title: Mucopolysaccharidosis I cats mount a cytotoxic T lymphocyte response after neonatal gene therapy that can be blocked with CTLA4-Ig.
abstract: Although gene therapy has reduced manifestations of genetic diseases, immune responses can abrogate the effect. One approach to inducing tolerance is to perform gene transfer in newborns when the immune system is immature. We demonstrate here that the dose of retroviral vector (RV) is important in mice, as mucopolysaccharidosis I (MPS I) mice that received neonatal intravenous gene therapy with a high dose of a canine alpha-L-iduronidase (cIDUA)-expressing RV had stable expression, while those that received a low dose did not. It was unclear, however, if neonatal transfer with any dose could induce tolerance in large animals. Therefore, newborn MPS I cats were injected intravenously with the RV expressing cIDUA. Although this resulted in high serum IDUA activity due to secretion by transduced cells, expression fell due to a CTL response. Cats that transiently received the immunosuppressive agent CTLA4-Ig did not develop a CTL response. In contrast, MPS I dogs, which can respond immunologically to canine IDUA, had stable serum IDUA activity after neonatal gene therapy. We conclude that cats, but not dogs, mount a potent CTL response to canine IDUA after neonatal gene therapy, which can be prevented with transient CTLA4-Ig.
authors.affiliation: Department of Internal Medicine, Department of Biochemistry and Molecular Biophysics, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104, USA. kponder@im.wustl.edu
authors.forename: Katherine P
authors.initials: KP
authors.lastname: Ponder
authors.forename: Baomei
authors.initials: B
authors.lastname: Wang
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Xiucui
authors.initials: X
authors.lastname: Ma
authors.forename: Ramin
authors.initials: R
authors.lastname: Herati
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Karyn
authors.initials: K
authors.lastname: Cullen
authors.forename: Patty
authors.initials: P
authors.lastname: O'Donnell
authors.forename: N Matthew
authors.initials: NM
authors.lastname: Ellinwood
authors.forename: Anne
authors.initials: A
authors.lastname: Traas
authors.forename: Tina M
authors.initials: TM
authors.lastname: Primeau
authors.forename: Mark E
authors.initials: ME
authors.lastname: Haskins
mesh_terms: D000069594:Abatacept; D000818:Animals; D000831:Animals, Newborn; D002415:Cats; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006025:Glycosaminoglycans / Q000378:metabolism; D007068:Iduronidase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007108:Immune Tolerance / Q000187:drug effects; D018796:Immunoconjugates / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008059:Mucopolysaccharidosis I / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D006025:Glycosaminoglycans; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept; D007068:Iduronidase