Neonatal Systemic AAV Induces Tolerance to CNS Gene Therapy in MPS i Dogs and Nonhuman Primates

Christian Hinderer, Peter Bell, Jean Pierre Louboutin, Yanqing Zhu, Hongwei Yu, Gloria Lin, Ruth Choa, Brittney L. Gurda, Jessica Bagel, Patricia O'donnell, Tracey Sikora, Therese Ruane, Ping Wang, Alice F Tarantal, Margret L. Casal, Mark E. Haskins, James M. Wilson

Research output: Contribution to journalArticlepeer-review

54 Scopus citations


The potential host immune response to a nonself protein poses a fundamental challenge for gene therapies targeting recessive diseases. We demonstrate in both dogs and nonhuman primates that liver-directed gene transfer using an adeno-associated virus (AAV) vector in neonates induces a persistent state of immunological tolerance to the transgene product, substantially improving the efficacy of subsequent vector administration targeting the central nervous system (CNS). We applied this approach to a canine model of mucopolysaccharidosis type I (MPS I), a progressive neuropathic lysosomal storage disease caused by deficient activity of the enzyme α-l-iduronidase (IDUA). MPS I dogs treated systemically in the first week of life with a vector expressing canine IDUA did not develop antibodies against the enzyme and exhibited robust expression in the CNS upon intrathecal AAV delivery at 1 month of age, resulting in complete correction of brain storage lesions. Newborn rhesus monkeys treated systemically with AAV vector expressing human IDUA developed tolerance to the transgene, resulting in high cerebrospinal fluid (CSF) IDUA expression and no antibody induction after subsequent CNS gene therapy. These findings suggest that inducing tolerance to the transgene product during a critical period in immunological development can improve the efficacy and safety of gene therapy.

Original languageEnglish (US)
Pages (from-to)1298-1307
Number of pages10
JournalMolecular Therapy
Issue number8
StatePublished - Aug 1 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology


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