Developing Small Activating RNA As a Therapeutic: Current Challenges and Promises

References

• Uesaka M Agata K Oishi T Nakashima K Imamura T . Evolutionary acquisition of promoter-associated non-coding RNA (pancRNA) repertoires diversifies species-dependent gene activation mechanisms in mammals . BMC Genomics18 ( 1 ), 285 ( 2017 ).
   PubMedGoogle Scholar
• Pennacchio LA Ahituv N Moses AM et al. In vivo enhancer analysis of human conserved non-coding sequences . Nature444 ( 7118 ), 499 – 502 ( 2006 ).
   PubMed Web of Science ®Google Scholar
• Visel A Prabhakar S Akiyama JA et al. Ultraconservation identifies a small subset of extremely constrained developmental enhancers . Nat. Genet.40 ( 2 ), 158 – 160 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Huang V Qin Y Wang J et al. RNAa is conserved in mammalian cells . PLoS ONE5 ( 1 ), e8848 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Guo D Barry L Lin SSH Huang V Li LC . RNAa in action: from the exception to the norm . RNA Biol.11 ( 10 ), 1221 – 1225 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Li L-C Okino ST Zhao H et al. Small dsRNAs induce transcriptional activation in human cells . Proc. Natl Acad. Sci. USA103 ( 46 ), 17337 – 17342 ( 2006 ).
   PubMed Web of Science ®Google Scholar
• Janowski BA Younger ST Hardy DB Ram R Huffman KE Corey DR . Activating gene expression in mammalian cells with promoter-targeted duplex RNAs . Nat. Chem. Biol.3 ( 3 ), 166 – 173 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Place RF Li L-C Pookot D Noonan EJ Dahiya R . MicroRNA-373 induces expression of genes with complementary promoter sequences . Proc. Natl Acad. Sci. USA105 ( 5 ), 1608 – 1613 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Yin H Lin H . An epigenetic activation role of Piwi and a Piwi-associated piRNA in Drosophila melanogaster . Nature450 ( 7167 ), 304 – 308 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Voutila J Reebye V Roberts TC et al. Development and mechanism of small activating RNA targeting CEBPA, a novel therapeutic in clinical trials for liver cancer . Mol. Ther.25 ( 12 ), 2705 – 2714 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Kalantari R Chiang CM Corey DR . Regulation of mammalian transcription and splicing by nuclear RNAi . Nucleic Acids Res.44 ( 2 ), 524 – 537 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Meister G Landthaler M Patkaniowska A Dorsett Y Teng G Tuschl T . Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs . Mol. Cell.15 ( 2 ), 185 – 197 ( 2004 ).
   PubMed Web of Science ®Google Scholar
• Rand TA Ginalski K Grishin N V Wang X . Biochemical identification of Argonaute 2 as the sole protein required for RNA-induced silencing complex activity . Proc. Natl Acad. Sci. USA101 ( 40 ), 14385 – 14389 ( 2004 ).
   PubMed Web of Science ®Google Scholar
• Liu J Carmell MA Rivas F V et al. Argonaute2 is the catalytic engine of mammalian RNAi . Science305 ( 5689 ), 1437 – 1441 ( 2004 ).
   PubMed Web of Science ®Google Scholar
• Weinmann L Höck J Ivacevic T et al. Importin 8 is a gene silencing factor that targets argonaute proteins to distinct mRNAs . Cell136 ( 3 ), 496 – 507 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Castel SE Martienssen RA . RNA interference in the nucleus: roles for small RNAs in transcription, epigenetics and beyond . Nat. Rev. Genet.14 ( 2 ), 100 – 112 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Core LJ Waterfall JJ Lis JT . Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters . Science322 ( 5909 ), 1845 – 1848 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Seila AC Calabrese JM Levine SS et al. Divergent transcription from active promoters . Science322 ( 5909 ), 1849 – 1851 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Schwartz JC Younger ST Nguyen NB et al. Antisense transcripts are targets for activating small RNAs . Nat. Struct. Mol. Biol.15 ( 8 ), 842 – 848 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Portnoy V Lin SHS Li KH et al. SaRNA-guided Ago2 targets the RITA complex to promoters to stimulate transcription . Cell Res.26 ( 3 ), 320 – 335 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Jaehning JA . The Paf1 complex: Platform or player in RNA polymerase II transcription . Biochim. Biophys. Acta1799 ( 5–6 ), 379 – 388 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Mueller CL Jaehning JA . Ctr9, Rtf1, and Leo1 are components of the Paf1/RNA polymerase II complex . Mol. Cell. Biol.22 ( 7 ), 1971 – 1980 ( 2002 ).
   PubMed Web of Science ®Google Scholar
• Tang W You W Shi F et al. RNA helicase A acts as a bridging factor linking nuclear β-actin with RNA polymerase II . Biochem. J.420 ( 3 ), 421 – 428 ( 2009 ).
   PubMedGoogle Scholar
• Zhang S Grosse F . Molecular characterization of nuclear DNA helicase II (RNA helicase A) . Methods Mol. Biol.587 , 291 – 302 ( 2010 ).
   PubMedGoogle Scholar
• Rondón AG Gallardo M García-Rubio M Aguilera A . Molecular evidence indicating that the yeast PAF complex is required for transcription elongation . EMBO Rep.5 ( 1 ), 47 – 53 ( 2004 ).
   PubMed Web of Science ®Google Scholar
• Marton HA Desiderio S . The Paf1 complex promotes displacement of histones upon rapid induction of transcription by RNA polymerase II . BMC Mol. Biol.9 ( 1 ), 4 ( 2008 ).
   PubMedGoogle Scholar
• Kim J Guermah M Roeder RG . The human PAF1 complex acts in chromatin transcription elongation both independently and cooperatively with SII/TFIIS . Cell140 ( 4 ), 491 – 503 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Chu Y Yue X Younger ST Janowski BA Corey DR . Involvement of argonaute proteins in gene silencing and activation by RNAs complementary to a noncoding transcript at the progesterone receptor promoter . Nucleic Acids Res.38 ( 21 ), 7736 – 7748 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Chu Y Simic R Warner MH Arndt KM Prelich G . Regulation of histone modification and cryptic transcription by the Bur1 and Paf1 complexes . EMBO J.26 ( 22 ), 4646 – 4656 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Faghihi MA Wahlestedt C . Regulatory roles of natural antisense transcripts . Nat. Rev. Mol. Cell Biol.10 ( 9 ), 637 – 643 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Johnsson P Ackley A Vidarsdottir L et al. A pseudogene long-noncoding-RNA network regulates PTEN transcription and translation in human cells . Nat. Struct. Mol. Biol.20 ( 4 ), 440 – 446 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Modarresi F Faghihi MA Lopez-Toledano MA et al. Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation . Nat. Biotechnol.30 ( 5 ), 453 – 459 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Wanowska E Kubiak MR Rosikiewicz W Makałowska I Szcześniak MW . Natural antisense transcripts in diseases: From modes of action to targeted therapies . Wiley Interdiscip. Rev. RNA9 ( 2 ), e1461 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• Melo CA Drost J Wijchers PJ et al. ERNAs are required for p53-dependent enhancer activity and gene transcription . Mol. Cell.49 ( 3 ), 524 – 535 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Wang D Garcia-Bassets I Benner C et al. Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA . Nature474 ( 7351 ), 390 – 397 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Hah N Murakami S Nagari A Danko CG Kraus WL . Enhancer transcripts mark active estrogen receptor binding sites . Genome Res.23 ( 8 ), 1210 – 23 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Ulitsky I Bartel DP . X LincRNAs: genomics, evolution, and mechanisms . Cell154 ( 1 ), 26 – 46 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Jiao AL Slack FJ . RNA-mediated gene activation . Epigenetics9 ( 1 ), 27 – 36 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Li W Notani D Rosenfeld MG . Enhancers as non-coding RNA transcription units: recent insights and future perspectives . Nat. Rev. Genet.17 ( 4 ), 207 – 223 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Mu X Greenwald E Ahmad S Hur S . An origin of the immunogenicity of in vitro transcribed RNA . Nucleic Acids Res.46 ( 10 ), 5239 – 5249 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• Triana-Alonso FJ Dabrowski M Wadzack J Nierhaus KH . Self-coded 3′-extension of run-off transcripts produces aberrant products during in vitro transcription with T7 RNA polymerase . J. Biol. Chem.270 ( 11 ), 6298 – 6307 ( 1995 ).
   PubMed Web of Science ®Google Scholar
• Kwon H Kim M Seo Y et al. Emergence of synthetic mRNA: in vitro synthesis of mRNA and its applications in regenerative medicine . Biomaterial156 , 172 – 193 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• Maeder ML Linder SJ Cascio VM Fu Y Ho QH Joung JK . CRISPR RNA-guided activation of endogenous human genes . Nat. Methods10 ( 10 ), 977 – 979 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Perez-Pinera P Kocak DD Vockley CM et al. RNA-guided gene activation by CRISPR-Cas9-based transcription factors . Nat. Methods10 ( 10 ), 973 – 976 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Xiong X Chen M Lim WA Zhao D Qi LS . CRISP R/Cas9 for human genome engineering and disease research . Annu. Rev. Genomics Hum. Genet.17 ( 1 ), 131 – 154 ( 2016 ).
   PubMedGoogle Scholar
• Liang XH Shen W Sun H Migawa MT Vickers TA Crooke ST . Translation efficiency of mRNAs is increased by antisense oligonucleotides targeting upstream open reading frames . Nat. Biotechnol.34 ( 8 ), 875 – 880 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Voutila J Sætrom P Mintz P et al. Gene expression profile changes after short-activating RNA-mediated induction of endogenous pluripotency factors in human mesenchymal stem cells . Mol. Ther. Nucleic Acids1 ( 8 ), e35 ( 2012 ).
   PubMedGoogle Scholar
• Jafari M Xu W Pan R Sweeting CM Karunaratne DN Chen P . Serum stability and physicochemical characterization of a novel amphipathic peptide C6M1 for siRNA delivery . PLoS ONE9 ( 5 ), e97797 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Morrissey DV Blanchard K Shaw L et al. Activity of stabilized short interfering RNA in a mouse model of hepatitis B virus replication . Hepatology41 ( 6 ), 1349 – 1356 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• Allerson CR Sioufi N Jarres R et al. Fully 2'-modified oligonucleotide duplexes with improved in vitro potency and stability compared to unmodified small interfering RNA . J. Med. Chem.48 ( 4 ), 901 – 904 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• Place RF Wang J Noonan EJ et al. Formulation of small activating RNA into lipidoid nanoparticles inhibits xenograft prostate tumor growth by inducing p21 expression . Mol. Ther. Nucleic Acids1 ( 3 ), e15 ( 2012 ).
   PubMedGoogle Scholar
• Watts JK Yu D Charisse K et al. Effect of chemical modifications on modulation of gene expression by duplex antigene RNAs that are complementary to non-coding transcripts at gene promoters . Nucleic Acids Res.38 ( 15 ), 5242 – 5259 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Wang J Place RF Huang V et al. Prognostic value and function of KLF4 in prostate cancer: RNAa and vector-mediated overexpression identify KLF4 as an inhibitor of tumor cell growth and migration . Cancer Res.70 ( 24 ), 10182 – 10191 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Juliano R Alam MR Dixit V Kang H . Mechanisms and strategies for effective delivery of antisense and siRNA oligonucleotides . Nucleic Acids Res.36 ( 12 ), 4158 – 4171 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Kang MR Yang G Place RF et al. Intravesical delivery of small activating RNA formulated into lipid nanoparticles inhibits orthotopic bladder tumor growth . Cancer Res.72 ( 19 ), 5069 – 5079 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Reebye V Huang KW Lin V et al. Gene activation of CEBPA using saRNA: preclinical studies of the first in human saRNA drug candidate for liver cancer . Oncogene37 ( 24 ), 3216 – 3228 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• Reebye V Sætrom P Mintz PJ et al. Novel RNA oligonucleotide improves liver function and inhibits liver carcinogenesis in vivo . Hepatology59 ( 1 ), 216 – 227 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Huan H Wen X Chen X et al. C/EBPα short-activating RNA suppresses metastasis of hepatocellular carcinoma through inhibiting EGFR/β-catenin signaling mediated EMT . PLoS ONE11 ( 4 ), e0153117 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Wang LL Feng CL Zheng WS et al. Tumor-selective lipopolyplex encapsulated small active RNA hampers colorectal cancer growth in vitro and in orthotopic murine . Biomaterials141 , 13 – 28 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Yoon S Huang KW Reebye V et al. Targeted delivery of C/EBPα -saRNA by pancreatic ductal adenocarcinoma-specific rna aptamers inhibits tumor growth in vivo . Mol. Ther.24 ( 6 ), 1106 – 1116 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Li C Jiang W Hu Q et al. Enhancing DPYSL3 gene expression via a promoter-targeted small activating RNA approach suppresses cancer cell motility and metastasis . Oncotarget7 ( 16 ), 22893 – 910 ( 2016 ).
   PubMedGoogle Scholar
• Ren S Kang MR Wang J et al. Targeted induction of endogenous NKX3-1 by small activating RNA inhibits prostate tumor growth . Prostate73 ( 14 ), 1591 – 601 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Wang T Li M Yuan H et al. saRNA guided iNOS up-regulation improves erectile function of diabetic rats . J. Urol.190 ( 2 ), 790 – 8 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Felgner PL Gadek TR Holm M et al. Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure . Proc. Natl. Acad. Sci. USA84 ( 21 ), 7413 – 7417 ( 1987 ).
   PubMed Web of Science ®Google Scholar
• Li W Szoka FC . Lipid-based nanoparticles for nucleic acid delivery . Pharm. Res.24 ( 3 ), 438 – 449 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Xu Y Szoka FC . Mechanism of DNA release from cationic liposome/DNA complexes used in cell transfection . Biochemistry35 ( 18 ), 5616 – 5623 ( 1996 ).
   PubMed Web of Science ®Google Scholar
• Hafez IM Maurer N Cullis PR . On the mechanism whereby cationic lipids promote intracellular delivery of polynucleic acids . Gene Ther.8 ( 15 ), 1188 – 1196 ( 2001 ).
   PubMed Web of Science ®Google Scholar
• Zelphati O Szoka FC . Mechanism of oligonucleotide release from cationic liposomes . Proc. Natl. Acad. Sci. USA93 ( 21 ), 11493 – 11498 ( 1996 ).
   PubMed Web of Science ®Google Scholar
• Kwok A . The challenges and current advances in delivering RNAi as therapeutics . In : DNA and RNA Nanobiotechnologies in Medicine: Diagnosis and Treatment of Diseases.ErdmannVABarciszewskiJ ( Eds ). Springer , Berlin, Heidelberg, Germany , 189 – 224 ( 2013 ).
   Google Scholar
• Akinc A Goldberg M Qin J et al. Development of lipidoid–sirna formulations for systemic delivery to the liver . Mol. Ther.17 ( 5 ), 872 – 879 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Aleku M Schulz P Keil O et al. Atu027, a liposomal small interfering RNA formulation targeting protein kinase N3, inhibits cancer progression . Cancer Res.68 ( 23 ), 9788 – 9798 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Nourbakhsh M Jaafari MR Lage H et al. Nanolipoparticles-mediated MDR1 siRNA delivery reduces doxorubicin resistance in breast cancer cells and silences MDR1 expression in xenograft model of human breast cancer . Iran. J. Basic Med. Sci.18 ( 4 ), 385 – 392 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Rodrigueza W V Woolliscroft MJ Ebrahim AS et al. Development and antitumor activity of a BCL-2 targeted single-stranded DNA oligonucleotide . Cancer Chemother. Pharmacol.74 ( 1 ), 151 – 166 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Whitehead KA Dorkin JR Vegas AJ et al. Degradable lipid nanoparticles with predictable in vivo siRNA delivery activity . Nat. Commun.5 ( 1 ), 4277 ( 2014 ).
   PubMedGoogle Scholar
• Akinc A Zumbuehl A Goldberg M et al. A combinatorial library of lipid-like materials for delivery of RNAi therapeutics . Nat. Biotechnol.26 ( 5 ), 561 – 569 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Ozcan G Ozpolat B Coleman RL Sood AK Lopez-Berestein G . Preclinical and clinical development of siRNA-based therapeutics . Adv. Drug Deliv. Rev.87 , 108 – 119 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Andreakos E Rauchhaus U Stavropoulos A et al. Amphoteric liposomes enable systemic antigen-presenting cell-directed delivery of CD40 antisense and are therapeutically effective in experimental arthritis . Arthritis Rheum.60 ( 4 ), 994 – 1005 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Arranz A Reinsch C Papadakis KA et al. Treatment of experimental murine colitis with CD40 antisense oligonucleotides delivered in amphoteric liposomes . J. Control. Rel.165 ( 3 ), 163 – 172 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Kwok A Hart SL . Comparative structural and functional studies of nanoparticle formulations for DNA and siRNA delivery . Nanomedicine7 ( 2 ), 210 – 219 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Kwok A McCarthy D Hart SL Tagalakis AD . Systematic comparisons of formulations of linear oligolysine peptides with siRNA and plasmid DNA . Chem. Biol. Drug Des.87 ( 5 ), 747 – 763 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Malkoch M Malmström E Nyström AM . Dendrimers: properties and applications . In : Polymer Science: A Comprehensive Reference, 10 Volume Set.MoellerMMatyjaszewskiK ( Eds ). Amsterdam, The Netherlands , 113 – 176 ( 2012 ).
   Google Scholar
• Biswas S Torchilin VP . Dendrimers for siRNA Delivery . Pharmaceuticals (Basel)6 ( 2 ), 161 – 83 ( 2013 ).
   PubMedGoogle Scholar
• Mintzer MA Grinstaff MW . Biomedical applications of dendrimers: a tutorial . Chem. Soc. Rev.40 ( 1 ), 173 – 190 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Kwok A Eggimann GA Reymond JL Darbre T Hollfelder F . Peptide dendrimer/lipid hybrid systems are efficient DNA transfection reagents: Structure-activity relationships highlight the role of charge distribution across dendrimer generations . ACS Nano7 ( 5 ), 4668 – 4682 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Kwok A Eggimann GA Heitz M Reymond JL Hollfelder F Darbre T . Efficient transfection of siRNA by peptide dendrimer–lipid conjugates . ChemBioChem17 ( 23 ), 2223 – 2229 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Heitz M Kwok A Eggimann G Hollfelder F Darbre T . Reymond J-L. peptide dendrimer–lipid conjugates as DNA and siRNA transfection reagents: role of charge distribution across generations . Chim. Int. J. Chem.71 ( 4 ), 220 – 225 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Tomalia DA Baker H Dewald J et al. A new class of polymers: starburst-dendritic macromolecules . Polym. J.17 ( 1 ), 117 – 132 ( 1985 ).
   Web of Science ®Google Scholar
• Bauer BJ Amis EJ . Characterization of dendritically branched polymers by small angle neutron scattering (SANS), small angle X-ray scattering (SAXS) and transmission electron microscopy (TEM) . In : Dendrimers and Other Dendritic PolymersFréchetJMJTomaliaDA ( Eds ). John Wiley & Sons, Ltd , Chichester, UK , 255 – 284 ( 2001 ).
   Google Scholar
• D'Emanuele A Attwood D . Dendrimer-drug interactions . Adv. Drug Deliv. Rev.57 ( 15 ), 2147 – 2162 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• Shcharbin D Pedziwiatr E Bryszewska M . How to study dendriplexes I: characterization . J. Control. Rel.135 ( 3 ), 186 – 197 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Shcharbin D Pedziwiatr E Blasiak J Bryszewska M . How to study dendriplexes II: transfection and cytotoxicity . J. Control. Rel.141 ( 2 ), 110 – 127 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Rejman J Bragonzi A Conese M . Role of clathrin-and caveolae-mediated endocytosis in gene transfer mediated by lipo-and polyplexes . Mol. Ther.12 ( 3 ), 468 – 474 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• Shen W Van Dongen MA Han Y et al. The role of caveolin-1 and syndecan-4 in the internalization of PEGylated PAMAM dendrimer polyplexes into myoblast and hepatic cells . Eur. J. Pharm. Biopharm.88 ( 3 ), 658 – 663 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Sahay G Alakhova DY Kabanov A V . Endocytosis of nanomedicines . J. Control. Rel.145 ( 3 ), 182 – 195 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Sakurai Y Hatakeyama H Sato Y et al. Endosomal escape and the knockdown efficiency of liposomal-siRNA by the fusogenic peptide shGALA . Biomaterials32 ( 24 ), 5733 – 5742 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Hufnagel H Hakim P Lima A Hollfelder F . Fluid phase endocytosis contributes to transfection of DNA by PEI-25 . Mol. Ther.17 ( 8 ), 1411 – 1417 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Haensler J Szoka FC . Polyamidoamine cascade polymers mediate efficient transfection of cells in culture . Bioconjug. Chem.4 ( 5 ), 372 – 379 ( 1993 ).
   PubMed Web of Science ®Google Scholar
• Tang MX Redemann CT Szoka FC . In vitro gene delivery by degraded polyamidoamine dendrimers . Bioconjug. Chem.7 ( 6 ), 703 – 714 ( 1996 ).
   PubMed Web of Science ®Google Scholar
• Sonawane ND Szoka FC Verkman AS . Chloride accumulation and swelling in endosomes enhances DNA transfer by polyamine-DNA polyplexes . J. Biol. Chem.278 ( 45 ), 44826 – 44831 ( 2003 ).
   PubMed Web of Science ®Google Scholar
• Midoux P Pichon C Yaouanc JJ Jaffrès PA . Chemical vectors for gene delivery: a current review on polymers, peptides and lipids containing histidine or imidazole as nucleic acids carriers . Br. J. Pharmacol.157 ( 2 ), 166 – 178 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Que-Gewirth NS Sullenger BA . Gene therapy progress and prospects: RNA aptamers . Gene Ther.14 ( 4 ), 283 – 291 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Yoon S Rossi JJ . Aptamers: uptake mechanisms and intracellular applications . Adv. Drug Deliv. Rev.134 , 22 – 35 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• McNamara JO Andrechek ER Wang Y et al. Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras . Nat. Biotechnol.24 ( 8 ), 1005 – 1015 ( 2006 ).
   PubMed Web of Science ®Google Scholar
• Stein CA Castanotto D . FDA-approved oligonucleotide therapies in 2017 . Mol. Ther.25 ( 5 ), 1069 – 1075 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Ledford H . Gene-silencing technology gets first drug approval after 20-year wait . Nature560 ( 7718 ), 291 – 292 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• Wood H . FDA approves patisiran to treat hereditary transthyretin amyloidosis . Nat. Rev. Neurol.14 ( 10 ), 570 ( 2018 ).
   Google Scholar
• Jiang K . Biotech comes to its “antisenses” after hard-won drug approval . Nat. Med.19 ( 3 ), 252 – 252 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Ottesen EW . ISS-N1 makes the first FDA-approved drug for spinal muscular atrophy . Transl. Neurosci.8 ( 1 ), 1 – 6 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Adams D Gonzalez-Duarte A O'Riordan WD et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis . N. Engl. J. Med.379 ( 1 ), 11 – 21 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• ClinicalTrials.gov . First-in-Human safety and tolerability study of MTL-CEBPA in patients with advanced liver cancer . https://clinicaltrials.gov/ct2/show/NCT02716012 . 2016 – 2017 ( 2016 ).
   Google Scholar
• Setten RL Lightfoot HL Habib NA Rossi JJ . Development of MTL-CEBPA: small activating RNA Drug for hepatocellular carcinoma . Curr. Pharm. Biotechnol.19 ( 8 ), 611 – 621 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• Medavaram S Zhang Y . Emerging therapies in advanced hepatocellular carcinoma . Exp. Hematol. Oncol.7 ( 1 ), 17 ( 2018 ).
   PubMedGoogle Scholar
• Llovet JM Montal R Sia D Finn RS . Molecular therapies and precision medicine for hepatocellular carcinoma . Nat. Rev. Clin. Oncol.15 ( 10 ), 599 – 616 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• Lohitesh K Chowdhury R Mukherjee S . Resistance a major hindrance to chemotherapy in hepatocellular carcinoma: an insight . Cancer Cell Int.18 , 44 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• Lourenço AR Coffer PJ . A tumor suppressor role for C/EBPα in solid tumors: more than fat and blood . Oncogene36 ( 37 ), 5221 – 5230 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Yang J Croniger CM Lekstrom-Himes J et al. Metabolic response of mice to a postnatal ablation of CCAAT/enhancer-binding protein α . J. Biol. Chem.280 ( 46 ), 38689 – 38699 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• Tomizawa M Wang Y-Q Ebara M et al. Decreased expression of the CCAAT/enhancer binding protein alpha gene involved in hepatocyte proliferation in human hepatocellular carcinomas . Int. J. Mol. Med.9 ( 6 ), 597 – 600 ( 2002 ).
   PubMed Web of Science ®Google Scholar
• Tomizawa M Watanabe K Saisho H Nakagawara A Tagawa M . Down-regulated expression of the CCAAT/enhancer binding protein alpha and beta genes in human hepatocellular carcinoma: a possible prognostic marker . Anticancer Res.23 ( 1a ), 351 – 354 ( 2003 ).
   PubMed Web of Science ®Google Scholar
• Tada Y Brena RM Hackanson B Morrison C Otterson GA Plass C . Epigenetic modulation of tumor suppressor CCAAT/enhancer binding protein alpha activity in lung cancer . J. Natl Cancer Inst.98 ( 6 ), 396 – 406 ( 2006 ).
   PubMedGoogle Scholar
• Halmos B Huettner CS Kocher O Ferenczi K Karp DD Tenen DG . Down-regulation and antiproliferative role of C/EBPalpha in lung cancer . Cancer Res.62 ( 2 ), 528 – 534 ( 2002 ).
   PubMed Web of Science ®Google Scholar
• Didon L Roos AB Elmberger GP Gonzalez FJ Nord M . Lung-specific inactivation of CCAAT/enhancer binding protein α causes a pathological pattern characteristic of COPD . Eur. Respir. J.35 ( 1 ), 186 – 197 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Sato A Xu Y Whitsett JA Ikegami M . CCAAT/enhancer binding protein-α regulates the protease/antiprotease balance required for bronchiolar epithelium regeneration . Am. J. Respir. Cell Mol. Biol.47 ( 4 ), 454 – 463 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Sugahara K Iyama K-I Kimura T et al. Mice lacking CCAAT/enhancer-binding protein-a show hyperproliferation of alveolar type II cells and increased surfactant protein mRNAs . Cell Tissue Res.306 ( 1 ), 57 – 63 ( 2001 ).
   PubMed Web of Science ®Google Scholar
• Anand S Ebner J Warren CB et al. C/EBP transcription factors in human squamous cell carcinoma: selective changes in expression of isoforms correlate with the neoplastic state . PLoS ONE9 ( 11 ), e112073 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Pan Z Zheng W Zhang J et al. Downregulation of the expression of CCAAT/enhancer binding protein α gene in cervical squamous cell carcinoma . BMC Cancer14 ( 1 ), 417 ( 2014 ).
   PubMedGoogle Scholar
• Bennett KL Hackanson B Smith LT et al. Tumor suppressor activity of CCAAT/enhancer binding protein is epigenetically down-regulated in head and neck squamous cell carcinoma . Cancer Res.67 ( 10 ), 4657 – 4664 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Kazkayasi I Burul-Bozkurt N Önder S Kelicen-Ugur P Pekiner C . Effects of experimental diabetes on C/EBP proteins in rat hippocampus, sciatic nerve and ganglia . Cell. Mol. Neurobiol.33 ( 4 ), 559 – 567 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Kai K Nasu K Kawano Y et al. Death receptor 6 is epigenetically silenced by histone deacetylation in endometriosis and promotes the pathogenesis of endometriosis . Am. J. Reprod. Immunol.70 ( 6 ), 485 – 496 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Borger P Black JL Roth M . Asthma and the CCAAT-enhancer binding proteins: a holistic view on airway inflammation and remodeling . J. Allergy Clin. Immunol.110 ( 6 ), 841 – 846 ( 2002 ).
   PubMed Web of Science ®Google Scholar
• Borger P Tamm M Black JL Roth M . Asthma: is it due to an abnormal airway smooth muscle cell . Am. J. Respir. Crit. Care Med.174 ( 4 ), 367 – 372 ( 2006 ).
   PubMed Web of Science ®Google Scholar
• Roth M Johnson PRA Borger P et al. Dysfunctional interaction of C/EBPα and the glucocorticoid receptor in asthmatic bronchial smooth-muscle cells . N. Engl. J. Med.351 ( 6 ), 560 – 574 ( 2004 ).
   PubMed Web of Science ®Google Scholar
• Wei J Zhao J Long M et al. P21WAF1/CIP1 gene transcriptional activation exerts cell growth inhibition and enhances chemosensitivity to cisplatin in lung carcinoma cell . BMC Cancer10 , 632 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Reebye V Sætrom P Mintz PJ et al. A short-activating RNA oligonucleotide targeting the islet β-cell transcriptional factor MafA in CD34+ cells . Mol. Ther. Nucleic Acids2 ( 6 ), e97 ( 2013 ).
   PubMedGoogle Scholar