Successful induction of immune tolerance to enzyme replacement therapy in canine mucopolysaccharidosis I

Abstract

Immune responses can interfere with the effective use of therapeutic proteins to treat genetic deficiencies and have been challenging to manage. To address this problem, we adapted and studied methods of immune tolerance used in canine organ transplantation research to soluble protein therapeutics. A tolerization regimen was developed that prevents a strong antibody response to the enzyme ␣-L-iduronidase during enzyme replacement therapy of a canine model of the lysosomal storage disorder mucopolysaccharidosis I. The tolerizing regimen consists of a limited 60-day course of cyclosporin A and azathioprine combined with weekly i.v. infusions of low-dose recombinant human ␣-L-iduronidase. The canines tolerized with this regimen maintain a reduced immune response for up to 6 months despite weekly therapeutic doses of enzyme in the absence of immunosuppressive drugs. Successful tolerization depended on high plasma levels of cyclosporin A combined with azathioprine. In addition, the induction of tolerance may require mannose 6-phosphate receptormediated uptake because ␣-L-iduronidase and ␣-glucosidase induced tolerance with the drug regimen whereas ovalbumin and dephosphorylated ␣-L-iduronidase did not. This tolerization method should be applicable to the treatment of other lysosomal storage disorders and provides a strategy to consider for other nontoleragenic therapeutic proteins and autoimmune diseases.

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

“…These strategies had variable outcomes and serious side effects were reported in some cases. 13,[27][28][29] There is a risk that intensifying the tolerance induction protocols by combination chemotherapy and immune suppression would result in significantly increased morbidity, as has been reported in hemophilia. 30,31 Development of immune tolerance with allogeneic HSCT has been reported in various autoimmune disorders and to date over a thousand HSCT have been carried out for this indication.…”

“…7,[10][11][12] Several clinical protocols for the induction of immune tolerance to exogenous enzyme have been reported for these diseases and others, including hemophiliac disorders 13 in which there is a similar host immune response against a foreign protein. Allogeneic hematopoietic stem cell transplantation (HSCT) can replace the recipient's immune system with that of the donor, thereby tolerizing the individual to the replaced enzyme (pharmacological or cellular).…”

Intrathecal enzyme replacement therapy: Successful treatment of brain disease via the cerebrospinal fluid

“…To mimic the clinical situation more accurately, these canines were also provided IV enzyme replacement therapy at 0.58 mg/kg (125,000 units/kg) once weekly as is approved for human use. The IV enzyme replacement is not expected to result in CNS benefit at this dose based on prior data [19][20][21]. These dogs were compared with four MPS I dogs previously published that received four weekly doses of about 1 mg IT rhIDU and no IV treatment [19].…”

“…The remaining low-dose dog (Bd) had a moderate, neutrophilic meningitis, which is not typical for an immune-mediated meningitis from IT rhIDU. Some dogs were made tolerant to rhIDU prior to study enrollment, which may limit our ability to assess their immune response [21]. CSF leukocyte counts at study end were ≤5 cells/μL in 6 dogs, 15-18 cells/μL in 3 dogs, and 74 cells/μL in one dog receiving monthly, quarterly, and low-dose IT regimens.…”

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

“…We recently reported a new method for inducing antigen-specific immune tolerance to lysosomal enzymes in the canine model of MPS I (17). Here, we utilized this specific tolerance induction method to produce MPS I canines that are immune tolerant to rhIDU and then compared the impact of immune tolerance on treatment effectiveness with that in MPS I canines that were nontolerant to rhIDU.…”