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Pharmacokinetics, Biodistribution, and Therapeutic Applications of Recently Developed siRNA and DNA Repair Genes Recurrence
Published in Loutfy H. Madkour, Nanoparticle-Based Drug Delivery in Cancer Treatment, 2022
Hepatitis virus infection accounts for most cases of liver infections. When left untreated, patients infected by hepatitis B, C, and D viruses are chronically disturbed and further develop liver cirrhosis and HCC [74]. Currently, 90% hepatitis B vaccine is effective in preventing hepatitis B virus (HBV) infection, but >700,000 deaths still occur worldwide as a consequence of HBV infection [75]. Patients with chronic HBV infection are currently treated with anti-viral agents such as tenofovir and entecavir together with immunomodulators like IFN-α 2b, but side effects and viral resistance limit the effectiveness of these therapies [76]. In this regard, RNAi is considered a potentially attractive treatment for HBV infection. Hepatitis B virion is composed of circular double-stranded DNA, which contains four overlapping open-reading frames (ORFs: S, Pol, X, and C) that encode essential proteins like pre-core protein (also known as HBeAg), core protein (HBcAg), envelope protein (HBsAg), X protein, and viral polymerase [77]. Among them, the X protein, encoded by ORF X gene, was known to regulate transcription and translation by transactivation of viral and cellular promoters, and several studies showed that HBx-specific siRNAs could suppress HBV viral replication [78,79]. ORF C is another valid target. It encodes polyadenylation region that plays important function in all the transcripts [80] and contains sequences that can encode nuclear localization signal needed for transporting covalently closed circular DNA, which serves as the template for viral transcription [81,82].
Novel RNA Interference (RNAi)-Based Nanomedicines for Treating Viral Infections
Published in Dan Peer, Handbook of Harnessing Biomaterials in Nanomedicine, 2021
Nyree Maes, Skye Zeller, Priti Kumar
One of earliest in vivo studies by McAffrey and coworkers [86] tested a panel of seven different U6 promoter driven anti-HBV shRNAs targeting sequences conserved across HBV genotypes for blocking HBV replication from a plasmid expressing the HBV genome. Hydrodynamic transfection of mice via tail vein injections with both the shRNA and HBV expression plasmids resulted in a reduction of serum HBV surface antigen (HBsAg) and liver-associated HBV core antigen (HBcAg). The negative strand of the HBV genome consists of four partially overlapping open-reading frames (ORFs) that encode the viral transcripts [104]. The most effective shRNA mapped to a sequence in the overlapping reading frames enabling the simultaneous targeting of 3 of the 4 viral RNA transcripts [86]. Another study treated mice with hepatocytes transgenic for HBV with hepatotropic recombinant adenoviruses expressing anti-HBV shRNAs targeting the same sequence in the overlapping ORFs. This also led to reduced serum HBsAg and liver HBcAg levels throughout a 26-day period of experimentation [112].
Immunotherapy and Vaccines
Published in Raj Bawa, János Szebeni, Thomas J. Webster, Gerald F. Audette, Immune Aspects of Biopharmaceuticals and Nanomedicines, 2019
Johanna Poecheim, Gerrit Borchard
Seen the conflicting data available in the literature, it is difficult to accurately predict particle size ranges that will induce a Th1 or a mixed Th1/Th2 immune response outcome (Oyewumi et al., 2010). Some data are suggesting that nanoparticles promote cellular immune responses. For instance, codelivery of the hepatitis B viral protein HBcAg and monophosphoryl lipid A (MPLA) in the copolymer PLGA nanoparticles of around 300 nm promoted antigen-specific Th1 immune responses, including IFN-γ production (Chong et al., 2005). In a different study, mice vaccinated with 300 nm sized PLGA particles loaded with a model antigen (ovalbumin, OVA) generated the highest fraction of OVA-specific CTLs. They also induced more than a 50-fold increase in the IgG2a/IgG1 ratio compared to microparticles, suggesting polarization toward a Th1-type immune response (Joshi et al., 2012).
The roadmap towards cure of chronic hepatitis B virus infection
Published in Journal of the Royal Society of New Zealand, 2022
In the first clinical studies of ARO-HBV (now JNJ-3989), patients received 3 subcutaneous injections at monthly intervals and then were followed up for 12 months thereafter. By end of treatment, HBsAg levels had reduced by at least 1 log in every patient who received doses of 100 mg or more, regardless of baseline HBeAg status or previous NUC treatment (Gane, Locarnini, et al. 2019). HBsAg reductions were accompanied by lesser reductions in other viral parameters, including HBV DNA, HBeAg, HBV RNA and HBcrAg (a circulating viral protein with both HBeAg and HBcAg antigenicity). HBsAg suppression was maintained for at least 4 months post-dose, suggesting that dosing intervals longer than monthly could be considered in future studies. In the current Phase 2 studies, ARO-HBV dosing will be continued for 12 months in combination with a NUC and a CAM. Future studies will combine siRNAs with immunomodulators, including therapeutic vaccines.