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Potential of siRNA Therapy in Chronic Myeloid Leukemia

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Intracellular Delivery II

Part of the book series: Fundamental Biomedical Technologies ((FBMT,volume 7))

Abstract

Leukemic cancers arise from genetic alterations in normal hematopoietic stem or progenitor cells, leading to impaired regulation of proliferation, differentiation, apoptosis and survival of the malignant cells. A range of molecular alterations is beginning to be elucidated in specific types of leukemias, providing potential targets for molecular modulation as the basis of a therapy. With the advent of RNA interference (RNAi) and, in particular, the short interfering RNA (siRNA) as its pharmacological mediator, it is becoming possible to specifically modulate desired leukemic targets at will. This chapter will summarize the current attempts to utilize siRNAs in leukemic therapy using chronic myeloid leukemia (CML) as a prototypical disease model. We first provide a brief background on the CML disease with particular emphasis on molecular mediators critical in this disease and the current drug therapy. The limitations of current drugs and potential of RNAi are presented. We then provide a summary of delivery efforts employed to deliver siRNA to CML cells, with emphasis on non-viral delivery approach due to its better safety profile for utility in a clinical setting. Important factors involved in intracellular delivery of siRNA are highlighted, emphasizing features critical for non-viral delivery. We conclude with a perspective on the future of siRNA therapy for the CML disease.

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Abbreviations

RNAi:

RNA interference

dsRNA:

Double stranded RNA

CML:

Chronic myeloid leukemia

AML:

Acute myeloid leukemia

LSC:

Leukemic stem cells

RISC:

RNA-induced silencing complex

siRNA:

Short interfering RNA

mRNA:

Messenger RNA

shRNS:

Short hairpin RNA

TKI:

Tyrosine-kinase inhibitors

SDF-1:

Stromal cell-derived factor-1

CXCR4:

C-X-C chemokine receptor type 4

IC50:

Concentration required for 50 % loss of cell viability

PRAME:

Preferentially expressed antigen of melanoma

STAT:

Signal transducer and activator of transcription

PPP2R5C:

Protein phosphatase 2, Regulatory subunit B′, gamma

PEI:

Polyethylenimine

PLL:

Poly-l-lysine

MW:

Molecular weight

kDa:

Kilo Dalton

PEI2:

2 kDa PEI

PEI2LA:

Linoleic acid substituted 2 kDa PEI

PEI1.2PA:

Palmitic acid substituted 1.2 kDa PEI

GFP:

Green fluorescent protein

MSC:

Mesenchymal stem cells

ECM:

Extracellular matrix

CPP:

Cell penetrating peptides

PTD-DRBD:

Peptide transduction domain and double-stranded RNA-binding domain

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Authors and Affiliations

  1. Department of Biomedical Engineering, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, T6G 2V2, Canada

    Juliana Valencia-Serna & Hasan Uludag

  2. Department of Chemical and Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton, AB, T6G 2G6, Canada

    Breanne Landry & Hasan Uludag

  3. Terry Fox Laboratories, British Columbia Cancer Agency, Department of Medical Genetics, University of British Columbia, Vancouver, BC, V5Z 1L3, Canada

    Xiaoyan Jiang

  4. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, T6G 2G6, Canada

    Hasan Uludag

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  1. Juliana Valencia-Serna
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  2. Breanne Landry
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  3. Xiaoyan Jiang
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  4. Hasan Uludag
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Correspondence to Hasan Uludag .

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  1. Chemical and Biological Engineering, Vanderbilt University, Nashville, Tennessee, USA

    Aleš Prokop

  2. Chemistry and Materials Engineering, Kansai University, Osaka, Japan

    Yasuhiko Iwasaki

  3. Department of Applied Chemistry, Osaka Prefecture University, Osaka, Japan

    Atsushi Harada

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Valencia-Serna, J., Landry, B., Jiang, X., Uludag, H. (2014). Potential of siRNA Therapy in Chronic Myeloid Leukemia. In: Prokop, A., Iwasaki, Y., Harada, A. (eds) Intracellular Delivery II. Fundamental Biomedical Technologies, vol 7. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-8896-0_21

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