CRIM-negative infantile Pompe disease: characterization of immune responses in patients treated with ERT monotherapy

Abstract

Purpose Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) prolongs survival in infantile Pompe disease (IPD). However, the majority of cross reactive immunologic material (CRIM)-negative (CN) patients have immune responses with significant clinical decline despite continued ERT. We aimed to characterize immune responses in CN IPD patients receiving ERT monotherapy. Methods A chart review identified 20 CN IPD patients treated with ERT monotherapy for ≥6 months. Patients were stratified by anti-rhGAA antibody titers: high sustained antibody titers (HSAT) ≥51,200 at least twice; low titers (LT) <6,400 throughout treatment; or sustained intermediate titers (SIT) 6,400–25,600. Results Despite early initiation of treatment, the majority (85%) of CN patients developed significant antibody titers, most with HSAT associated with invasive ventilation and death. Nearly all patients with HSAT had at least one nonsense GAA mutation, while the LT group exclusively carried splice site or frameshift mutations. Only one patient in the HSAT group is currently alive after successful immune modulation in the entrenched setting. Conclusion Immunological responses are a significant risk in CN IPD; thus, immune tolerance induction in the naïve setting should strongly be considered. Further exploration of factors influencing immune responses is required, particularly with the advent of newborn screening for Pompe disease.

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

“…Additional factors, such as the age and the stage of disease at ERT initiation, also contribute to clinical outcome [45,46]. A recent study that focused only on the treatment outcomes of CRIM-negative patients also suggested that the majority but not all of CRIM-negative patients mounted a significant immune response [47]. The ones that did not develop a significant immune response had unique genotypes, either a frameshift or a splice site mutation in GAA [47].…”

“…A recent study that focused only on the treatment outcomes of CRIM-negative patients also suggested that the majority but not all of CRIM-negative patients mounted a significant immune response [47]. The ones that did not develop a significant immune response had unique genotypes, either a frameshift or a splice site mutation in GAA [47]. Thus, we should consider CRIM status also as a continuum, from CRIM-negative at one end to strongly CRIMpositive at the other end of the spectrum.…”

Response to de Vries et al.

“…3 Herbert and colleagues may have missed the fact that only a few adult patients develop high sustained antibodies, which is in contrast to the situation in classic infantile patients. A recent study by Masat et al 4 on behalf of the French Pompe Registry Study Group also concluded that antibodies are not a major concern in adults with Pompe disease. 4 …”

“…A recent study by Masat et al 4 on behalf of the French Pompe Registry Study Group also concluded that antibodies are not a major concern in adults with Pompe disease. 4 …”

“…In our experience, a small fraction of CRIM-negative IPD patients do not develop high antibody titers and respond favorably to ERT, which suggests that genotype alone is not responsible for the immune response. 4 Thus, the observation of genotype association in LOPD should be stated with caution.…”