAbs mediate (1) receptor-mediated transcytosis of the THL complex through the BBB, (2) endocytosis into brain cells, and (3) transport to the brain cell nuclear compartment. More recently, conjugates of an anti-TfR MAb and streptavidin were able to deliver biotinylated-siRNA to brain tumors in vivo following intravenous administration, and to produce silencing of a target transcript within the brain tumor. This review presents an overview on this RNAi transport technology and its current application to experimental brain tumor models.

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Authors and Affiliations

  1. Department of Medicine, UCLA Warren Hall 13-164, 900 Veteran Avenue, Los Angeles, CA, 90024, USA

    Ruben J. Boado & William M. Pardridge

  2. ArmaGen Technologies, Inc., 90401, Santa Monica, CA, USA

    Ruben J. Boado

Authors
  1. Ruben J. Boado
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  2. William M. Pardridge
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Correspondence to Ruben J. Boado .

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Editors and Affiliations

  1. Inst. Chemie und Biochemie, FU Berlin, Thielallee 63, Berlin, 14195, Germany

    Volker A. Erdmann

  2. Inst. Neuropathologie, Universitätsklinikum Düsseldorf, Moorenstr. 5, Düsseldorf, 40225, Germany

    Guido Reifenberger

  3. Inst. Bioorganic Chemistry, PAN Poznan, ul. Z. Noskowskiego 12/14, Poznan, 61-704, Poland

    Jan Barciszewski

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Boado, R.J., Pardridge, W.M. (2009). Blood-Brain Barrier Transport for RNAi. In: Erdmann, V., Reifenberger, G., Barciszewski, J. (eds) Therapeutic Ribonucleic Acids in Brain Tumors. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-00475-9_12

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