RNA plasticity and selectivity applicable to therapeutics and novel biosensor development

Department of Basic Medical Sciences, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Genes to Cells (Impact Factor: 2.81). 04/2012; 17(5):344-64. DOI: 10.1111/j.1365-2443.2012.01596.x
Source: PubMed


Aptamers are short, single-stranded nucleic acid sequences that are selected in vitro from large oligonucleotide libraries based on their high affinity to a target molecule. Hence, aptamers can be thought of as a nucleic acid analog to antibodies. However, several viewpoints hold that the potential of aptamers arises from interesting characteristics that are distinct from, or in some cases, superior to those of antibodies. This review summarizes the recent achievements in aptamer programs developed in our laboratory against basic and therapeutic protein targets. Through these studies, we became aware of the remarkable conformational plasticity and selectivity of RNA, on which the published report has not shed much light even though this is evidently a crucial feature for the strong specificity and affinity of RNA aptamers.

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    • "In drug discovery, the search for aptamers as candidate molecules is undoubtedly expected to rise in coming years. So far some visible progresses have already been made [21]. Table 1 summarizes a group of aptamers that are in various stages of drug discovery. "
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    ABSTRACT: Aptamers are short nucleic acid oligos. They may serve as both drugs and drug-carriers. Their use as diagnostic tools is also evident. They can be generated using various experimental, theoretical, and computational techniques. The systematic evolution of ligands by exponential enrichment which uses iterative screening of nucleic acid libraries is a popular experimental technique. Theory inspired methodology entropy-based seed-and-grow strategy that designs aptamer templates to bind specifically to targets is another one. Aptamers are predicted to be highly useful in producing general drugs and theranostic drugs occasionally for certain diseases like cancer, Alzheimer’s disease, and so on. They bind to various targets like lipids, nucleic acids, proteins, small organic compounds, and even entire organisms. Aptamers may also serve as drug-carriers or nanoparticles helping drugs to get released in specific target regions. Due to better target specific physical binding properties aptamers cause less off-target toxicity effects. Therefore, search for aptamer based drugs, drug-carriers, and even diagnostic tools is expanding fast. The biophysical properties in relation to the target specific binding phenomena of aptamers, energetics behind the aptamer transport of drugs, and the consequent biological implications will be discussed. This review will open up avenues leading to novel drug discovery and drug delivery.
    BioMed Research International 09/2014; Volume 2014 (2014), Article ID 697923. DOI:10.1155/2014/697923 · 1.58 Impact Factor
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    • "Regarded as “chemical antibodies”, aptamers have many attributes that are advantageous in comparison with monoclonal antibodies and small molecules. These attributes include higher affinity and specificity, greater ease of manufacture and modification in vitro, and better tissue penetration [14,15]. United States Food and Drug Administration (FDA) approval of the first aptamer drug (Macugen) for the treatment of age-related macular degeneration has proven to be a milestone in the applications of aptamer technology [16,17]. "
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    ABSTRACT: Lymphomas are cancers that arise from white blood cells and usually present as solid tumors. Treatment of lymphoma often involves chemotherapy, and can also include radiotherapy and/or bone marrow transplantation. There is an un-questioned need for more effective therapies and diagnostic tool for lymphoma. Aptamers are single stranded DNA or RNA oligonucleotides whose three-dimensional structures are dictated by their sequences. The immense diversity in function and structure of nucleic acids enable numerous aptamers to be generated through an iterative in vitro selection technique known as Systematic Evolution of Ligands by EXponential enrichment (SELEX). Aptamers have several biochemical properties that make them attractive tools for use as potential diagnostic and pharmacologic agents. Isolated aptamers may directly inhibit the function of target proteins, or they can also be formulated for use as delivery agents for other therapeutic or imaging cargoes. More complex aptamer identification methods, using whole cancer cells (Cell-SELEX), may identify novel targets and aptamers to affect them. This review focuses on recent advances in the use of nucleic acid aptamers as diagnostic and therapeutic agents and as targeted delivery carriers that are relevant to lymphoma. Some representative examples are also discussed.
    Journal of Cancer Therapy 06/2013; 4(4):872-890. DOI:10.4236/jct.2013.44099
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    ABSTRACT: Midkine (MK, MDK) is a heparin-binding growth factor highly expressed in various cancers, including neuroblastoma (NB), the most common extracranial pediatric solid tumor. Prognosis of NB patients where MYCN is amplified remains particularly poor. In this study, we employed a MYCN transgenic model for NB where MK is highly expressed in precancerous lesions of sympathetic ganglia. Genetic ablation of MK in this model delayed tumor formation and reduced tumor incidence. Furthermore, an RNA aptamer that specifically bound MK suppressed the growth of NB cells in vitro and in vivo in tumor xenografts. In precancerous lesions, MK-deficient MYCN Tg mice exhibited defects in activation of Notch2, a candidate MK receptor, and expression of the Notch target gene HES1. Similarly, RNA aptamer-treated tumor xenografts also showed attenuation of Notch2-HES1 signaling. Our findings establish a critical role for the MK-Notch2 signaling axis in NB tumorigenesis, which implicates new strategies to treat NB.
    Cancer Research 12/2012; 73(4). DOI:10.1158/0008-5472.CAN-12-3070 · 9.33 Impact Factor
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