Abstract
Infectious nucleic acid has been proposed as a superior formulation for oncolytic virus therapy. Oncolytic picornaviruses can be formulated as infectious RNA (iRNA), and their unwanted tropisms eliminated by microRNA (miRNA) detargeting. However, genomic insertion of miRNA target sequences into coxsackievirus A21 (CVA21) iRNA compromised its specific infectivity, negating further development as a novel oncolytic virus formulation. To address this limitation, we substituted a muscle-specific miRNA response element for the spacer region downstream of the internal ribosomal entry site in the 5′ non-coding region of CVA21 iRNA, thereby preserving genome length while avoiding the disruption of known surrounding RNA structural elements. This new iRNA (R-CVA21) retained high specific infectivity, rapidly generating replicating miRNA-detargeted viruses following transfection in H1-HeLa cells. Further, in contrast with alternatively configured iRNAs that were tested in parallel, intratumoral administration of R-CVA21 generated a spreading oncolytic infection that was curative in treated animals without associated myotoxicity. Moreover, R-CVA21 also exhibited superior miRNA response element stability in vivo. This novel formulation is a promising agent for clinical translation.
Highlights
Oncolytic viruses are proving safe, their efficacy as monotherapies is far inadequate
Infectious nucleic acid (INA) can be less immunogenic than virus particles, The 30 non-coding region (NCR) of enteroviruses contain a pseudoknot replication element known as the oriR that is involved in viral RNA synthesis and poly(A) tail elongation.[19,20,21,22,23,24,25]
IRNA coxsackievirus A21 (CVA21)-30miRT, previously generated in our lab, contained a musclespecific miRNA response element comprising two copies each of sequences completely complementary to miRNA 133 and miR-206, each separated by 4-6-nt-long linkers (133-133-206-206).[7]
Summary
Oncolytic viruses are proving safe, their efficacy as monotherapies is far inadequate. Among the most efficacious oncolytic viruses is a proprietary formulation of coxsackievirus A21 (CVA21; CAVATAK). The tolerability and efficacy of CVA21 has been demonstrated in phase I and II clinical trials.[1,2,3,4,5] these studies are limited to immune-competent patients R18 years of age, leaving the safety of CVA21, which has the potential to cause myositis in immunocompromised hosts, in pediatric/adolescent or severely immunocompromised patients largely unknown.[6,7] clinical protocols can include up to 19 treatments, a significant financial burden that will continually increase with combination therapies These studies set a precedent for developing a more cost-effective oncolytic CVA21 formulation with enhanced potency and safety to further improve clinical outcomes and expand the patient population eligibility
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