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Recombinant Myxoma Virus Expressing Walleye Dermal Sarcoma Virus orfC Is Attenuated in Rabbits
Laura V Ashton1, Sandra L Quackenbush1, Jake Castle2
1Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523, USA.
Abstract:
The poxvirus, myxoma virus (MYXV) has shown efficacy as an oncolytic virus (OV) in some cancer models. However, MYXV replication within murine cancer models and spontaneous canine sarcomas is short-lived. In mice, successful treatment of tumors requires frequent injections with MYXV. We hypothesize that treatment of cancer with a recombinant MYXV that promotes apoptosis could improve the efficacy of MYXV. The orfC gene of walleye dermal sarcoma virus (WDSV), which induces apoptosis, was recombined into the MYXV genome (MYXVorfC). A marked increase in apoptosis was observed in cells infected with MYXVorfC. To ensure that expression of WDSV orfC by MYXV does not potentiate the pathogenesis of MYXV, we evaluated the effects of MYXVorfC inoculation in the only known host of MYXV, New Zealand white rabbits. Virus dissemination in rabbit tissues was similar for MYXVorfC and MYXV. Virus titers recovered from tissues were lower in MYXVorfC-infected rabbits as compared to MYXV-infected rabbits. Importantly, rabbits infected with MYXVorfC had a delayed onset of clinical signs and a longer median survival time than rabbits infected with MYXV. This study indicates that MYXVorfC is attenuated and suggests that MYXVorfC will be safe to use as an OV therapy in future studies.
Insights
Recombinant myxoma virus (MYXV) engineered to induce apoptosis shows promise as an oncolytic virus (OV). This enhanced MYXVorfC demonstrated reduced viral load and increased survival in rabbits, suggesting potential for safer cancer therapy.
Area of Science:
- Virology
- Oncology
- Gene Therapy
Background:
- Myxoma virus (MYXV) shows oncolytic virus (OV) potential but has limited replication in tumors.
- Frequent MYXV injections are needed for effective cancer treatment in mice.
- Enhancing MYXV to promote apoptosis may improve oncolytic efficacy.
Purpose of the Study:
- To investigate the efficacy of a recombinant MYXV (MYXVorfC) engineered to express the apoptosis-inducing orfC gene from walleye dermal sarcoma virus (WDSV).
- To assess the safety and pathogenicity of MYXVorfC in the natural host, New Zealand white rabbits.
Main Methods:
- Recombination of the WDSV orfC gene into the MYXV genome to create MYXVorfC.
- In vitro assessment of apoptosis induction in infected cells.
- In vivo evaluation of MYXVorfC pathogenicity, virus dissemination, and survival rates in New Zealand white rabbits compared to wild-type MYXV.
Main Results:
- MYXVorfC infection significantly increased apoptosis in infected cells.
- Virus dissemination in rabbit tissues was comparable between MYXVorfC and MYXV.
- MYXVorfC-infected rabbits exhibited lower virus titers, delayed clinical signs, and longer median survival times than MYXV-infected rabbits.
Conclusions:
- MYXVorfC is attenuated compared to wild-type MYXV.
- The enhanced MYXVorfC demonstrates improved safety profile in rabbits.
- MYXVorfC holds promise as a potentially safer oncolytic virus therapy for cancer treatment.
