Gene delivery from the E3 region of replicating human adenovirus: evaluation of the 6.7 K/gp19 K region

Gene delivery from the E3 region of replicating human adenovirus: evaluation of the E3B region

“…8,9 The substituted genes were expressed similarly to the genes they replaced and the remaining E3 genes continued to be expressed in keeping with the original hypotheses. In this study, the E3B region (deleted in ONYX-015) was genetically engineered so that it could be removed and replaced with the therapeutic transgene.…”

“…It may be related to mTNF expression, however, other recombinant Ads expressing mTNF do not overexpress ADP. 8,9 Alterations in splicing, polyadenylation signal usage and mRNA levels are being explored.…”

“…7 In the replicating adenovirus we have taken advantage of several properties of the Ad E3 region transcription unit to create an efficient replicating adenovirus-based gene delivery system. 8,9 Ultimately, this system should allow investigators to create viruses that deliver multiple transgenes at predictable times and levels through the course of the viral infection. One of the regions of the E3 transcription unit, the E3B region ( Figure 1) encodes three proteins; two of the three genes form the RID (receptor internalization and degradation) complex, composed of RID␣ (10.4 K) and RID␤ (14.5 K), respectively.…”

Pilot trial of intravenous infusion of a replication-selective adenovirus (ONYX-015) in combination with chemotherapy or IL-2 treatment in refractory cancer patients

“…Specifically, delivery of herpes simplex type I thymidine kinase and cytosine deaminase genes correlate with greater transgene expression and antitumor effect when delivered via a replicating adenoviral vector as opposed to a nonreplicating adenoviral vector. 80,81 Additionally, other gene modified viruses variant from ONYX-015 (i.e. ONYX-411) have been shown preclinically to have greater replicative capacity by 1000-fold while monitoring similar tumor specificity.…”

5-Fluorocytosine increases the toxicity of Wnt-targeting replicating adenoviruses that express cytosine deaminase as a late gene

“…[17][18][19] Replacement of the E1B 55K gene with a CD-tk fusion gene under a heterologous promoter permits high level CD-tk expression, and combination virus, prodrug and radiation therapy has given promising results in preclinical studies and a phase I clinical study in prostate cancer. 13,14,20 The E3 genes are nonessential and can be replaced with therapeutic genes, [21][22][23][24] although retention of the E3 region has been shown to increase the efficacy of oncolytic adenoviruses in mouse xenograft models. 25,26 Despite E3 being labelled as an early transcription unit, two groups of E3 transcripts, ADP and E3B, are predominantly expressed from the major late promoter with late kinetics.…”