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Advancing cancer treatment: in vivo delivery of therapeutic small noncoding RNAs.

ABSTRACT: In recent years, small non-coding RNAs (ncRNAs) have emerged as a new player in the realm of cancer therapeutics. Their unique capacity to directly modulate genetic networks and target oncogenes positions them as valuable complements to existing small-molecule drugs. Concurrently, the advancement of small ncRNA-based therapeutics has rekindled the pursuit of efficacious in vivo delivery strategies. In this review, we provide an overview of the most current clinical and preclinical studies in the field of small ncRNA-based cancer therapeutics. Furthermore, we shed light on the pivotal challenges hindering the successful translation of these promising therapies into clinical practice, with a specific focus on delivery methods, aiming to stimulate innovative approaches to address this foundational aspect of cancer treatment.

SUBMITTER: Yang X

PROVIDER: S-EPMC10791939 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Advancing cancer treatment: <i>in vivo</i> delivery of therapeutic small noncoding RNAs.

Yang Xiaoyue X Liang Ying Y Tong Sheng S

Frontiers in molecular biosciences 20240103

In recent years, small non-coding RNAs (ncRNAs) have emerged as a new player in the realm of cancer therapeutics. Their unique capacity to directly modulate genetic networks and target oncogenes positions them as valuable complements to existing small-molecule drugs. Concurrently, the advancement of small ncRNA-based therapeutics has rekindled the pursuit of efficacious <i>in vivo</i> delivery strategies. In this review, we provide an overview of the most current clinical and preclinical studies ...[more]

PMID: 38234581

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Project description:UNLABELLED:Many viruses express noncoding RNAs (ncRNAs). The gammaherpesviruses (?HVs), including Epstein-Barr virus, Kaposi's sarcoma-associated herpesvirus, and murine ?HV68, each contain multiple ncRNA genes, including microRNAs (miRNAs). While these ncRNAs can regulate multiple host and viral processes in vitro, the genetic contribution of these RNAs to infection and pathogenesis remains largely unknown. To study the functional contribution of these RNAs to ?HV infection, we have used ?HV68, a small-animal model of ?HV pathogenesis. ?HV68 encodes eight small hybrid ncRNAs that contain both tRNA-like elements and functional miRNAs. These genes are transcribed by RNA polymerase III and are referred to as the ?HV68 TMERs (tRNA-miRNA-encoded RNAs). To determine the total concerted genetic contribution of these ncRNAs to ?HV acute infection and pathogenesis, we generated and characterized a recombinant ?HV68 strain devoid of all eight TMERs. TMER-deficient ?HV68 has wild-type levels of lytic replication in vitro and normal establishment of latency in B cells early following acute infection in vivo. In contrast, during acute infection of immunodeficient mice, TMER-deficient ?HV68 has reduced virulence in a model of viral pneumonia, despite having an enhanced frequency of virus-infected cells. Strikingly, expression of a single viral tRNA-like molecule, in the absence of all other virus-encoded TMERs and miRNAs, reverses both attenuation in virulence and enhanced frequency of infected cells. These data show that ?HV ncRNAs play critical roles in acute infection and virulence in immunocompromised hosts and identify these RNAs as a new potential target to modulate ?HV-induced infection and pathogenesis. IMPORTANCE:The gammaherpesviruses (?HVs) are a subfamily of viruses associated with chronic inflammatory diseases and cancer, particularly in immunocompromised individuals. These viruses uniformly encode multiple types of noncoding RNAs (ncRNAs) that are not translated into proteins. It remains unclear how virus-expressed ncRNAs influence the course and outcome of infection in vivo. Here, we generated a mouse ?HV that lacks the expression of multiple ncRNAs. Notably, this mutant virus is critically impaired in the ability to cause disease in immunocompromised hosts yet shows a paradoxical increase in infected cells early during infection in these hosts. While the original mouse virus encodes multiple ncRNAs, the expression of a single domain of one ncRNA can partially reverse the defects of the mutant virus. These studies demonstrate that ?HV ncRNAs can directly contribute to virus-induced disease in vivo and that these RNAs may be multifunctional, allowing the opportunity to specifically interfere with different functional domains of these RNAs.

Project description:Many herpesviruses express small noncoding RNAs (sncRNAs), including microRNAs (miRNAs), that may play roles in regulating lytic and latent infections. None have yet been reported in varicella-zoster virus (VZV; also known as human herpesvirus 3 [HHV-3]). Here we analyzed next-generation sequencing (NGS) data for small RNAs in VZV-infected fibroblasts and human embryonic stem cell-derived (hESC) neurons. Two independent bioinformatics analyses identified more than 20 VZV-encoded 20- to 24-nucleotide RNAs, some of which are predicted to have stem-loop precursors potentially representing miRNAs. These sequences are perfectly conserved between viruses from three clades of VZV. One NGS-identified sequence common to both bioinformatics analyses mapped to the repeat regions of the VZV genome, upstream of the predicted promoter of the immediate early gene open reading frame 63 (ORF63). This miRNA candidate was detected in each of 3 independent biological repetitions of NGS of RNA from fibroblasts and neurons productively infected with VZV using TaqMan quantitative PCR (qPCR). Importantly, transfected synthetic RNA oligonucleotides antagonistic to the miRNA candidate significantly enhanced VZV plaque growth rates. The presence of 6 additional small noncoding RNAs was also verified by TaqMan qPCR in productively infected fibroblasts and ARPE19 cells. Our results show VZV, like other human herpesviruses, encodes several sncRNAs and miRNAs, and some may regulate infection of host cells.IMPORTANCE Varicella-zoster virus is an important human pathogen, with herpes zoster being a major health issue in the aging and immunocompromised populations. Small noncoding RNAs (sncRNAs) are recognized as important actors in modulating gene expression, and this study demonstrates the first reported VZV-encoded sncRNAs. Many are clustered to a small genomic region, as seen in other human herpesviruses. At least one VZV sncRNA was expressed in productive infection of neurons and fibroblasts that is likely to reduce viral replication. Since sncRNAs have been suggested to be potential targets for antiviral therapies, identification of these molecules in VZV may provide a new direction for development of treatments for painful herpes zoster.

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Advancing cancer treatment: in vivo delivery of therapeutic small noncoding RNAs.

Publications

Advancing cancer treatment: <i>in vivo</i> delivery of therapeutic small noncoding RNAs.

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