In Vivo Delivery of Cassettes Encoding Anti-HBV Primary MicroRNAs Using an Ancestral Adeno-Associated Viral Vector

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Despite being vaccine-preventable, hepatitis B virus (HBV) infection remains the seventh leading cause of mortality in the world. In South Africa (SA), over 1.9 million people are chronically infected with HBV, and 70% of all Black chronic carriers are infected with HBV subgenotype A1. The virus remains a significant burden on public health in SA despite the introduction of an infant immunization program implemented in 1995 and the availability of effective treatment for chronic HBV infection. In addition, the high prevalence of HIV infection amplifies HBV replication, predisposes patients to chronicity, and complicates management of the infection. HBV research has made significant progress leading to better understanding of HBV epidemiology and management challenges in the SA context. This has led to recent revision of the national HBV infection management guidelines. Research on developing new vaccines and therapies is underway and progress has been made with designing potentially curative gene therapies against HBV. This review summarizes research carried out in SA on HBV molecular biology, epidemiology, treatment, and vaccination strategies.

Section: Gene Deliverymentioning

confidence: 87%

Hepatitis B Virus Research in South Africa

Maepa

Ely

Kramvis

et al. 2022

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“…Despite smaller transgene capacity of scAAVs, an important advantage of these vectors is their faster transgene expression. Expression cassettes encoding shRNAs or apri-miRNAs are typically small and can usually be accommodated by scAAVs [62,110,111]. Moreover, the interesting observation that HBV infection enhances AAV transduction of hepatocytes makes these vectors well suited to delivery of anti-HBV RNAi expression cassettes [112].…”

Section: Viral Vectorsmentioning

confidence: 99%

Advances with RNAi-Based Therapy for Hepatitis B Virus Infection

Berg

Limani

Mnyandu

et al. 2020

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Infection with hepatitis B virus (HBV) remains a global health challenge. Approximately 292 million people worldwide are chronically infected with HBV and the annual mortality from the infection is approaching 900,000. Despite the availability of an effective prophylactic vaccine, millions of individuals are at risk of potentially fatal complicating cirrhosis and hepatocellular carcinoma. Current drug treatments can suppress viral replication, slow the progression of liver fibrosis, and reduce infectivity, but can rarely clear the viral covalently closed circular DNA (cccDNA) that is responsible for HBV persistence. Alternative therapeutic strategies, including those based on viral gene silencing by harnessing the RNA interference (RNAi) pathway, effectively suppress HBV replication and thus hold promise. RNAi-based silencing of certain viral genes may even lead to disabling of cccDNA during chronic infection. This review summarizes different RNAi activators that have been tested against HBV, the advances with vectors used to deliver artificial potentially therapeutic RNAi sequences to the liver, and the current status of preclinical and clinical investigation.

“…Significant suppression of HBV replication was observed in mice after systemic intravenous administration for at least 32 weeks. In another approach for HBV silencing by AAV vectors, an ancestral AAV (Anc80L65) vector was designed in silico and synthesized in vitro to evade prevailing AAV neutralizing antibodies and can now be characterized in vivo for anti-HBV RNAi activity [ 65 ].…”

Section: Virus-based Rnai Antiviral Therapymentioning

confidence: 99%

Viral Vectors Applied for RNAi-Based Antiviral Therapy

Lundström¹

2020

RNA interference (RNAi) provides the means for alternative antiviral therapy. Delivery of RNAi in the form of short interfering RNA (siRNA), short hairpin RNA (shRNA) and micro-RNA (miRNA) have demonstrated efficacy in gene silencing for therapeutic applications against viral diseases. Bioinformatics has played an important role in the design of efficient RNAi sequences targeting various pathogenic viruses. However, stability and delivery of RNAi molecules have presented serious obstacles for reaching therapeutic efficacy. For this reason, RNA modifications and formulation of nanoparticles have proven useful for non-viral delivery of RNAi molecules. On the other hand, utilization of viral vectors and particularly self-replicating RNA virus vectors can be considered as an attractive alternative. In this review, examples of antiviral therapy applying RNAi-based approaches in various animal models will be described. Due to the current coronavirus pandemic, a special emphasis will be dedicated to targeting Coronavirus Disease-19 (COVID-19).