459. Long-Term Treatment of Canine Cyclic Neutropenia by G-CSF-Lentivirus
Molecular Therapy(2005)
Abstract
Cyclic neutropenia (CN) occurs both in man and grey collie dogs and is characterized by recurrent periods of neutropenia leading to bacterial infections and shortened life expectancy. Daily rG-CSF provides therapy for patients and dogs. To treat CN by gene therapy we constructed a VSV-G pseudotyped lentivirus encoding canine G-CSF cDNA regulated by CMV promoter, cPPT from HIV 1 and PRE from human hepatitis B virus. At 7 weeks of age when an affected grey collie dog was weaned, serial blood counts were monitored. These data showed the dog's absolute neutrophil counts (ANC) were cycling and observations over 4 cycles established a 12 day periodicity. The ANC meanSD during nadirs and peaks were 560787 cells/l and 10,7601,120 cells/l respectively and overall counts were 5,2404,790 cells/l. Having established that neutrophils were cycling, recombinant canine G-CSF was administered subcutaneously at a dose of 1.5 g/kg per weekday for two months. Although ANC continued to cycle, we observed significant increases in neutrophils both at the nadirs and the peaks of cycles (p<0.0001) with mean values of 4,8602,670 cells/l and 28,8709,830 cells/l respectively. Over this period the mean count was 17,82011,100 cells/l. After demonstrating that rG-CSF elevated neutrophil production cytokine administration was stopped and we administered IM 2109 infectious units(IU) of G-CSF-lentivirus. The dog showed no ill effects to the virus injections. Serial monitoring of blood cells showed elevated ANC for over 17 months with mean value of 29,23012,930 cells/l (n=217) that was significantly increased over both no treatment and rG-CSF treatment (p<0.0001). The increases in ANC from recombinant G-CSF and lentivirus administration were associated with absence of clinical signs of infection and fever.
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