Immune tolerance improves the efficacy of enzyme replacement therapy in canine mucopolysaccharidosis I

Abstract

Mucopolysaccharidoses (MPSs) are lysosomal storage diseases caused by a deficit in the enzymes needed for glycosaminoglycan (GAG) degradation. Enzyme replacement therapy with recombinant human α-l-iduronidase successfully reduces lysosomal storage in canines and humans with iduronidase-deficient MPS I, but therapy usually also induces antibodies specific for the recombinant enzyme that could reduce its efficacy. To understand the potential impact of α-l-iduronidase-specific antibodies, we studied whether inducing antigen-specific immune tolerance to iduronidase could improve the effectiveness of recombinant iduronidase treatment in canines. A total of 24 canines with MPS I were either tolerized to iduronidase or left nontolerant. All canines received i.v. recombinant iduronidase at the FDA-approved human dose or a higher dose for 9-44 weeks. Nontolerized canines developed iduronidase-specific antibodies that proportionally reduced in vitro iduronidase uptake. Immune-tolerized canines achieved increased tissue enzyme levels at either dose in most nonreticular tissues and a greater reduction in tissue GAG levels, lysosomal pathology, and urinary GAG excretion. Tolerized MPS I dogs treated with the higher dose received some further benefit in the reduction of GAGs in tissues, urine, and the heart valve. Therefore, immune tolerance to iduronidase improved the efficacy of enzyme replacement therapy with recombinant iduronidase in canine MPS I and could potentially improve outcomes in patients with MPS I and other lysosomal storage diseases.

Therapies for the bone in mucopolysaccharidoses

“…Patients treated with ERT show clinical improvement of somatic manifestations and improved quality of life (QOL). However, there are several limitations with current ERT: i) limited effect on skeletal symptoms [15][16] ii) rapid clearance from the circulation, and iii) immunological issues (antibody production leads to reduced therapeutic efficacy) [7,[17][18][19]. To resolve the above issues, a long circulating or bone-targeting enzyme was devised to deliver the enzyme to bone [20,21].…”

Hematopoietic stem cell transplantation improves the high incidence of neutralizing allo-antibodies observed in Hurler's syndrome after pharmacological enzyme replacement therapy

“…7 More recent studies in canine models of MPSI demonstrated up to 90% inhibition of enzyme uptake by MPSI fibroblasts by serum taken from dogs that had high titer anti-IDUA antibodies. 8 There is increasing evidence, mostly derived from animal models of LSD, of an inverse correlation between an observed antibody response and metabolic and clinical outcome. Even though the immune response currently reported in patients with MPSI is 91%, 9 the true incidence of functionally active (neutralizing) antibodies is unknown.…”

Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction

“…Studies in the canine model of MPS I have demonstrated that ADA can alter the distribution and effectiveness of ERT at the tissue level, and that immune tolerizing regimens can prevent ADA formation and improve the effectiveness of ERT as shown by enhanced enzyme activity in critical target tissues as compared to the enzyme activity in such tissues in non-tolerant dogs [27]. Moreover, in murine KO models of Fabry Disease, ERT activity was dramatically decreased in target tissues in seropositive as opposed to seronegative animals.…”