Cyclic neutropenia is a rare disease that occurs both in man and grey collie dogs. The recurrent severe neutropenia leads to bacterial infections and shortened life expectancy. Long-term daily administration of recombinant G-CSF eliminates the severe recurrent neutropenia and provides therapy for dogs and patients. This research will study the treatment of grey collie dogs with cyclic hematopoiesis by delivery of G-CSF using two different approaches. In one aim we will study in vivo lentivirus-mediated delivery of canine G-CSF. In another aim G-CSF will be delivered by cell implants employing transduced allogeneic cells in bioisolator devices that eliminate the need for immunosuppression. We have previously shown that long-term administration of recombinant canine G-CSF abolishes the recurrent hematopoietic cycling in affected dogs and we have data showing increased neutrophil production in an affected dog administered lentivirus encoding canine G-CSF. We will administer G-CSF encoding lentivirus to muscle of grey collie and normal dogs and rats. We will investigate implantation of transduced vascular smooth muscle cells in bio-isolator devices to provide safe long-term expression of G-CSF in rats, normal dogs and grey collies. These target cells were chosen for ease of culture, transplantability and potential to allow stable long-term expression of transduced genes.
The Specific Aims are: l. To administer G-CSF lentivirus to grey collie, normal dogs and rats to determine the duration of vector-mediated cytokine expression and the feasibility of virus re-administration. We will determine the tissue distribution of virus. 2. To investigate the use of bioisolator devices to deliver sustained therapeutic levels of G-CSF to rats and dogs. We believe this research will demonstrate that gene transfer can be used for long-term treatment of cyclic neutropenia, and will have an application in the treatment of other neutropenias and genetic disorders responding to secreted hormones and clotting factors. The overall goal of this proposal is to generate clinical data in a large animal model that can be applied to the treatment of patients.
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