Abstract

This is a renewal application for the use of cat and rat models of human mucopolysaccaridoses for the development of approaches to therapy. Two disorders are presented: MPS I due to alpha-iduronidase (ID) deficiency, for which there is a cat model, and MPS VI due to aryl sulfatase B (ASB) deficiency for which there are cat and rat models.
The specific aims are to (1) investigate pathogenesis, in particular as it applies to collagen synthesis on skeletal and ocular abnormalities, abnormal storage in neural cells, and the cell types catabolizing dermatan sulfate; (2) evaluate enzyme replacement and bone marrow transplantation as therapeutic strategies in both disorders; and (3) evaluate gene therapy approaches for MPS I and VI, including continuation of studies using progenitor cell implants in MPS VI cats, development of methods for fluorescence-based enrichment of of transduced bone marrow progenitors, development of novel vectors and procedure systems, and development of organ specific gene transfer technology.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK025759-20
Application #
2733989
Study Section
Medical Biochemistry Study Section (MEDB)
Program Officer
Mckeon, Catherine T
Project Start
1979-07-01
Project End
2001-06-30
Budget Start
1998-07-10
Budget End
1999-06-30
Support Year
20
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Pennsylvania
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Hinderer, Christian; Bell, Peter; Louboutin, Jean-Pierre et al. (2015) Neonatal Systemic AAV Induces Tolerance to CNS Gene Therapy in MPS I Dogs and Nonhuman Primates. Mol Ther 23:1298-1307
Bradbury, Allison M; Gurda, Brittney L; Casal, Margret L et al. (2015) A review of gene therapy in canine and feline models of lysosomal storage disorders. Hum Gene Ther Clin Dev 26:27-37
Hinderer, Christian; Bell, Peter; Gurda, Brittney L et al. (2014) Intrathecal gene therapy corrects CNS pathology in a feline model of mucopolysaccharidosis I. Mol Ther 22:2018-27
Hinderer, Christian; Bell, Peter; Gurda, Brittney L et al. (2014) Liver-directed gene therapy corrects cardiovascular lesions in feline mucopolysaccharidosis type I. Proc Natl Acad Sci U S A 111:14894-9
Simonaro, Calogera M; Sachot, Sylvain; Ge, Yi et al. (2013) Acid ceramidase maintains the chondrogenic phenotype of expanded primary chondrocytes and improves the chondrogenic differentiation of bone marrow-derived mesenchymal stem cells. PLoS One 8:e62715
Ferla, Rita; O'Malley, Thomas; Calcedo, Roberto et al. (2013) Gene therapy for mucopolysaccharidosis type VI is effective in cats without pre-existing immunity to AAV8. Hum Gene Ther 24:163-9
Malik, Saafan Z; Lewis, Melissa; Isaacs, Alison et al. (2012) Identification of the rostral migratory stream in the canine and feline brain. PLoS One 7:e36016
Sewell, Adrian C; Haskins, Mark E; Giger, Urs (2012) Dried blood spots for the enzymatic diagnosis of lysosomal storage diseases in dogs and cats. Vet Clin Pathol 41:548-57
Ponder, Katherine P; O'Malley, Thomas M; Wang, Ping et al. (2012) Neonatal gene therapy with a gamma retroviral vector in mucopolysaccharidosis VI cats. Mol Ther 20:898-907
Sleeper, Meg; Bish, Lawrence T; Haskins, Mark et al. (2011) Status of therapeutic gene transfer to treat cardiovascular disease in dogs and cats. J Vet Cardiol 13:131-40

Showing the most recent 10 out of 71 publications