RNA Interference (RNAi)-Based Therapeutics: Delivering on the Promise?

Bobbin, Maggie; Rossi, John J.

doi:10.1146/annurev-pharmtox-010715-103633

Cited by 308 publications

(246 citation statements)

References 45 publications

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“…To date, a number of approaches for reducing cellular mRNA levels including siRNA and antisense oligonucleotides have reached the clinic [1,2]. However, the ability to upregulate mRNA or increase protein production remains challenging.…”

Section: Introductionmentioning

confidence: 99%

Optimization of mRNA untranslated regions for improved expression of therapeutic mRNA

et al. 2018

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ABSTRACTmRNA based therapies hold great promise for the treatment of genetic diseases. However, this therapeutic approach suffers from multiple challenges including the short half-life of exogenously administered mRNA and subsequent protein production. Modulation of untranslated regions (UTR) represents one approach to enhance both mRNA stability and translation efficiency. The current studies describe and validate screening methods using a diverse set of 5′UTR and 3′UTR combinations for improved expression of the Arginase 1 (ARG1) protein, a potential therapeutic mRNA target. Data revealed a number of critical aspects which need to be considered when developing a screening approach for engineering mRNA improvements. First, plasmid-based screening methods do not correlate with protein expression driven by exogenously expressed mRNA. Second, improved ARG1 protein production was driven by increased translation and not improved mRNA stability. Finally, the 5′ UTR appears to be the key driver in protein expression for exogenously delivered mRNA. From the testing of the combinatorial library, the 5′UTR for complement factor 3 (C3) and cytochrome p4502E1 (CYP2E1) showed the largest and most consistent increase in protein expression relative to a reference UTR. Collectively, these data provide important information for the development and optimization of therapeutic mRNAs.

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Section: Introductionmentioning

confidence: 99%

Optimization of mRNA untranslated regions for improved expression of therapeutic mRNA

et al. 2018

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“…To realize the potential of RNAi based therapeutics, efficient delivery of an RNAi trigger (siRNA) has been a major obstacle (25), particularly to target tissues other than liver (26,27). Previously, we described an efficient and selective liver targeting siRNA delivery system termed dynamic polyconjugates (DPC; refs.…”

Section: Introductionmentioning

confidence: 99%

HIF2α-Targeted RNAi Therapeutic Inhibits Clear Cell Renal Cell Carcinoma

Wong

Cheng

Hamilton

et al. 2018

Molecular Cancer Therapeutics

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Targeted therapy against VEGF and mTOR pathways has been established as the standard-of-care for metastatic clear cell renal cell carcinoma (ccRCC); however, these treatments frequently fail and most patients become refractory requiring subsequent alternative therapeutic options. Therefore, development of innovative and effective treatments is imperative. About 80%-90% of ccRCC tumors express an inactive mutant form of the von Hippel-Lindau protein (pVHL), an E3 ubiquitin ligase that promotes target protein degradation. Strong genetic and experimental evidence supports the correlate that pVHL functional loss leads to the accumulation of the transcription factor hypoxia-inducible factor 2a (HIF2a) and that an overabundance of HIF2a functions as a tumorigenic driver of ccRCC. In this report, we describe an RNAi therapeutic for HIF2a that utilizes a targeting ligand that selectively binds to integrins avb3 and avb5 frequently overexpressed in ccRCC. We demonstrate that functional delivery of a HIF2a-specific RNAi trigger resulted in HIF2a gene silencing and subsequent tumor growth inhibition and degeneration in an established orthotopic ccRCC xenograft model.

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“…RNA interference (RNAi) technology, which is a new technology that has been widely used to explore gene function, infectious diseases and malignant tumour gene therapy, can specifically remove or inhibit target gene expression [14][15][16]. The first step in its mechanism is that the double-stranded RNA induces highly conserved and homologous mRNA degradation.…”

Section: Introductionmentioning

confidence: 99%

One-cell model for inhibiting Cav3.3 mRNA expression by RNA interference

Peng

Wang

et al. 2017

Biotechnology & Biotechnological Equipment

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To gain insights into the function of Cav3.3 T-type calcium channel in dorsal root ganglion neurons, we designed a one-cell model in dorsal root ganglion neurons that specifically inhibits the expression of Cav3.3 mRNA. We designed three different shRNA sequences and then connected them to pYr-1.1 plasmid and labelled them as pYr-1.1-Cav3.3 shRNA1, pYr-1.1-Cav3.3 shRNA2 and pYr-1.1-Cav3.3 shRNA3, respectively. The correct sequence vector (pYr-1.1-Cav3.3 shRNA3) was then recombined with the pAd/PL-DEST vector into pAd-Cav3.3 shRNA the adenovirus vector. The dorsal root ganglion neurons were infected with the pAd-Cav3.3 shRNA adenovirus vector. After detecting the expression of Cav3.3 mRNA and protein, the pAd-Cav3.3 shRNA adenovirus vector was verified by digestion and sequencing. These results showed that the constructed pAd-Cav3.3 shRNA adenovirus vector could infect dorsal root ganglion cells and inhibit the expression of Cav3.3 mRNA or protein. These results established a one-cell model for further functional study of Cav3.3.

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RNA Interference (RNAi)-Based Therapeutics: Delivering on the Promise?

Cited by 308 publications

References 45 publications

Optimization of mRNA untranslated regions for improved expression of therapeutic mRNA

Optimization of mRNA untranslated regions for improved expression of therapeutic mRNA

HIF2α-Targeted RNAi Therapeutic Inhibits Clear Cell Renal Cell Carcinoma

One-cell model for inhibiting Cav3.3 mRNA expression by RNA interference

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