William R.A. Osborne, PhD
Title:
Research Professor, Department of Pediatrics
Email Address:
Background:
Bill Osborne received his PhD from King’s College, University of London in 1973. He did post-doctoral training in Dr. Richard Tashian’s laboratory at the University of Michigan. He is currently a Research Professor at the Diabetes and Obesity Center of Excellence at the University of Washington.
Focus:
Dr. Osborne’s research is focused on virus-mediated gene therapy to treat diabetes and cyclic neutropenia in rat and dog models respectively. He is Director of the Virus, Molecular Biology and Cell Core of the Diabetes Endocrinology Research Center at the University of Washington. This Core produces lentivirus and retrovirus vectors for affiliated researchers.
Treatment of diabetes by encapsulated cells
Encapsulation of genetically modified cells permits insulin delivery for Type 1 diabetes without the need for immunosuppression. The long term goals of this work are (1) to develop cloned, well characterized cell lines that may be transplanted to treat rats with diabetes and (2) to develop methods to permit implantation of allogeneic islets for long term survival and therapy without the need for immunosuppression. This approach has the benefit that only one human cell line will be generated and characterized for the treatment of all patients. These studies will provide valuable preclinical information from diabetic rodents that may be applied to treat patients with type 1 diabetes.
Lentivirus-mediated transfer of Gimap5 to treat type 1 diabetic rats
The objective of this research is to investigate lentivirus-mediated gene therapy to treat spontaneously diabetic BB rats, a well characterized model of T1DM. The mutant lymphopenia (lyp) gene in BB rats is a novel GTPase immune-associated (Gimap5) protein. We propose that loss of Gimap5 function in thymocytes of BB rats leads to lymphopenia and autoimmunity and diabetes and hypothesize that lentivirus-mediated Gimap5 expression in thymocytes will delay or reverse diabetes. We will use lentivirus vectors to transduce lyp/lyp bone marrow stem cells to express wild type Gimap5 cDNA under the control of lck proximal promoter, a thymocyte specific promoter. Specific Aim 1: in vitro studies to document transduction efficiency and tissue specific transgene expression targeted at rat bone marrow and T and B cells. In Specific aim 2 we will study in vivo gene expression by transplanting transduced bone marrow to irradiated recipient rats. The well characterized diabetic BB rat affords us the opportunity to study gene therapy treatment before onset, at onset and after onset when insulin secreting β cells have been destroyed by the autoimmune process. These three stages of intervention in the disease process are applicable to the treatment of T1DM patients.
Treatment of grey collie dogs with cyclic hematopoiesis by lentivirus delivery of G-CSF
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. Daily administration of recombinant G-CSF eliminates the severe recurrent neutropenia and provides therapy for dogs and patients. The aim of this research is to employ two different approaches to treat grey collie dogs with cyclic neutropenia: virus-mediated G-CSF delivery; and cell therapy using bioisolator devices. In the first aim we will administer G-CSF-lentivirus to grey collie, normal dogs and rats to determine the duration of vector-mediated cytokine expression, dose response relationships, the ability to re-administer virus and the tissue distribution of virus after administered to the muscle. In the second aim we will investigate the use of bioisolator devices to deliver sustained therapeutic levels of G-CSF to dogs and rats. We will also determine if allogeneic cells can be used to deliver G-CSF to rats and normal dogs before treating grey collie dogs. We have successfully treated four dogs with cyclic neutropenia by administration of G-CSF-lentivirus to muscle. A successfully treated dog has been returned to its owner in Wisconsin and is healthy and living a normal life. We believe lentivirus-mediated gene expression may be applied to the sustained delivery of glucose regulated insulin in diabetic animals and patients.
Representative Publications:
Barry SC, Ramesh N, Lejnieks DV, Simonson WT, Kemper L, Lernmark A, Osborne WRA: Glucose-regulated insulin expression in diabetic rats. Human Gene Therapy, 12:131-139, 2001.
Yanay O, Flint LY, Brzezinski M, Barry SC, Barton RW, Osborne WRA: Long term erythropoietin gene expression form transduced cells in bioisolator devices. Human Gene Therapy 14: 1587-1593, 2003.
Yanay O, Brzezinski M, Christensen J, Liggitt D. Dale DC. Osborne, WRA: An adult dog with cyclic neutropenia treated by lentivirus-mediated G-CSF delivery. Human Gene Therapy 17: 464-469, 2006.
Brzezinski M, Yanay O, Waldron L, Barry SC, Osborne WRA. G-CSF-lentivirus administration in rats provided sustained elevated neutrophil counts and subsequent EPO-lentivirus administration increased hematocrits. J Gene Med 9:571-578, 2007.
Sweet IR, Yanay O, Waldron L, Gilbert M, Fuller JM, Tupling T, Lernmark A, Osborne WRA: Treatment of Diabetic Rats with Encapsulated Islets. Journal of Cellular and Molecular Medicine, Epub ahead of print, 2008.
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Current Collaborations:
Within the Diabetes and Obesity Center of Excellence and its Affiliated Members
Ofer Yanay, MD
Alan Chait, MD
Ian Sweet, PhD
Jack Oram, PhD
Michael Schwartz, MD
Outside the Diabetes and Obesity Center of Excellence
Ake Lernmark, PhD, Sweden
Daniel Moralejo, DVM, PhD, University of Washington
Lab Members:
Kelly Kernan, BS
Brian Van Yserloo, BS
Margaret Brezinzski, BS
Ofer Yanay, MD