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Non-Viral Delivery of Genome-Editing Nucleases for Gene Therapy
Published in Yashwant Pathak, Gene Delivery, 2022
The siRNA based lipid vectors showed targeted delivery of siRNA to silence the target genes with a nanoparticle size of 200nm [64]. It was first discovered in 2005 to treat hepatitis B virus (HBV) in a mouse model HBV replication [65]. In two separate clinical trials, efficacy of LNP-based siRNA delivery has been evaluated in patients with hepatocellular carcinoma. Tekmira pharmaceuticals corporation investigated the antitumor activity of drug TKM-080301 targeted to suppress the polo-like kinase 1 (PLK1). On the other hand, Alnylam pharmaceuticals developed ALN-VSP02 to target KIF11 (which encodes kinesin spindle protein) and VEGF. In addition, ALN-TTR02 (Alnylam pharmaceuticals) based siRNA formulations are shown to have the ability of silencing the transthyretin (TTR) in TTR-mediated amyloidosis. Patisiran is a second-generation SNALP formulation ALN-TTR02, which is a DLinDMA analogue. In preclinical studies, it showed a tenfold increase in therapeutic activity [1, 66].
Designing siRNA-conjugated plant oil-based nanoparticles for gene silencing and cancer therapy
Published in Journal of Microencapsulation, 2019
Nur Merve Anilmis, Goknur Kara, Ebru Kilicay, Baki Hazer, Emir Baki Denkbas
Other researchers used the stable nucleic acid lipid particles (SNALPs) 1,2-dioleyloxy-N,Ndimethyl-3-aminopropane (DODMA) (includes a single double bond/lipid chain) to synthesize lipids with 0, 1, 2, or 3 double bonds. They reported that H11 phase was affected from the saturation degree of the hydrophobic lipid part. The increasing number of double bonds tended to form the non-bilayer phase. The SNALP bilayer showed propensity to form the fusogenic H11 due to the decrease of saturation degree in the lipid hydrophobic domain at the cationic lipid component (Heyes et al. 2005).
Advances in siRNA delivery in cancer therapy
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Aishwarya Singh, Piyush Trivedi, Narendra Kumar Jain
Other lipid-like delivery systems are lipidoid nanoparticles, which are comprised of cholesterol and PEG-modified lipids specific for siRNA delivery [50]. To improve SNALP-mediated delivery, Akinc et al. developed a new chemical method to allow rapid synthesis of a large library of lipidoids and tested their efficacy in siRNA delivery [51]. The 98N12–5 lipidoid-based siRNA formulation, showed 75–90% reduction in ApoB or FVII factor expression in hepatocytes in nonhuman primates and mice [51].
Patent landscape of novel technologies for combating category-A Arenavirus infections
Published in Expert Opinion on Therapeutic Patents, 2020
Harshal Sudhakar, Jignesh Bhate, Asish Kumar Patra
CN106511343B [43] discloses the use of lacidipine for antiviral treatment. Lacidipine is a synthetic dihydro pyrrole pyridine molecule and a potent calcium channel blocker, currently used for treating hypertension. Lacidipine was tested for inhibition of Lassa virus in Vero E6 cells, EC50 was found to be 2.6 µM. Lacidipine interferes with the GP mediated viral entry into the Vero cells. 8148428 USDB2 [44] discloses a high-throughput screen consisting of 400,000 small molecules against Lassa virus glycoprotein. Ten compounds were found to have EC50 below 100 nM in plaque reduction assay. Among the tested compounds, compound 408,306 was the most potent and selective to Lassa virus with EC50 of 20 nM. Compound-408,306 is a hydrazide compound that inhibits the entry of viral particle into the cell. 20190203211 USDA1 [45] discloses REV-ERBα as a target for inhibition of viral entry in cells. REV-ERBα regulates cellular metabolism and immunity, also functions as a major component of the feedback loop in transcriptional regulation of the circadian clock. Pseudo particles expressing viral envelope glycoprotein from Lassa virus and reporter genes were inoculated to Huh-7 cells, pretreated with GSK4112 or SR9009 at different concentrations. Inhibition was observed at sub-optimal concentrations and broad spectrum inhibition was also seen. In further experiments, siRNA directed against REV-ERBα also inhibited viral entry into Huh-7 cells. 8455455 USDB1 [46] discloses siRNA-lipid complex called Stable Nucleic Acid Lipid Particle (SNALP) for inhibition of Lassa virus. The siRNA has been chemically modified to obtain low immunogenic profile. siRNA were designed to target various sections of the Lassa virus genome particularly the Nucleoprotein and the RNA polymerase. siRNA in combination with lipoFectamine-2000 were added to HepG2 expressing LASV proteins., The siRNA targeting the Nucleoprotein showed inhibition at lower concentration (KD50). 8999925 USDB2 [47] discloses peptides for the treatment of Lassa virus infection. The synthetic peptides were tested against the recombinant Vesicular stomatitis virus (rVSV) expressing Lassa virus glycoprotein. The peptides were tested for plaque reduction in Vero cells, peptides showed sequence specificity and complete inhibition of plaque formation at 20 µM. For rVSV, peptide-1 showed IC50 of 63.8 µM. The possible mechanism of viral inhibition is through change in bilayer rigidity of the viral particle and interference in viral entry.