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Development of MTL-CEPBA: Sarna Drug for Liver Disease Send Orders for Reprints to [email protected] Journal Name, Year, Volume 1 Development of MTL-CEPBA: SaRNA drug for Liver Disease Helen L Lightfoot†a, Ryan L Setten†b,c, John J Rossib,c and Nagy A Habibd* aMiNA Therapeutics Limited, Translation & Innovation Hub, 80 Wood Lane, London, W12 0BZ, United Kingdom; bDepartment of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA; cIrell & Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA; dDepartment of Surgery and Cancer, Imperial College London, London, UK. †authors contributed equally Abstract: Oligonucleotide drug development has revolutionised the drug discovery field allowing the notorious “undruggable” genome to become “druggable”. Of course, as with all, there are caveats to this new technology, which include restricted delivery and mode of actions – such drugs usually alter splicing and reduce RNA at the post- transcriptional level. Small activating RNA (saRNA)-mediated gene activation has opened a new potential therapeutic avenue for oligonucleotide drugs. SaRNAs promote endogenous transcription, a phenomenon known as RNA activation (RNAa), hence they function to increase gene expression levels. SaRNA based oligonucleotide therapeutics present great promise in expanding the “druggable” genome, with particular areas of interest including transcription factor activation and haploinsufficency. In this mini-review, we describe the pre-clinical development of the first saRNA drug to enter the clinic. This saRNA, referred to as MTL-CEPBA, targets the transcription factor CCAAT/enhancer-binding protein alpha (CEBPα), a tumour suppressor and critical regulator of hepatocyte function. MTL-CEPBA is presently in Phase I clinical trials for hepatocellularcarcinoma (HCC). The clinical development of MTL-CEPBA will provide the “proof of concept”, demonstrating that saRNAs can provide the basis for drugs which enhance gene expression and consequently improve disease outcome in patients. Keywords: MiNA Therapeutics, MTL-CEBPA, CEBPα, saRNA, HCC, Liver, RNA therapeutics. INTRODUCTION Most of these candidates and drugs directly inhibit gene expression. The development of such oligonucleotide With the recent FDA approval of several oligonucleotide antisense drugs which have the ability to directly enhance antisense drugs, the RNA therapeutics field has made its gene expression also have great promise, particularly as they mark.1 After decades of setbacks associated with stability, can piggy back on the strategies (chemistry, delivery, off target effects, delivery and targeting, the fields of targeting) used in the development of the corresponding gene chemistry, RNA biology and genome sequencing have inhibition field. Several companies are developing gene revolutionised RNA therapeutics in terms of possible drug activation technologies including CRISPR/Cas9, structural compositions, mechanism of actions and target/indications. RNAs and small activating RNAs (saRNAs), with such Furthermore, the ability of the technology to utilize the same approaches6-7 complementing the more established mRNA production platform, developmental profiles (toxicology and therapeutics.8-9 In 2016, MTL-CEBPA was the first RNA pharmacokinetic) and delivery approaches when targeting a activating oligonucleotide antisense drug to enter clinical particular tissue, could help further reduce the bench to development. MTL-CEBPA is being developed by MiNA bedside timeline.2 This will likely lead to a rapid and robust Therapeutics (London) to treat liver disease among other pipeline of RNA therapeutics. The recent expansion of indications by directly activating the CCAAT/Enhancer- validated delivery approaches including the application of Binding Protein Alpha (CEBPα). This mini review will focus targeting agents for selective delivery of oligonucleotide on the research and pre-clinical development of MTL- antisense targeting drugs3, has also dramatically improved CEBPA for treatment of liver cancer. the targeting potential of this technology. For antisense targeting drugs, this is a time to celebrate. SARNAs Approved oligonucleotide antisense targeting drugs Short activating RNAs (saRNA) induce long lasting and function via a variety of mechanisms spanning mRNA exon sequence specific expression of their target gene (Table1). skipping to RNase-H induced mRNA cleavage; with all This remarkable finding was made in the mid 2000’s by targeting the mRNA.4-5 In addition, late stage clinical trials Long-Chen Li and colleagues when they observed short have also involved additional oligonucleotide antisense double stranded RNAs (dsRNA) targeting gene promoter targeting drugs which sequester microRNAs.5 sequences activated, rather than suppressed, transcription of p21WAF1/CIP1 (p21), VEGF, and E-cadherin.10 This newly *Address correspondence to this author at Department of Surgery and discovered phenomenon was named RNA activation (RNAa) Cancer, Imperial College London, London, UK.; E-mail: [email protected]. and the dsRNAs which cause it were subsequently termed XXX-XXX/14 $58.00+.00 © 2017 Bentham Science Publishers 2 Journal Name, 2017, Vol. 0, No. 0 Principal Author Last Name et al. [Place holder, legend and figure will be replaced] Figure 1 – RNAa vs RNAi (a) saRNA and siRNA are similarly structured dsRNAs which differ only in their functional outcomes. (b)When delivered into cells siRNAs are loaded while in the cytoplasm into AGO1-4 and cause post transcriptional gene silencing (PTGS) of their target RNA. (c) PTGS can also occur in the nucleus when siRNA has been loaded into AGO2(x). (d) Additionally, siRNA can induce transcriptional gene silencing when siRNA is loaded into AGO1 and translocated into the nucleus (x). In contrast, saRNA must be loaded into AGO2 to be functional. (e) Once loaded, AGO2 is translocated into the nucleus with the help of import factors such as importin-8 (x). (f) In the nucleus, saRNA binds either directly to DNA or to chromatin bound RNA such as promoter associated transcripts or long non-coding RNA while AGO2 recruits RHA and CTR9 to the target promoter. AGO2 also binds TNCR6 proteins which might in turn recruit proteins involved in histone modification, mediator complex, and CCR4-NOT complex to the target gene promoter. (g) Following saRNA treatment, target promoters are more transcriptionally active and show: decreased H3K9me2, reduced acetylation of H3K9ac and H3K14ac, increased H3K4me2/3 and increased RNA pol-II occupancy. ‘ saRNAs’ to differentiate them from short interfering RNAs cytoplasmic shuttling of AGO2 appears to be, in part, 23 (siR NA). Critically, it was found that the RNA interference dependent on importin-8 as knockdown of this importin 24 (RNAi) factor, Argonaute 2 (AGO2), was required for reduces the nuclear pool of AGO2. However, Importin-8 RNAa.10 Shortly after, Bethany Janowski et al showed that knockout does not completely exclude nuclear translocation progesterone receptor (PR) expression could also be induced of AGO2. This indicates other import factors may also by dsRNA targeting PR promoter.11 Endogenously, micro shuttle AGO2.25-26 RNA (miRNA) mir-373 target the promoters of e-cadherin and CSDC2 and induce their expression.12 Together, these Once in the nucleus, AGO2 can bind promoter associated transcripts27-28 that contain a complementary sequence or reports laid the groundwork for understanding how RNAa RNAs that are transcribed through a promoter region with influences gene regulation and pointed to the potential for complementary sequence (Fig1).10,29 saRNAs are also saRNA mediated gain-of-function therapy in the clinic.13,14 capable of inducing RNAa of genes when designed to target saRNAs are structurally identical to siRNA. The critical RNA transcribed from outside a gene promoter such as long design difference between the two is their intended targets. non-coding RNAs (lncRNA) (Fig1). 7, 30 Here, the targeted saRNAs act in the nucleus and are typically designed to nascent RNA likely acts as a ‘tether’ for the saRNA-AGO2 contain sequences complimentary to regions near or within complex keeping the complex in close proximity to the gene promoters10-11 while siRNAs are complimentary to target gene promoter and allowing physical contact between mRNA (Fig1).8 Both are double stranded, ~21-mer, RNA the two (Fig1). Supporting an RNA targeting model, oligonucleotides. Short dsRNAs that are introduced into a knockdown of these RNAs by antisense oligonucleotides cell are recognized in the cytoplasm by dsRNA loading (ASOs) abolishes the effect of saRNA (Fig1).29 In addition factors and subsequently loaded into one of the four AGO to saRNA targeting RNA, there is chromatin proteins (Fig1).15 The guide strand (complementary to the immunoprecipitation (ChIP) based evidence that biotinylated target RNA of interest) is retained upon loading while the saRNA might also recognize and bind directly to DNA. 13, 31 passenger strand (matching the target RNA sequence) is AGO2 is believed to recruit proteins that establish discarded. Critically, loading of AGO2 is required for 10 10-11 decreased H3K9me2 , reduced acetylation of H3K9ac and RNAa. RNA-AGO complexes have post-transcriptional 11 10-11 gene silencing (PTGS) potential in agreement with their H3K14ac , increased H3K4me2/3 and increased RNA pol-II occupancy31-33 when localized at a target gene by a canonical role in the RNA induced silencing complex saRNA (Fig.1). Still, the current mechanistic explanation
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