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Enzyme therapy and immune response in relation to CRIM status: the Dutch experience in classic infantile Pompe
Carin M van Gelder1, Marianne Hoogeveen-Westerveld, Marian A Kroos
1Department of Pediatrics, Division of Metabolic Diseases and Genetics, Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, The Netherlands, carinvangelder@gmail.com.
Insights
Enzyme-replacement therapy (ERT) for Pompe disease can trigger antibody formation, impacting treatment effectiveness. Early ERT initiation and immune modulation may minimize adverse immune responses in infants with this rare genetic disorder.
Area of Science:
- Biochemistry
- Immunology
- Genetics
Background:
- Pompe disease is an inherited metabolic disorder caused by acid α-glucosidase deficiency.
- It presents in infants with muscle weakness and cardiomyopathy.
- Enzyme-replacement therapy (ERT) can be complicated by immune responses, particularly in CRIM-negative patients.
Purpose of the Study:
- To assess the clinical outcome of Dutch infants with Pompe disease in relation to their CRIM status and immune response.
- To investigate the correlation between antibody formation and treatment efficacy.
- To evaluate the impact of ERT initiation timing on immune response and clinical outcomes.
Main Methods:
- Genotyping and CRIM status determination for eleven patients.
- Assessment of antibody formation and clinical outcomes over a minimum of 4 years.
- Analysis of ERT start age and antibody titers.
Main Results:
- All patients developed antibodies; high titers (above 1:31,250) correlated with poor ERT response.
- Antibody titers varied significantly and did not strictly correlate with CRIM status.
- Patients starting ERT after 2 months of age tended to develop higher antibody titers.
Conclusions:
- Antibody formation is common in ERT for infantile Pompe disease and counteracts treatment effects.
- Early ERT initiation and immune modulation may minimize immune responses.
- CRIM-negative status appears associated with a poorer clinical outcome.
Background:
Enzyme-replacement therapy (ERT) in Pompe disease--an inherited metabolic disorder caused by acid α-glucosidase deficiency and characterized in infants by generalized muscle weakness and cardiomyopathy--can be complicated by immune responses. Infants that do not produce any endogenous acid α-glucosidase, so-called CRIM-negative patients, reportedly develop a strong response. We report the clinical outcome of our Dutch infants in relation to their CRIM status and immune response.
Methods:
Eleven patients were genotyped and their CRIM status was determined. Antibody formation and clinical outcome were assessed for a minimum of 4 years.
Results:
ERT was commenced between 0.1 and 8.3 months of age, and patients were treated from 0.3 to 13.7 years. All patients developed antibodies. Those with a high antibody titer (above 1:31,250) had a poor response. The antibody titers varied substantially between patients and did not strictly correlate with the patients' CRIM status. Patients who started ERT beyond 2 months of age tended to develop higher titers than those who started earlier. All three CRIM-negative patients in our study succumbed by the age of 4 years seemingly unrelated to the height of their antibody titer.
Conclusion:
Antibody formation is a common response to ERT in classic infantile Pompe disease and counteracts the effect of treatment. The counteracting effect seems determined by the antibody:enzyme molecular stoichiometry. The immune response may be minimized by early start of ERT and by immune modulation, as proposed by colleagues. The CRIM-negative status itself seems associated with poor outcome.
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