Algorithm for the Early Diagnosis and Treatment of Patients with Cross Reactive Immunologic Material-Negative Classic Infantile Pompe Disease: A Step towards Improving the Efficacy of ERT

Abstract

ObjectiveAlthough enzyme replacement therapy (ERT) is a highly effective therapy, CRIM-negative (CN) infantile Pompe disease (IPD) patients typically mount a strong immune response which abrogates the efficacy of ERT, resulting in clinical decline and death. This study was designed to demonstrate that immune tolerance induction (ITI) prevents or diminishes the development of antibody titers, resulting in a better clinical outcome compared to CN IPD patients treated with ERT monotherapy.MethodsWe evaluated the safety, efficacy and feasibility of a clinical algorithm designed to accurately identify CN IPD patients and minimize delays between CRIM status determination and initiation of an ITI regimen (combination of rituximab, methotrexate and IVIG) concurrent with ERT. Clinical and laboratory data including measures of efficacy analysis for response to ERT were analyzed and compared to CN IPD patients treated with ERT monotherapy.ResultsSeven CN IPD patients were identified and started on the ITI regimen concurrent with ERT. Median time from diagnosis of CN status to commencement of ERT and ITI was 0.5 months (range: 0.1–1.6 months). At baseline, all patients had significant cardiomyopathy and all but one required respiratory support. The ITI regimen was safely tolerated in all seven cases. Four patients never seroconverted and remained antibody-free. One patient died from respiratory failure. Two patients required another course of the ITI regimen. In addition to their clinical improvement, the antibody titers observed in these patients were much lower than those seen in ERT monotherapy treated CN patients.ConclusionsThe ITI regimen appears safe and efficacious and holds promise in altering the natural history of CN IPD by increasing ERT efficacy. An algorithm such as this substantiates the benefits of accelerated diagnosis and management of CN IPD patients, thus, further supporting the importance of early identification and treatment initiation with newborn screening for IPD.

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

“…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. Effectively mitigating the immune response to ERT is thus an area of therapeutic intervention where potential improvements can be made to significantly improve clinical outcomes [18,19,48,49]. An important focus in the future is the early identification of patients with Pompe disease who are at greatest risk of developing HSAT subsequent to ERT initiation.…”

“…Overall, the risk-benefit profile favors treating CRIM-negative patients with ITI, because the likelihood of developing HSAT in CRIM-negative cases is extremely high [47]. Currently accepted practice for CRIM-negative patients is to initiate ITI at the time of initiation of ERT and to monitor anti-rhGAA IgG Ab titers monthly [49].…”

“…Sixteen of these patients were ERT-naïve when ITI was commenced, and 2 patients had initiated ITI after starting ERT. Data from 11 CRIM-negative patients who received ITI based on the described protocol have been published [19,49]. Nine patients were ERT-naïve, and 2 had recently commenced ERT.…”

Synergistic Efficacy from Gene Therapy with Coreceptor Blockade and a β2-Agonist in Murine Pompe Disease

“…Furthermore, suppressing the formation of anti-rhGAA antibodies by immunosuppression significantly prolongs the survival of CRIM-negative infants. 5,6 The relevance of antibody formation to therapeutic efficacy in Pompe disease has been emphasized by the poor response of CRIM-negative patients to ERT, which correlates with the onset of HSAT. 4,7 To overcome the obstacle posed by HSAT, we have focused on developing tools for the suppression of immune responses as well as induction of immune tolerance against introduced GAA.…”

Transient Low-Dose Methotrexate Generates B Regulatory Cells That Mediate Antigen-Specific Tolerance to Alglucosidase Alfa

“…Low-dose methotrexate induction treatment was subsequently included in a clinical immune tolerance protocol that coadministered the B cell-depleting agent, Rituximab, with optional IVIG (30)(31)(32). The dose of methotrexate used in mice and in patients is considered to be low, as the human equivalent dose is 0.4 mg/kg s.c. in infants.…”