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Green Synthesis of Nanoparticles in Oligonucleotide Drug Delivery System
Published in Yashwant Pathak, Gene Delivery, 2022
Manish P. Patel, Praful D. Bharadia, Kunjan B. Bodiwala, Mustakim M. Mansuri, Jayvadan Patel
Oligonucleotides are nucleic acid polymers which can be a major impact on treatment or management of wide range of diseases. This therapeutics’ particular role is to be the silencing gene. Other roles like splice modulation and gene activation are under investigation.
Receptor Tyrosine Kinase Signaling Pathways as a Goldmine for Targeted Therapy in Head and Neck Cancers
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Muzafar A. Macha, Satyanarayana Rachagani, Sanjib Chaudhary, Zafar Sayed, Dwight T. Jones, Surinder K. Batra
Besides using mAbs and TKIs, many other strategies aimed at inhibiting the ErbB signaling pathway have been investigated in HNSCC and other cancers. Antisense oligonucleotides are —20 nucleotides, single stranded DNA molecules that bind to the mRNA and prevent translation of protein. Using this strategy, EGFR was downregulated and seen to be associated with DNA fragmentation, induction of apoptosis in vitro and significantly reduced growth of xenograft tumors in vivo [104]. In addition, targeting EGFR ligand using the oligonucleotides also resulted in tumor regression in HNSCC xenograft mouse model [105]. Like EGFR inhibitors in combination with cytotoxic drugs showed improved response, combination of EGFR antisense oligonucleotides with docetaxel significantly reduced xenograft tumors compared to docetaxel alone [106]. While a moderate response with no cytotoxicity using the antisense oligonucleotides was observed in phase I trial [107], its combination with RT and cetuximab in advanced locoregional HNSCC was investigated (NCT00903461). Many of the clinical trials using this technology in HNSCC and their outcomes are summarized in Table 1. Further, siRNA (double stranded 2Ont RNA molecules) mediated down regulation of EGFR in combination with cisplatin also significantly reduced the tumor volume in mouse xenografts models [108].
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
This approach involves chemical modification of the oligonucleotide backbone to make the siRNA constructs more stable, and/or to improve their penetration through cell membranes. For example, Solstice Inc developed a core RNAi delivery technology known as “ribonucleic neutrals” (or “RNN”s). RNNs appeared to be best suited for delivering siRNA payloads to the skin, lungs, and blood compartment, although details of the technology have not been fully disclosed. It is a prodrug approach, with the RNNs having protective side groups on the nucleic acids that keep them stable in plasma and also neutral and biocompatible. Due to its neutrality, an RNN can pass across membranes and, once inside a cell, ubiquitous enzymes remove the side groups completely, at which point the payload triggers the RNAi mechanism. It works in most mammalian cell lines including primary cells in culture, and also in vivo in animal models.
RNAi therapeutics for diseases involving protein aggregation: fazirsiran for alpha-1 antitrypsin deficiency-associated liver disease
Published in Expert Opinion on Investigational Drugs, 2023
Pavel Strnad, Javier San Martin
RNA interference (RNAi) is a natural cellular mechanism whereby short oligonucleotide molecules (commonly referred to as RNAi triggers or siRNA) silence gene expression and regulate the production of proteins. siRNA technology uses this mechanism whereby synthetic, double-stranded oligonucleotides are introduced into a cell, which are then loaded into the RNA-induced silencing complex, or RISC, in the cytoplasm [7]. After loading, the strands are separated leaving an active RISC/RNAi trigger complex. This complex can then pair with and degrade the complementary messenger RNA (mRNA) and thereby inhibit protein synthesis. Because RNAi is a catalytic process, each RNAi trigger can degrade mRNA hundreds of times resulting in a relatively long biological efficacy. To date, five siRNA drugs have been approved (givosiran, lumasiran, inclisiran, patisiran, and vutrisiran) [8,9]. More than 30 additional siRNA drugs are currently being evaluated in clinical trials [9].
Meeting report: oligonucleotide ADME workshop
Published in Xenobiotica, 2022
Steve Hood, David Kenworthy, Jesper Kammersgaard Christensen
Oligonucleotides represent a powerful therapeutic modality capable of selectively impacting the production or splicing of RNA that might otherwise be difficult to target with classical small molecule drugs or biologics. This has been clearly demonstrated by the large number of oligonucleotides in clinical trials and successfully launched therapies on the market. However, specifically targeting mRNA in extra-hepatic tissues and cell types after systemic administration continues to be a challenge. The OligoNova scientific network aims to build national and international collaborations to tackle scientific challenges within the area of therapeutic oligonucleotides such as targeted delivery, enhanced cellular uptake and intracellular trafficking. All together OligoNova will help catalyse and translate novel ideas into oligonucleotide therapeutics that will benefit patients and strengthen research capabilities in the field in Sweden.
One small step in time, one giant leap for DMPK kind – a CRO perspective of the evolving core discipline of drug development
Published in Xenobiotica, 2022
John S. Kendrick, Colin Webber
The impact on how large molecules are developed is also heavily influenced by the regulatory landscape. The recent guidance issued by the FDA on the clinical development of oligonucleotide therapies (Food and Drug Administration Center for Drug Evaluation and Research 2022c) illustrates this perfectly. Where conventional knowledge acknowledges that traditional assays to investigate drug-drug-interactions are not wholly suitable, the guidance does describe the need to justify the reasons why, if DDI potential is not investigated. The guidance further describes the fact that oligonucleotide therapeutics may modulate CYP enzymes or transporters directly via off-target etabolizing with CYP enzyme or transporter mRNA transcripts) or indirectly (e.g. by interfering with the synthesis or degradation of haem or by modulating cytokines) should be evaluated. Of course, the nature of the assays and approaches to establishing these endpoints will vary from company to company, and so further discussions with a stakeholder group of DMPK scientists will be required.