Haskins, Mark E
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PublicationThe Pathology of the Feline Model of Mucopolysaccharidosis VI(1980-12-01) Haskins, Mark E; Haskins, Mark E; Aguirre, Gustavo D; Jezyk, Peter F; Patterson, Donald FThree cats with feline arylsulfatase-B-deficient mucopolysaccharidosis were studied by light and transmission electron microscopy. Membrane-bound cytoplasmic inclusions were present in hepatocytes, bone marrow granulocytes, vascular smooth muscle cells, and fibroblasts in skin, cornea, and cardiac valves. Central nervous system lesions were restricted to mild ventricular dilatation, perithelial cell vacuolation, and, in one animal, cord compression by vertebral exostoses. The lesions in these cats closely resembled those described in human patients with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). PublicationEvaluation of Adeno-Associated Viral Vectors for Liver-Directed Gene Transfer in Dogs(2011-08-22) Haskins, Mark E; Gao, Guangping; Sleeper, Margaret M; Wang, Lili; Sleeper, Margaret M; Wang, Huan; Calcedo, Roberto; Vandenberghe, Luk H; Chen, Shu-Jen; Weisse, Chick; Withnall, Elanor; Wilson, James MThis study evaluated six adeno-associated viral (AAV) vectors expressing green fluorescent protein (GFP) from the liver-specific thyroid hormone–binding globulin (TBG) promoter made with novel capsids in canine liver-directed gene transfer. Studies in 1.5-month-old dogs, which were administered vector through a peripheral vein, showed that AAV8 capsid vectors had the most favorable performance profiles. Interestingly, the absolute levels of hepatocyte transduction achieved with AAV8 were lower in dogs compared with what had been achieved in mice and nonhuman primates. Additional studies were performed with AAV8 delivered into the hepatic artery in adult dogs, with higher doses of vector used to assess potential dose-limiting toxicities. These studies showed good transduction on day 7 in one dog that apparently was lost by day 28 in another dog through the generation of GFP-specific T cells. Each adult dog was carefully monitored for any hemodynamic changes associated with vector infusion. Both animals demonstrated mild to moderate hypotension and bradycardia, which appeared to be anesthesia-related, making it difficult to evaluate contributions of the vector. PublicationThe Pathology of the Feline Model of Mucopolysaccharidosis I(1983-07-01) Haskins, Mark E; Haskins, Mark E; Aguirre, Gustavo D; Jezyk, Peter F; Desnick, Robert J; Patterson, Donald FFive cats with feline α-L-iduronidase-deficient mucopolysaccharidosis were studied. Membrane-bound cytoplasmic inclusions were present in central nervous system neurons, hepatocytes, chondrocytes, vascular and splenic smooth muscle cells, bone marrow leukocytes, and fibroblasts of the skin, eye, and cardiac valves. The lesions in these cats closely resemble those described in human patients with mucopolysaccharidosis I H (Hurler syndrome). PublicationTherapeutic Neonatal Hepatic Gene Therapy in Mucopolysaccharidosis VII Dogs(2002-10-01) Parker Ponder, Katherine; Melniczek, John R; Xu, Lingfei; Weil, Margaret A; O'Malley, Thomas M; Sleeper, Margaret M; Knox, Van W; Volk, Susan W; Mazrier, Hamutal; Zweigle, Jean; Wolfe, John H; Haskins, Mark E; Volk, Susan W; Mango, Robert L; Zweigle, Jean; Wolfe, John H; Haskins, Mark EDogs with mucopolysaccharidosis VII (MPS VII) were injected intravenously at 2–3 days of age with a retroviral vector (RV) expressing canine β-glucuronidase (cGUSB). Five animals received RV alone, and two dogs received hepatocyte growth factor (HGF) before RV in an attempt to increase transduction efficiency. Transduced hepatocytes expanded clonally during normal liver growth and secreted enzyme with mannose 6-phosphate. Serum GUSB activity was stable for up to 14 months at normal levels for the RV-treated dogs, and for 17 months at 67-fold normal for the HGF/RV-treated dog. GUSB activity in other organs was 1.5–60% of normal at 6 months for two RV-treated dogs, which was likely because of uptake of enzyme from blood by the mannose 6-phosphate receptor. The body weights of untreated MPS VII dogs are 50% of normal at 6 months. MPS VII dogs cannot walk or stand after 6 months, and progressively develop eye and heart disease. RV- and HGF/RV-treated MPS VII dogs achieved 87% and 84% of normal body weight, respectively. Treated animals could run at all times of evaluation for 6–17 months because of improvements in bone and joint abnormalities, and had little or no corneal clouding and no mitral valve thickening. Despite higher GUSB expression, the clinical improvements in the HGF/RV-treated dog were similar to those in the RV-treated animals. This is the first successful application of gene therapy in preventing the clinical manifestations of a lysosomal storage disease in a large animal. PublicationAnimal Model of Human Disease: Mucopolysaccharidosis Type VII (Sly Syndrome). Beta-Glucuronidase-Deficient Mucopolysaccharidosis in the Dog(1991-06-01) Haskins, Mark E; Haskins, Mark E; Aguirre, Gustavo D; Jezyk, Peter F; Schuchman, Edward H; Desnick, Robert J; Patterson, Donald F PublicationBone Marrow Transplantation for Feline Mucopolysaccharidosis I(2007-07-01) Aguirre, Gustavo D; Ellinwood, Norman Matthew; Vite, Charles H; Colle, Marie-Anne; Weil, Margaret A; Casal, Margret L; Vite, Charles H; Wiemelt, Staci; Hasson, Christopher W; O'Malley, Thomas M; He, Xingxuan; Prociuk, Ulana; Evans, Sydney M; Melniczek, John R; Lannon, Anne; Knox, Van W; Haskins, Mark E; Vanier, Marie T; Schuchman, Edward H; Walkley, Steven U; Haskins, Mark ESevere mucopolysaccharidosis type I (MPS I) is a fatal neuropathic lysosomal storage disorder with significant skeletal involvement. Treatment involves bone marrow transplantation (BMT), and although effective, is suboptimal, due to treatment sequelae and residual disease. Improved approaches will need to be tested in animal models and compared to BMT. Herein we report on bone marrow transplantation to treat feline mucopolysaccharidosis I (MPS I). Five MPS I stably engrafted kittens, transplanted with unfractionated bone marrow (6.3 × 107–1.1 × 109 nucleated bone marrow cells per kilogram) were monitored for 13–37 months post-engraftment. The tissue total glycosaminoglycan (GAG) content was reduced to normal levels in liver, spleen, kidney, heart muscle, lung, and thyroid. Aorta GAG content was between normal and affected levels. Treated cats had a significant decrease in the brain GAG levels relative to untreated MPS I cats and a paradoxical decrease relative to normal cats. The α-l-iduronidase (IDUA) activity in the livers and spleens of transplanted MPS I cats approached heterozygote levels. In kidney cortex, aorta, heart muscle, and cerebrum, there were decreases in GAG without significant increases in detectable IDUA activity. Treated animals had improved mobility and decreased radiographic signs of disease. However, significant pathology remained, especially in the cervical spine. Corneal clouding appeared improved in some animals. Immunohistochemical and biochemical analysis documented decreased central nervous system ganglioside storage. This large animal MPS I study will serve as a benchmark of future therapies designed to improve on BMT.