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.

Liver-directed gene therapy corrects cardiovascular lesions in feline mucopolysaccharidosis type I

“…The reason for this decline was not clear. The high vector copy numbers in the liver samples collected at necropsy rule out death of transduced hepatocytes as a cause of this decline as was seen previously when the normal canine IDUA cDNA was used in a retroviral vector (29). The kinetics of the loss of IDUA activity were identical to those observed in a previous study of CNS-directed gene therapy in feline MPS I, which were linked to the induction of antibodies against IDUA (30).…”

Clinical characterization of cardiovascular abnormalities associated with feline mucopolysaccharidosis I and VI

“…In fact, studies have already evaluated therapeutic approaches in these models (Kakkis et al 2001;Ponder et al 2006;Sleeper et al 2004;Traas et al 2007) and physical, biochemical, and pathological findings in affected cats have been described (Haskins et al 1979a(Haskins et al , b, 1983. One study suggests that the feline model may be particularly useful for predicting an approach around a potential immune response to gene therapy (Ponder et al 2006). Moreover, cats affected with MPS I and VI survive comfortably for more than 5 years, even without treatment, which allows their use in chronic therapeutic trials (Haskins et al 1983).…”

“…MPS I cats have less than 3% of normal serum activity of a-l-iduronidase (Ponder et al 2006). MPS VI (Maroteaux-Lamy syndrome, 4-sulfatase deficiency) leads to accumulation of dermatan sulfate (Norrdin et al 1995).…”

Gene Therapy Approaches for Lysosomal Storage Disease: Next-Generation Treatment

“…However, in the MPS I dog, the same strategy resulted in 25% of the serum cIDUA levels seen in mice and only moderate clinical improvement (Traas et al, 2007). And in the MPS I cat, whereas cIDUA expression was similar to that seen in dogs, expression was transient because of a robust cytotoxic T lymphocyte response against cIDUAexpressing cells (Ellinwood et al, 2004;Ponder et al, 2006). In another example, RV-mediated liver-directed expression of b-glucuronidase resulted in significantly increased survival and long-term expression (11 years) in both the murine and canine models of MPS VII.…”