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High-titer, purified herpes simplex virus thymidine kinase (HSV-TK) retroviral particles, followed with intraperitoneal ganciclovir (GCV) were tested in Fischer rats bearing 1-week established 9L gliosarcomas. 9L cells were infused intracranially through a cannula on day 0, given intracranial infusions of HSV-TK retroviral particles on days 7-12, and given 5 or 10 daily doses of intraperitoneal GCV starting at day 14. Tumor volumetric studies performed on rat brains at day 26 after tumor infusion revealed significant differences in experimental groups receiving HSV-TK retroviral particles plus 10-day GCV or the 100% transduced 9L-TK group receiving GCV versus control groups treated with either buffer, HSV-TK vector, or either 5-or 10-day regimens of GCV alone. The duration of GCV administration and the volume of tumor burden influenced efficacy. Adjuvant dexamethasone did not significantly affect efficacy. Experiments in which 9L rechallenge of animals treated with 9L-TK/GCV or 9L tumors treated with HSV-TK vector/GCV indicated that a host immune response was involved in rejecting the rechallenge tumor. Outcome was dependent upon the site and size of the rechallenge inoculum. In vitro, bystander effects were significant but were especially marked when cell-to-cell contact was maintained. Cumulatively, the data indicate that both the bystander effect and the host immune response are responsible for the efficacy observed in the suicide gene therapy paradigm using purified HSV-TK retroviral particles and GCV to treat smaller tumor burden in rats with 9L gliosarcoma.

CLI remains an under-recognized condition associated with high rates of major amputation and disparities in care. Optimal medical therapy can reduce the risk of major adverse cardiovascular and limb events, but revascularization combined with close wound care remains the cornerstone of amputation prevention. Endovascular revascularization has become more common over time and has been associated with a reduction in amputation rates. Ongoing clinical trials will help inform best practices for revascularization strategies and techniques. Vascular care is inconsistent across the USA, with significant variation in access to care revascularization rates and rates of major amputation. Major amputation can be prevented in patients with CLI when optimal medical therapy, lifestyle modification, and revascularization are provided in a multidisciplinary setting.