Insights into immunogenicity and therapeutic strategies to mitigate the immune response in infantile-onset Pompe disease: a comprehensive systematic literature review

Introduction: Pompe disease, a rare autosomal recessive metabolic myopathy, is primarily treated with enzyme replacement therapy (ERT); however, ERT response depends on several factors, including ERT initiation age, dose, and cross-reactive immunological material (CRIM) status, especially in infantile-onset Pompe disease (IOPD).

Aim: This systematic literature review (SLR) focused on three research questions (1): how CRIM status is determined in patients with IOPD in clinical practice, and how CRIM-negative status impacts outcomes (2); how health professionals use CRIM status to inform their decisions on immune tolerance induction (ITI) regimens; and (3) which regimens are used in real-world clinical practice.

Methods: The SLR was conducted using Embase and PubMed databases covering the literature from January 1, 2003, to August 4, 2022. The search terms used were “Pompe or IOPD” and “cross-reactive immunological material or CRIM.” Data extraction was performed using pre-designed tables in Microsoft Excel. Among those identified, 54, 51, and 69 studies provided meaningful data for the respective research questions. The key theme was the importance of early diagnosis/treatment. Recently, there has been a major shift from direct CRIM testing using western blotting and mutation analysis to CRIM status prediction based on genetic variant analysis. The ITI regimen was mostly prescribed for CRIM-negative patients and some CRIM-positive cases in a prophylactic/naïve setting at ERT initiation to prevent the development of high antibodies and for IOPD patients irrespective of CRIM status in the ERT-experienced setting due to the presence of high and sustained anti-drug antibody levels. The frequently reported ITI regimen includes a short rituximab and methotrexate course in an ERT naïve setting, with/without intravenous immunoglobulin. CRIM-negative patients receiving ITI with ERT have better clinical outcomes than those not receiving the ITI regimen. Presently, the ITI regimen used in CRIM-positive patients is variable and based on physician preference, family history, or specific variants.

Conclusion: The study concluded that CRIM status determination is important in patients with IOPD and impacts management approaches. ITI use has been predominantly reported in CRIM-negative patients to improve the clinical outcomes, with other important factors being early initiation of ERT and treatment above label dose of alglucosidase alpha and many are doing upto 40 mg/kg/2 weeks.

1 Introduction

Pompe disease is a rare autosomal recessive metabolic myopathy caused by a deficiency in the lysosomal glycogen-hydrolyzing enzyme, acid-α-glucosidase (GAA) (1). A recent study using data from newborn screening (NBS) between 2010 and 2022 reported the birth prevalence of Pompe disease as one per 18,711 births, i.e., 5.3 per 100,000 births across Asia, Europe, the United States (US), and South America (2). Based on the age of onset, Pompe disease is broadly classified into two subtypes: infantile-onset Pompe disease (IOPD), with the most severe being classic infantile Pompe disease, and late-onset Pompe disease (LOPD). Classic infantile Pompe disease is a rapidly progressive form that presents with severe cardiomyopathy and early death, whereas LOPD can manifest as early as the first year of life and is characterized by slower progression and the absence of hypertrophic cardiomyopathy (HCM) in the first year of life (3, 4).

Globally, IOPD occurs in approximately one per 150,000 births (5). IOPD is primarily characterized by a clinical signs, including hypotonia, progressive muscle weakness, and HCM in first year of life. It has low GAA activity in blood and <1% in the skin or muscle (1, 6). The clinical onset in infants with classic infantile-onset Pompe disease where HCM is noted prior to age 12 months (5, 7). These symptoms often progress rapidly, leading to respiratory and cardiac failure, which is generally fatal within the first year of life (6, 8).

Enzyme replacement therapy (ERT) is presently the standard lifesaving treatment for patients with Pompe disease (9, 10). Early initiation of ERT can improve cardiac, respiratory, and motor functions, thereby improving overall and ventilator-free survival in patients with IOPD (5). Alglucosidase alfa (ALG) was the first approved treatment for IOPD and LOPD in 2006 (11); avalglucosidase alfa (AVA), a next-generation ERT, was approved for LOPD patients greater than 12 months of age in the US in 2021 (12) and later for LOPD and IOPD in the European Union (EU) (13), Japan (14, 15), and Australia (16). Cipaglucosidase alfa plus miglustat is another next-generation ERT approved for LOPD in 2023 and is currently under clinical evaluation for IOPD and also in clinical trials as per the expanded access programme (NCT04327973) (17).

ERT improves the prognosis of patients by providing the missing enzyme and ameliorating the symptoms of Pompe disease (18, 19). However, the degree of response can vary based on several factors, including patient age at the time of treatment initiation, severity of symptoms at diagnosis, and dose used (cumulative, 20–40 mg/kg/2 weeks up to 40 mg/kg/week) (20, 21). In addition, the response of the body to protein-based therapeutics, such as ERT, may vary. In certain cases, the immune system may respond with the production of immunoglobulin G (IgG) anti-drug antibodies (ADAs) (22). These ADAs can potentially affect the safety and efficacy of protein-based therapies, which is a cause of concern (23). Its efficacy can change owing to altered pharmacokinetics and/or interference with activity. Patients with Pompe disease can present with very high anti-recombinant human acid alpha-glucosidase (rhGAA) IgG antibody titers (24), which can lead to a decline in the effect of therapy and infusion-associated reactions (25).

The cross-reactive immunological material (CRIM) status of patients with IOPD is an important aspect in predicting treatment response to ERT (26, 27). Patients with residual amounts of nonfunctional GAA protein on western blotting are classified as CRIM-positive, whereas patients with no detectable GAA protein are classified as CRIM-negative (27). There is a lack of immune tolerance to the administered rhGAA in CRIM-negative patients, whereas most CRIM-positive patients retaining some enzyme (nonfunctional/reduced in function) can recognize the rhGAA as self, whereas some behave like CRIM-negative patients. Thus, CRIM-negative patients and a subset of CRIM-positive patients (approximately 32%) have a poor response to ERT, mainly attributable to the development of high and sustained levels of ADAs. These responses can neutralize enzyme uptake into cells or the catalytic activity of the enzyme, thereby significantly reducing the effectiveness of treatment (27, 28). The neutralizing effect seems determined by the antibody: enzyme molecular stoichiometry (29). Following ERT initiation, CRIM-negative patients tended to seroconvert earlier than CRIM-positive patients (4 weeks, versus 12.7 weeks) (27, 28). High ADAs can develop even if ERT is initiated early, as noted in babies identified by NBS (30).

Given these complexities, immune tolerance induction (ITI) strategies have been developed to mitigate the immune response by preventing the development of ADAs and reducing their levels in response to ERT, thereby maintaining the effectiveness of treatment (30–33). Thus, based on patients’ experiences with ERT, different regimens to mitigate ITI are used (a naïve setting or an established/entrenched setting) (32, 34). In an ERT-naïve setting, prophylactic ITI can be administered using rituximab, low-dose methotrexate, and intravenous immunoglobulin (IVIg) for a short duration (35, 36). It is important to note that there is no delay in ERT initiation as prophylactic ITI regimen is done concurrently with ERT (30, 37). In ERT-experienced patients with an entrenched immune response, longer ITI regimens, including rituximab, methotrexate, IVIg, and plasma-cell targeting agents, such as bortezomib, have been used (30, 34, 38). Other therapeutic approaches for an entrenched setting include cyclophosphamide, methylprednisolone, or rapamycin (39–41).

The safety and efficacy of the ITI use in CRIM-negative patients have been reported globally (35, 36, 42). However, there is a need to increase understanding of how CRIM status influences ITI decisions and the real-world use of ITI regimens. The current article presents findings from a systematic literature review (SLR) that explores the following three research questions to understand the relationship between CRIM status, ITI regimens, and clinical outcomes in patients with IOPD.

Research question 1: How is CRIM status determined in clinical practice, and how does a CRIM-negative status with ERT alone impact the outcome in patients with IOPD?

Research question 2: How do healthcare professionals use CRIM status to inform their decisions on ITI regimens in patients with IOPD?

Research question 3: Which ITI regimens have been used in real-world clinical practice in patients with IOPD?

2 Methods

2.1 SLR

The SLR was conducted using the Embase and PubMed databases covering the literature from January 1, 2003, to August 4, 2022, and was in alignment with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search terms used were “Pompe or IOPD” and “cross-reactive immunological material or CRIM.” This broad search strategy aimed to encompass all relevant literature pertaining to the three research questions, minimizing the risk of missing significant articles. The titles and abstracts of the articles identified through the searches were independently reviewed by two analysts. All identified articles were checked for relevance to the predefined inclusion criteria for each research question mentioned in Table 1. In cases of disagreement, the analysts conferred to reach a consensus. If unresolved, a third senior analyst was available for decision-making. Duplicate articles were identified and removed. The full texts of the articles that met the inclusion criteria were reviewed to confirm eligibility. Data extraction was conducted using pre-designed tables in Microsoft Excel. Non-English language papers were translated using Google Translate, and accuracy checks were conducted by a medical writer who was fluent in the original language. Statistical analyses were not performed.

Table 1

Table 1. Screening criteria for research questions: CRIM status determination, ITI regimen decision-making, and clinical outcomes in patients with IOPD.

2.2 Expert discussion

Two 2-hour advisory board meetings were organized with six experts from the US (n = 2), the Netherlands (n = 2), Germany (n = 1), and Taiwan (n = 1) in July and November 2023; results from the SLR report were presented and discussed in detail. The advisory board meetings were recorded and transcribed; the SLR report was updated based on these discussions.

3 Results

Systematic searches of the Embase and PubMed databases yielded 186 and 78 articles, respectively. After removing duplicates, screening, and full-text review, 103 reports were deemed potentially relevant for research question 1; 54 were further considered to provide meaningful data for analysis (Figure 1A). For research question 2, from a total of 70 articles included, 51 were deemed to provide meaningful analytical data (Figure 1B). For research question 3, all 69 articles included were considered to provide meaningful data for analysis (Figure 1C).

Figure 1

Figure 1. PRISMA flow diagram for research question 1 (A), research question 2 (B), and research question 3 (C). *54 provided meaningful data out of the included 103 articles; **51 provided sufficient information for data extraction out of the included 70 articles. This determination was based on the relevance of the study’s methodological details; some of the reports were initially not included because they did not mention clinical decision-making methods, which were later found to be relevant. These full journal articles ^†(n = 16) and ^‡(n = 19) were subsequently included. n, number of studies; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

3.1 General findings

Figure 2 depicts the evolution of knowledge regarding the diagnosis and treatment of patients with IOPD, including the key initial ITI therapies. Over time, more ERTs and ITI regimens have become available to treat CRIM-negative and -positive patients with IOPD. The articles varied in terms of detail; however, the commonly reported details included patient characteristics such as low GAA enzyme activity, hypertrophic cardiomyopathy, muscle weakness, hypotonia, elevated serum creatinine, respiratory distress, and developmental delay. Some case studies have reported diagnoses either prenatally or shortly after birth, frequently triggered by cardiac symptoms (57–60). Furthermore, a number of GAA variants, including previously unclassified variants for CRIM status (c.2744A>C [p.Gln915Pro]) (61), (delT525/delT525) (18), and (c.1935C>A [p.D645E]) (46) have been reported. Overall, for research question 1, 63 reports described CRIM-negative patients with IOPD, and 64 reports described CRIM-positive patients with IOPD. Across all three research questions, most studies were conducted in the US or Europe (research question 1: 35.9% or 26.2%; research question 2: 45.7% or 25.7%; research question 3: 44.3% or 27.5%), respectively.

Figure 2

Figure 2. Summary of timeline pertaining to Pompe disease for the SLR (26, 31, 32, 41, 42, 50–56) *Pompe disease was added to the Recommended Uniform Screening Panel (RUSP) for the USA in 2015.ALG, alglucosidase alfa; AVA, avalglucosidase alfa; CRIM, cross-reactive immunological material; ERT, enzyme replacement therapy; EU, European Union; GAA, acid α-galactosidase; HSAT, high sustained antibody titers; ITI, immune tolerance induction; IOPD, infantile-onset Pompe disease; LOPD, late-onset Pompe disease; IVIg, intravenous immunoglobulin; NBS, newborn screening; rhGAA, recombinant human acid alpha-glucosidase; SLR, systematic literature review; US, United States.

3.2 Evolution of CRIM status determination

Previous publications mentioned CRIM testing using methods such as western blot analysis of skin fibroblasts and pathogenic variants as the preferred method for CRIM status determination; however, the test results may take a long time, with a wait time of up to several weeks (26, 62). To overcome the long wait time with western blot analysis of skin fibroblasts, techniques like blood-based CRIM assay and mutation analysis are used to determine the CRIM status of the patients; these techniques yield quicker results within 48–72 hours (63). Recently, a trend towards increased usage of CRIM prediction by utilizing GAA variant analysis has been observed, as this leads to early treatment initiation and superior patient outcomes. However, the results of both techniques (blood-based CRIM assay and variant analysis) need to be interpreted with thorough knowledge and expertise. In a study conducted by Bali et al. (62) on 33 patients with IOPD, the CRIM status in peripheral blood mononuclear cells of 27 patients were in alignment with the CRIM status predicted by GAA pathogenic variants, but discordant or indeterminant in 6 patients, highlighting the need to validate the accuracy of the result obtained with blood-based assay alone and the importance of having the pathogenic variants to help further confirm CRIM status (62).

3.3 Determination of CRIM status in clinical practice (research question 1)

3.3.1 Testing to determine CRIM status

Among the 103 reviewed articles, 49 were excluded because of insufficient information (Figure 1A). The key studies for research question 1 are summarized in Table 2.

Table 2

Table 2. Summary of key studies for research question 1.

Of the 54 included articles, a total of 32 articles used CRIM testing; 66% (n = 21) of the studies were conducted in North America or Europe. The primary CRIM testing method used in the studies to ascertain patients’ CRIM status was Western blot analysis of skin fibroblasts (43). Presently, the label for ALG provides details on the influence of CRIM testing and ITI on patient outcomes (64, 65). However, the EU and US labels for AVA do not provide guidance regarding CRIM testing (13, 66).

3.3.2 CRIM status prediction

CRIM status was predicted using detailed genetic analyses facilitated by the Pompe variant database accessible via the internet (67). GAA pathogenic variants were identified through comparison with the GenBank reference DNA sequence (Accession: NM_000152) (68). Pathogenicity assessments of missense mutations utilized the PolyPhen-2 program, and splice-site changes were evaluated using the Berkeley Drosophila Genome Project’s tool (68). CRIM status prediction was reported in 33 articles post-2016 and utilized GAA mutational analysis, thus indicating a recent trend towards the increased use of mutational analysis. This may be due to improved understanding of the role of CRIM status prediction in early treatment initiation, overall improvements in DNA sequencing, and increased cataloguing of pathogenic variants. Most of the 33 included articles (CRIM status testing: 65.6%, n = 22; CRIM prediction: 69.7%, n = 23; CRIM testing and prediction: 69.2%, n = 23) were from Europe and the US.

3.3.3 Use of both CRIM testing and prediction

Thirteen articles post-2016 reported CRIM testing and prediction to determine the CRIM status in patients with IOPD. Of these, the majority (69%, n = 9) have reported studies that were conducted in the US or Europe, and a small proportion (31%, n = 4) in Asia and other unspecified regions (49, 69). One study reviewed patient data from treatment centers and national audits, whereas another study utilized variant analysis for rapid CRIM status determination, confirmed through western blot analysis in cases where direct testing was unavailable (31, 45).

3.4 CRIM status in decisions on ITI use (research question 2)

Of the 70 articles reviewed, 73% (n = 51) focused on decision-making and rationale or guidance regarding ITI in IOPD treatment strategies (Figure 1B). The key studies for research question 2 are summarized in Table 3.

Table 3

Table 3. Summary of key studies for research question 2.

Substantial contributions were provided by two studies, Desai et al. (70) and Li et al. (37), who examined the impact of prophylactic ITI with rituximab, methotrexate, and IVIg in CRIM-negative patients (35, 37) and a small subset of high-risk CRIM-positive patients (variants susceptible to the development of high and sustained antibody titers [HSAT] or sibling history of HSAT) (35). The studies found benefits of ITI in ERT-naïve settings in terms of both safety and effectiveness (35, 37). Some adverse effects of ITI were reported; however, the use of ITI was not discontinued, and overall, the adverse effects were transient. In a study by Desai et al. (35), out of 25 patients, five CRIM-negative patients required treatment with antibiotics and two required central line removal in two patients. Similarly, Chen et al. reported treatable infection episodes and transient symptoms like numbness and diarrhea in a couple of patients (30).

Several articles mentioned the use of ITI regimens prophylactically and in patients with CRIM-negative status. A case study of CRIM-negative patients with IOPD reported that a regimen of high-dose weekly ERT (40 mg/kg) combined with ITI may lead to favorable clinical outcomes by preventing the development of HSAT (71). Among articles that described the use of ITI in CRIM-positive patients, a specific case of sibling history leading to prenatal diagnosis of a younger sibling was noted (44). This resulted in better clinical outcomes in younger siblings due to prophylactic ITI initiation simultaneously with ERT (48). ITI was recommended in cases where a variant puts a patient at an increased risk of developing HSAT, potentially triggering an immune response to ERT treatment (72).

Fifteen articles reported non-use of ITI, primarily due to CRIM-positive status (46) or the family not consenting to initiate ITI therapy (57). CRIM-negative patients who do not receive ITI often experience rapid disease progression (47).

3.5 Association between ITI regimens and CRIM status (research question 3)

Among the identified articles (n = 69) (Figure 1C), 64% (n = 44) reported rituximab, methotrexate, and IVIg (n = 29, all three in combination) as the most commonly used drugs in ITI regimens for patients with IOPD. Three studies with relatively larger sample sizes reported the effectiveness of ITI therapies, including rituximab, methotrexate, and IVIg, in CRIM-negative and CRIM-positive patients with IOPD (36, 49, 73). A subset of these patients had higher doses or early treatment with ERT and ITI, which has been reported to be associated with better clinical outcomes, such as increased ventilator-free survival rates (74).

Individual reports of ITI treatment alone or in combination mostly included rituximab (n = 39), methotrexate (n = 37), and IVIg (n = 34). The use of bortezomib (n = 6), sirolimus (n = 3), cyclophosphamide (n = 3), methylprednisolone (n = 1), or rapamycin (n = 1) in an ERT-experienced setting was reported less often. The key studies for research question 3 are summarized in Table 4.

Table 4

Table 4. Summary of key studies for research question 3.

3.5.1 CRIM status and use of ITI

Of the 45 articles, a higher proportion of articles focused on CRIM-negative (58%, n = 26) than CRIM-positive patients (42%, n = 19). Most studies (81%, n = 21) of CRIM-negative patients, and a lower proportion (47%, n = 9) of CRIM-positive patients mentioned ITI. Rituximab, methotrexate, and IVIg-based ITI regimens were more commonly described in articles that focused on CRIM-negative patients (46%, n = 12) than CRIM-positive patients (11%, n = 5). Kazi et al. mentioned the use of a transient low-dose methotrexate (TLDM) protocol as an ITI treatment in CRIM-positive patients (32). Additionally, in 24 articles that included both CRIM-negative and CRIM-positive patients, the majority (75%, n = 18) mentioned ITI use, predominantly utilizing rituximab, methotrexate, and IVIg-based regimens.

3.5.2 Clinical outcomes

Overall, studies have indicated that ITI therapies combining a short course of rituximab, methotrexate, and IVIg have been effective in mitigating antibody titer, a critical factor for treatment success, in both CRIM-negative and CRIM-positive patients (35, 38, 50, 70). IVIg continued until B-cell recovery (till CD19 count increased). After 52 weeks of treatment, a study on CRIM-negative patients treated with ERT alone with no ITI clearly showed an attenuated response to the enzyme in all outcome measures, including a significant decrease in survival, invasive ventilation-free survival, reduced improvement in cardiac response, and regression of motor milestones compared with CRIM-positive patients (27). In a Dutch study, patients with IOPD (n = 18, CRIM-positive [n = 13] and CRIM-negative [n = 5]) who received ERT (40 mg/kg every week, age at last follow-up 6.0 years [3.1 to 8.3 years]) plus ITI had higher ventilator-free survival (100%) than patients who received ERT monotherapy (86%, age at last follow-up 3.8 years [3.0 to 4.8 years]) (73).In total, five out of 20 articles on respiratory function reported ventilator-free survival after receiving treatment with ITI (35, 36, 61, 73, 74).

Among the studies that reported data on mobility, muscle strength, or motor function on CRIM-negative and CRIM-positive patients, improvement with ITI and ERT was reported when compared to ERT monotherapy, especially in CRIM-negative patients and CRIM-positive patients who developed HSAT (30, 50).

Evidence suggests that rituximab, methotrexate, and IVIg may be associated with positive cardiac outcomes (37). Several studies have reported a reduction in left ventricular mass index (LVMI) after receiving ERT plus ITI, despite the CRIM status in patients with IOPD (77–80). Although a difference in cardiac outcomes based on CRIM status was not noted, one study reported that a reduction in LVMI continued in patients who had received ERT plus ITI vs. ERT alone (36). Another study noted that CRIM-negative patients with IOPD experienced LVMI normalization after ITI was initiated along with ERT (75). This may be attributed to ERT being more effective in the absence of ADAs.

Biomarker data, as reported in 11 articles (21, 32, 35–37, 39, 46, 76–78, 81), highlighted the effectiveness of early intervention in the management of IOPD, particularly the role of ITI in enhancing ERT outcome by reducing the risk of immunogenic response. Evidence suggests the benefit of early treatment initiation with ERT and ITI in CRIM-negative patients in improving biomarkers, such as creatinine kinase and urinary glucose tetrasaccharide, compared to those treated later (37).

Bortezomib (34, 39, 48, 71, 75, 82), cyclophosphamide (40, 51, 83), methylprednisolone (43), and rapamycin (39) were less commonly reported in the studies included in the current SLR (n = 12 articles) as part of ITI regimens in ERT-experienced patients with IOPD. Despite initially good clinical effect with ERT and immunomodulation, a second course of immunomodulation with bortezomib followed by a maintenance regimen with rituximab and methotrexate was required in certain patients to decrease the antibody titers. This establishes the successful use of a bortezomib-based regimen (34, 71, 75).

3.6 Key recommendations from published guidelines

This section summarizes the key recommendations from previously published expert panels based on the systematic evidence by Pascual-Pascual et al. (84) (Spanish expert panel), Gragnaniello et al. (85) (Italian expert panel), and Al-Hassnan et al. (5) (expert panel from the Gulf region published in October 2022 [after the search period for the SLR; it has been summarized because of its relevance]).

The key recommendations are mentioned below:

● CRIM status should be determined before initiating ERT since CRIM-negative patients have a very high risk of developing an immune response against ERT, potentially leading to treatment failure (5, 84, 85).

● CRIM status can be determined by analysis of the genetic variants (86) in >90% of the patients with IOPD with a turnaround time of less than a week (5, 84, 85).

● Western blot analysis of proteins from blood is a rapid method for determining CRIM status (within 48–72 hours of sample collection) (63). When combined with genetic prediction, western blotting can lead to well-informed treatment decisions, often within a week. This method is appropriate when there is doubt about the CRIM status based on genetic analysis. Western blot analysis of GAA in skin fibroblasts has been used in the past for CRIM status determination; however, it can take longer to obtain results (85).

● Initiating ITI therapy concurrent or prior to the first dose of ERT can improve the prognosis of patients with IOPD with either CRIM-negative or CRIM-positive status (85).

● ERT can significantly improve clinical outcomes when treatment is initiated promptly after diagnosis (84). Early initiation of ERT in IOPD has been associated with improved survival and motor functions in a cohort of patients with an average age at ERT initiation of 9.75 ± 3.17 days (74). Prophylactic ITI regimens can be used to preempt immune response in CRIM-negative and CRIM-positive patients in an ERT-naïve setting (85). Nearly 32% of the CRIM-positive patients develop HSAT. It is difficult to predict which CRIM-positive patients have a high risk; hence, a prophylactic ITI regimen is preferred based on clinician insights (33, 70).

● ITI regimen in an ERT naïve setting in IOPD includes a 5-week regimen of rituximab and methotrexate plus monthly IVIg (until B cell recovery) in CRIM-negative and CRIM-positive patients (85). A TLDM can also be used in patients with CRIM-positive disease (32).

● The clinical condition of the patient, or the presence of other risk factors, may prompt consideration of the risks and benefits of ITI in an individual patient. In certain very severe cases, it is recommended to start ITI before CRIM status is known.

● Recommendations from an expert panel from the Gulf region suggest that combining ITI with ERT could provide substantial clinical benefit, particularly in CRIM-negative patients (who make up a high proportion of patients with IOPD in the region), but that evidence is limited (5).

● CRIM status can often be predicted from GAA variants or confirmed by Western blot when the association between variants and CRIM status is unclear. However, limited test availability and a lack of globally standardized protocols for Western blot analysis for CRIM status and criteria can affect consistent CRIM-status classification. Despite this, assessment of CRIM status should not delay the initiation of treatment when IOPD is confirmed or highly suspected (35).

● Implementing ITI concurrent with ERT initiation according to the protocol described by Banugaria et al. (31) for all patients with IOPD, particularly CRIM-negative patients, along with high-dose ERT, significantly improves outcomes and reduces mortality and morbidity.

● Regular monitoring and quantification of anti-rhGAA antibodies at baseline and throughout the treatment are required to assess the need to repeat the ITI regimen (34). The threshold for HSAT is different in patients treated with different doses of ERT (29, 87).

3.7 Key findings and expert opinion

The findings from the current SLR agree with the available global recommendations, indicating the increased use of CRIM status prediction, along with formal testing, to identify patients at risk of developing high antibody titers. ITI regimens are beneficial and have been extensively used in CRIM-negative patients. Regimens, notably those including rituximab along with methotrexate and IVIg, have led to clinical improvements, such as reduced antibody titers and mortality, improved mobility, and respiratory and cardiac functions, in addition to positive changes in biomarkers. Increased NBS, followed by swift CRIM status determination, enables early initiation of ITI in conjunction with ERT, especially in CRIM-negative patients. This leads to better clinical outcomes and better overall survival for most patients.

3.7.1 Expert suggestions

● ERT initiation: ERT should be initiated as early as possible. Higher doses of ERT have been shown to be beneficial.

● Timely treatment: Assessing CRIM status should not delay the initiation of treatment when IOPD is confirmed or suspected (71).

● Using blood for CRIM status determination: Determination of CRIM status in fibroblasts is not time-efficient due to the interval of weeks needed to culture fibroblasts; this method is not suitable in clinical practice. However, in some situations, it is good to do this in the setting of novel variants and inconclusive results on blood CRIM testing. This should, however, not result in a delay in treatment, and ITI should be initiated. The prediction of CRIM status based on the patient’s GAA mutation or testing in blood should be done in accredited and licensed clinical laboratories with validated methodologies. Interpretation of results should be very careful in reference to experts.

● ITI with unclear CRIM status: If a patient’s CRIM status cannot be predicted using mutational analysis, or if there is a delay in getting variant reports, the use of ITI with unclear CRIM status is suggested. However, this should be handled with caution by expert centers.

● ITI Protocol implementation: ITI was implemented according to the protocol described by Banugaria et al. (31) for all patients with IOPD, particularly for CRIM-negative patients. High-dose ERT, in conjunction with ITI, significantly improved outcomes and reduced mortality and morbidity (20). ITI with transient low-dose methotrexate can be considered in CRIM-positive patients with IOPD (35).

● Safety of ITI regimens: ITI regimens have been found to be well-tolerated based on published evidence (9, 29) and clinical experience.

● Regular Monitoring: Regularly monitor and quantify anti-rhGAA antibodies at baseline and throughout treatment. Repetition of ITI should be based on these assessments (34).

● HSAT risk in CRIM-positive patients: Predicting the risk of developing HSAT in most CRIM-positive patients is difficult (88). However, if ITI is administered simultaneously with the first ERT infusion, patients may develop lower levels of ADAs.

● Management of HSAT: In cases of HSAT, management with longer-term immunomodulatory treatment, including bortezomib, methotrexate, and rituximab, or other B-cell and plasma cell agents, is needed.

4 Discussion

This SLR summarizes the published evidence and provides guidance on CRIM status, its impact in a clinical setting, testing and prediction, and various treatment regimens used in real-world practice to improve the outcomes of ERT-naïve patients with IOPD. The publications identified (from January 1, 2003, to August 4, 2022) provide a comprehensive overview of the evolution of CRIM status determination and ITI regimens used for patients with IOPD.

While examining the impact of CRIM status on patients, the recent increase in the understanding of the importance of NBS in the early detection of IOPD is noteworthy. Prenatal screening and NBS can lead to early identification of patients before significant clinical manifestations develop, facilitating early treatment initiation (21, 59). Initial studies focusing on NBS were primarily concentrated in Taiwan, the US, and Italy (37, 46, 59, 69, 77, 89). There has been evidence indicating that antibodies develop in early-treated patients within the first month of life, irrespective of CRIM status (90). Furthermore, long-term waiting for a CRIM status should be avoided. It is recommended to initiate ITI in severe cases.

ERT, as a primary treatment modality, has been the focus of IOPD (71, 91). However, the effectiveness of ERT depends on many factors, including the patient’s CRIM status (50), early age at ERT initiation (92) and dose administered (71). Patients may develop ADAs to ERT, which affects the overall efficacy of ERT in managing disease manifestations (33). Established ADAs are more commonly noted in patients with CRIM-negative status (24). Evidence suggests the development of ADAs in infants, leading to neutralized outcomes of ERT, thus necessitating the use of immunomodulation therapy (40, 93). Up to one-third CRIM-positive patients can also develop antibodies; hence, there is a need to recognize them either by using a prophylactic approach or by close monitoring (88). There is a need for regular monitoring of antibody titers as patients with high and sustained antibody titers (HSAT) can lose the therapeutic benefits of enzyme replacement therapy (ERT) (30, 34). Desai et al. reported the median time of the development of high HSAT since ERT to be 10 weeks (range, 4–24 weeks), with an upward trend within the first 24 weeks (34). Banugaria et al. have developed an algorithm to rapidly diagnose CRIM-negative patients with IOPD and determine and initiation of an ITI regimen along with ERT at the earliest possible time point (5, 31).

Additionally, it is important to recognize that in rare instances, patients showing ERT tolerance may have a break in tolerance and develop HSAT. In an LOPD patient who was initiated on ERT at age 20 months, there was a breach in tolerance after 11 years on ERT, minimize delays between CRIM status (94). The CRIM status determination has evolved over time. Traditionally, western blot analysis of skin in skin fibroblasts and GAA sequencing or genetic testing was undertaken for the CRIM status determination and has been pivotal in adapting treatment strategies (63). However, this process is time-consuming and delays the initiation of therapy. A blood-based CRIM assay is now performed, which is less time-consuming (49, 61, 62). Genetic testing reveals specific GAA variants, with guiding predictions of CRIM status in ~92% of patients (26); a combination of blood CRIM and mutation analysis has also been reported (71). This has prevented delays as blood testing CRIM results can be performed in 48 to 72 hours. Moreover, this offers rapid treatment decisions and augments clinical outcomes in patients with IOPD. In case of variants with an unknown effect on CRIM status, testing of CRIM status should be performed in an expert center. Currently, genetic testing is the preferred method, as it identifies specific variants and guides more precise treatment decisions. Nonetheless, detailed genotypic information is critical for optimizing long-term management, including the application of ITI in CRIM-negative cases to increase ERT effectiveness (36).

CRIM-negative patients require ITI regimens in the prophylactic setting (i.e., at the time of ERT initiation) to prevent the development of HSAT antibody formation against ERT (36, 39), whereas CRIM-positive patients with IOPD largely exhibit a more favorable response to ERT owing to lower immunogenicity, among other factors, generally resulting in less severe immune responses (21). However, a subset of CRIM-positive patients may elicit a stronger immune response similar to CRIM-negative patients (28, 70). In the real world, administering a TLDM protocol to high-risk CRIM-positive patients with IOPD and, in some instances, CRIM-negative patients have been used. TLDM is particularly used where rituximab is not readily available and is also based on an acceptable safety profile, although requiring long-term follow-up data (32). Notedly, ITI regimens using rituximab, methotrexate, and/or IVIg were well-tolerated in many patients with IOPD (35).

Early initiation of ERT for IOPD has shown promising results in improving the outcomes of therapy, especially cardiomyopathy, motor status, and respiratory status (84, 85, 95). The effectiveness of ERT and ITI in treating IOPD has been extensively documented as being safe and tolerable. Several reports have documented the successful use of ITI protocols to mitigate the immune response against ERT, addressing the challenges of immunogenicity, particularly in CRIM-negative patients (35, 75, 96). Evidence suggests that ITI regimens using rituximab, methotrexate, and IVIg in ERT-naïve patients with IOPD are generally well-tolerated (36, 47). In a study by Desai et al. (35), five CRIM-negative patients required treatment with antibiotics and two required central line removal. Similarly, Chen et al. (30) reported treatable infection episodes and transient symptoms like numbness and diarrhea in a couple of patients. In all these cases the ITI course was completed. A recent case study found that early initiation of bortezomib-based regimens was successful in patients that broke tolerance despite prophylactic ITI (34).

While the use of ITI in CRIM-positive IOPD patients has been less consistent compared to CRIM-negative patients, likely due to varying clinical practices and perceived lower risk, the potential for improved outcomes with prophylactic ITI supports its consideration as an important strategy even in CRIM-positive cases. Further research is warranted to better define its role (35, 37). In addition to early treatment and antibody management, the use of higher doses of ERT has been identified as a critical factor contributing to the improved treatment outcomes (37). A study published in 2024 demonstrated that bortezomib, along with rituximab, methotrexate, and IVIg, was successful in reducing high sustained ADA titers (30). It is important to understand how ITI agents are used for treatment; for example, bortezomib is used in the ERT-experienced patients.

The inclusion of a comparison between patients who received ITI at the initiation of ERT and those who received ITI after high ADA levels have developed is critical to understand the impact of ITI timing on the efficacy and safety of ERT in naive patients. This evidence, while present, is not currently obtained from a systematic, prospective data collection and requires retrospective analysis and expert consensus to fill this gap. Future research should be directed toward specifically designed studies to address this important clinical question. This approach will help provide a comprehensive understanding of the optimal timing of ITI in the context of ERT, ultimately leading to improved patient outcomes and more informed clinical practice. For individualized treatment regimens, factors such as the age at diagnosis, family history, HLA-binding predictions, GAA genotype, and CRIM status offer the prospect of improved patient outcomes (24).

A review by Desai et al. noted that available publications, including immunomodulation, reported the use of various clinical endpoints, making it difficult to compare the effectiveness of various immunomodulation strategies (33). Similar barriers to comparison were noted in the current review. The included articles reported diverse patient data in terms of age, sex, clinical presentations, dose level, and frequency of treatment, indicating that comparisons between patient groups, i.e., ERT-naïve and ERT-experienced, were not feasible. The review only provided a qualitative synthesis of the findings, without statistical analyses. The statistical analysis could not be undertaken because of the variability in the included publications, which was outside the scope of the present review. Most of the studies included in this review had small sample sizes, which is often a challenge for rare diseases.

5 Conclusions

Most studies on CRIM testing and prediction have been conducted initially in the US and subsequently in Europe. Recently, there has been a significant shift from direct CRIM testing using western blotting to CRIM status prediction based on genetic mutational analysis. The use of ITI, particularly in CRIM-negative patients, was noted to minimize the impact of ADAs on the treatment response. Overall, the benefits of early diagnosis and intervention are significant, particularly in patients with a family history of Pompe disease. Early treatment initiation can improve patient outcomes, underscoring the importance of genetic counseling and family history assessments in managing Pompe disease.

Large-scale studies with standardized endpoints are warranted to generate unified guidance regarding ITI regimens in CRIM-positive and CRIM-negative patients. Uniform guidance can then be tailored to meet the region-specific requirements. Additionally, there is a need for guidance supported by real-world evidence regarding treatment strategies based on the CRIM status to assist clinicians in managing patients with IOPD.

Data availability statement

The datasets presented in this article are not readily available because the datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Requests to access the datasets should be directed to PK, cHJpeWEua2lzaG5hbmlAZHVrZS5lZHU=.

Author contributions

PSK: Conceptualization, Investigation, Project administration, Resources, Validation, Writing – original draft, Writing – review & editing. JV: Conceptualization, Investigation, Methodology, Resources, Supervision, Visualization, Writing – original draft, Writing – review & editing. AH: Data curation, Formal analysis, Methodology, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. DK: Data curation, Investigation, Methodology, Project administration, Resources, Software, Writing – original draft, Writing – review & editing. Y-HC: Investigation, Project administration, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. MH: Conceptualization, Methodology, Project administration, Resources, Supervision, Visualization, Writing – original draft, Writing – review & editing. JH: Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Writing – original draft, Writing – review & editing. SS: Conceptualization, Investigation, Resources, Validation, Visualization, Writing – original draft, Writing – review & editing. CG: Data curation, Formal analysis, Resources, Validation, Visualization, Writing – original draft, Writing – review & editing. ND: Conceptualization, Formal analysis, Methodology, Resources, Validation, Visualization, Writing – original draft, Writing – review & editing.

Funding

The author(s) declared that financial support was received for this work and/or its publication. This study was funded by Sanofi.

Acknowledgments

Zoe Toland from Lucid was one of the analysts who conducted the systematic literature review. Medical writing support for this manuscript, under the direction of the authors, was provided by Mrigna Malhotra and Amit D. Kandhare from Sanofi in accordance with the Good Publication Practice guidelines.

Conflict of interest

Author SS, ND were employed by companySanofi, Cambridge, MA, United States. Author JH was employed by company Sanofi, Netherlands and CG was employed by Lucid Group, United Kingdom.

The remaining author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

1. Taverna S, Cammarata G, Colomba P, Sciarrino S, Zizzo C, Francofonte D, et al. Pompe disease: pathogenesis, molecular genetics and diagnosis. Aging (Albany NY). (2020) 12:15856–74. doi: 10.18632/aging.103794

PubMed Abstract | Crossref Full Text | Google Scholar

2. Colburn R and Lapidus D. An analysis of Pompe newborn screening data: a new prevalence at birth, insight and discussion. Front Pediatr. (2023) 11:1221140. doi: 10.3389/fped.2023.1221140

PubMed Abstract | Crossref Full Text | Google Scholar

3. Kishnani PS, Steiner RD, Bali D, Berger K, Byrne BJ, Case LE, et al. Pompe disease diagnosis and management guideline. Genet Med. (2006) 8:267–88. doi: 10.1097/01.gim.0000218152.87434.f3

PubMed Abstract | Crossref Full Text | Google Scholar

4. Kishnani PS, Hwu WL, Mandel H, Nicolino M, Yong F, and Corzo D. A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease. J Pediatr. (2006) 148:671–6. doi: 10.1016/j.jpeds.2005.11.033

PubMed Abstract | Crossref Full Text | Google Scholar

5. Al-Hassnan Z, Hashmi NA, Makhseed N, Omran TB, Al Jasmi F, and Teneiji AA. Expert Group Consensus on early diagnosis and management of infantile-onset pompe disease in the Gulf Region. Orphanet J Rare Dis. (2022) 17:388. doi: 10.1186/s13023-022-02545-w

PubMed Abstract | Crossref Full Text | Google Scholar

6. van den Hout HM, Hop W, van Diggelen OP, Smeitink JA, Smit GP, Poll-The BT, et al. The natural course of infantile Pompe's disease: 20 original cases compared with 133 cases from the literature. Pediatrics. (2003) 112:332–40. doi: 10.1542/peds.112.2.332

PubMed Abstract | Crossref Full Text | Google Scholar

7. Kohler L, Puertollano R, and Raben N. Pompe disease: from basic science to therapy. Neurotherapeutics. (2018) 15:928–42. doi: 10.1007/s13311-018-0655-y

PubMed Abstract | Crossref Full Text | Google Scholar

8. Hahn A and Schänzer A. Long-term outcome and unmet needs in infantile-onset Pompe disease. Ann Transl Med. (2019) 7:283. doi: 10.21037/atm.2019.04.70

PubMed Abstract | Crossref Full Text | Google Scholar

9. Kishnani PS, Chien Y-H, Berger KI, Thibault N, and Sparks S. Clinical insight meets scientific innovation to develop a next generation ERT for Pompe disease. Mol Genet Metab. (2024) 143:108559. doi: 10.1016/j.ymgme.2024.108559

PubMed Abstract | Crossref Full Text | Google Scholar

10. George KA, Anding AL, van der Flier A, Tomassy GS, Berger KI, Zhang TY, et al. Pompe disease: Unmet needs and emerging therapies. Mol Genet Metab. (2024) 143:108590. doi: 10.1016/j.ymgme.2024.108590

PubMed Abstract | Crossref Full Text | Google Scholar

11. Kishnani PS, Kronn D, Suwazono S, Broomfield A, Llerena J, Al-Hassnan ZN, et al. Higher dose alglucosidase alfa is associated with improved overall survival in infantile-onset Pompe disease (IOPD): data from the Pompe Registry. Orphanet J Rare Dis. (2023) 18:381. doi: 10.1186/s13023-023-02981-2

PubMed Abstract | Crossref Full Text | Google Scholar

12. Kishnani PS, Diaz-Manera J, Toscano A, Clemens PR, Ladha S, Berger KI, et al. Efficacy and safety of avalglucosidase alfa in patients with late-onset pompe disease after 97 weeks: A phase 3 randomized clinical trial. JAMA Neurol. (2023) 80:558–67. doi: 10.1001/jamaneurol.2023.0552

PubMed Abstract | Crossref Full Text | Google Scholar

13. Sanofi. Nexviadyme® (avalglucosidase alfa) approved by European Commission as a potential new standard of care for the treatment of Pompe Disease(2022). Available online at: https://www.sanofi.com/en/media-room/press-releases/2022/2022-06-28-05-30-00-2469979 (Accessed February 27, 2025).

Google Scholar

14. Tocan V, Mushimoto Y, Kojima-Ishii K, Matsuda A, Toda N, Toyomura D, et al. The earliest enzyme replacement for infantile-onset Pompe disease in Japan. Pediatr Int. (2022) 64:e15286. doi: 10.1111/ped.15286

PubMed Abstract | Crossref Full Text | Google Scholar

15. Mori-Yoshimura M, Ohki H, Mashimo H, Inoue K, Kumada S, Kiyono T, et al. Efficacy and safety of avalglucosidase alfa in Japanese patients with late-onset and infantile-onset Pompe diseases: A case series from clinical trials. Mol Genet Metab Rep. (2025) 42:101163. doi: 10.1016/j.ymgmr.2024.101163

PubMed Abstract | Crossref Full Text | Google Scholar

16. Sanofi. New Phase 3 data presented at WORLDSymposium™ reinforce Nexviazyme® (avalglucosidase alfa) as potential new standard of care for all people living with late-onset Pompe disease. Available online at: https://www.sanofi.com/assets/dotcom/pressreleases/2023/2023-02-24-15-31-00-2615384-en.pdf (Accessed February 27, 2025).

Google Scholar

17. Blair HA. Cipaglucosidase alfa: first approval. Drugs. (2023) 83:739–45. doi: 10.1007/s40265-023-01886-5

PubMed Abstract | Crossref Full Text | Google Scholar

18. Van den Hout JM, Kamphoven JH, Winkel LP, Arts WF, De Klerk JB, Loonen MC, et al. Long-term intravenous treatment of Pompe disease with recombinant human alpha-glucosidase from milk. Pediatrics. (2004) 113:e448–57. doi: 10.1542/peds.113.5.e448

PubMed Abstract | Crossref Full Text | Google Scholar

19. Kishnani PS, Corzo D, Nicolino M, Byrne B, Mandel H, Hwu WL, et al. Recombinant human acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease. Neurology. (2007) 68:99–109. doi: 10.1212/01.wnl.0000251268.41188.04

PubMed Abstract | Crossref Full Text | Google Scholar

20. Ditters IAM, Huidekoper HH, Kruijshaar ME, Rizopoulos D, Hahn A, Mongini TE, et al. Effect of alglucosidase alfa dosage on survival and walking ability in patients with classic infantile Pompe disease: a multicentre observational cohort study from the European Pompe Consortium. Lancet Child Adolesc Health. (2022) 6:28–37. doi: 10.1016/s2352-4642(21)00308-4

PubMed Abstract | Crossref Full Text | Google Scholar

21. Chien YH, Tsai WH, Chang CL, Chiu PC, Chou YY, Tsai FJ, et al. Earlier and higher dosing of alglucosidase alfa improve outcomes in patients with infantile-onset Pompe disease: Evidence from real-world experiences. Mol Genet Metab Rep. (2020) 23:100591. doi: 10.1016/j.ymgmr.2020.100591

PubMed Abstract | Crossref Full Text | Google Scholar

22. Goulet DR and Atkins WM. Considerations for the design of antibody-based therapeutics. J Pharm Sci. (2020) 109:74–103. doi: 10.1016/j.xphs.2019.05.031

PubMed Abstract | Crossref Full Text | Google Scholar

23. Fernandez L, Bustos RH, Zapata C, Garcia J, Jauregui E, and Ashraf GM. Immunogenicity in protein and peptide based-therapeutics: an overview. Curr Protein Pept Sci. (2018) 19:958–71. doi: 10.2174/1389203718666170828123449

PubMed Abstract | Crossref Full Text | Google Scholar

24. De Groot AS, Kazi ZB, Martin RF, Terry FE, Desai AK, Martin WD, et al. HLA- and genotype-based risk assessment model to identify infantile onset pompe disease patients at high-risk of developing significant anti-drug antibodies (ADA). Clin Immunol. (2019) 200:66–70. doi: 10.1016/j.clim.2019.01.009

PubMed Abstract | Crossref Full Text | Google Scholar

25. Kishnani PS, Corzo D, Leslie ND, Gruskin D, Van der Ploeg A, Clancy JP, et al. Early treatment with alglucosidase alfa prolongs long-term survival of infants with Pompe disease. Pediatr Res. (2009) 66(3):329–35. doi: 10.1203/PDR.0b013e3181b24e94

PubMed Abstract | Crossref Full Text | Google Scholar

26. Bali DS, Goldstein JL, Banugaria S, Dai J, Mackey J, Rehder C, et al. Predicting cross-reactive immunological material (CRIM) status in Pompe disease using GAA mutations: lessons learned from 10 years of clinical laboratory testing experience. Am J Med Genet C Semin Med Genet. (2012) 160C:40–9. doi: 10.1002/ajmg.c.31319

PubMed Abstract | Crossref Full Text | Google Scholar

27. Kishnani PS, Goldenberg PC, DeArmey SL, Heller J, Benjamin D, Young S, et al. Cross-reactive immunologic material status affects treatment outcomes in Pompe disease infants. Mol Genet Metab. (2010) 99:26–33. doi: 10.1016/j.ymgme.2009.08.003

PubMed Abstract | Crossref Full Text | Google Scholar

28. Banugaria SG, Prater SN, Ng Y-K, Kobori JA, Finkel RS, Ladda RL, et al. The impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: Lessons learned from infantile Pompe disease. Genet Med. (2011) 13:729–36. doi: 10.1097/GIM.0b013e3182174703

PubMed Abstract | Crossref Full Text | Google Scholar

29. van Gelder CM, Hoogeveen-Westerveld M, Kroos MA, Plug I, van der Ploeg AT, and Reuser AJ. Enzyme therapy and immune response in relation to CRIM status: the Dutch experience in classic infantile Pompe disease. J Inherit Metab Dis. (2015) 38:305–14. doi: 10.1007/s10545-014-9707-6

PubMed Abstract | Crossref Full Text | Google Scholar

30. Chen H-A, Hsu R-H, Fang C-Y, Desai AK, Lee N-C, Hwu W-L, et al. Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapy. Front Immunol. (2024) 15:1336599. doi: 10.3389/fimmu.2024.1336599

PubMed Abstract | Crossref Full Text | Google Scholar

31. Banugaria SG, Prater SN, Patel TT, Dearmey SM, Milleson C, Sheets KB, et al. 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. PloS One. (2013) 8:e67052. doi: 10.1371/journal.pone.0067052

PubMed Abstract | Crossref Full Text | Google Scholar

32. Kazi ZB, Desai AK, Troxler RB, Kronn D, Packman S, Sabbadini M, et al. An immune tolerance approach using transient low-dose methotrexate in the ERT-naive setting of patients treated with a therapeutic protein: experience in infantile-onset Pompe disease. Genet Med. (2019) 21:887–95. doi: 10.1038/s41436-018-0270-7

PubMed Abstract | Crossref Full Text | Google Scholar

33. Desai AK, Li C, Rosenberg AS, and Kishnani PS. Immunological challenges and approaches to immunomodulation in Pompe disease: a literature review. Ann Transl Med. (2019) 7:285. doi: 10.21037/atm.2019.05.27

PubMed Abstract | Crossref Full Text | Google Scholar

34. Desai AK, Shrivastava G, Grant CL, Wang RY, Burt TD, and Kishnani PS. An updated management approach of Pompe disease patients with high-sustained anti-rhGAA IgG antibody titers: experience with bortezomib-based immunomodulation. Front Immunol. (2024) 15:1360369. doi: 10.3389/fimmu.2024.1360369

PubMed Abstract | Crossref Full Text | Google Scholar

35. Desai AK, Baloh CH, Sleasman JW, Rosenberg AS, and Kishnani PS. Benefits of prophylactic short-course immune tolerance induction in patients with infantile pompe disease: demonstration of long-term safety and efficacy in an expanded cohort. Front Immunol. (2020) 11:1727. doi: 10.3389/fimmu.2020.01727

PubMed Abstract | Crossref Full Text | Google Scholar

36. Kazi ZB, Desai AK, Berrier KL, Troxler RB, Wang RY, Abdul-Rahman OA, et al. Sustained immune tolerance induction in enzyme replacement therapy-treated CRIM-negative patients with infantile Pompe disease. JCI Insight. (2017) 2:e94328. doi: 10.1172/jci.insight.94328

PubMed Abstract | Crossref Full Text | Google Scholar

37. Li C, Desai AK, Gupta P, Dempsey K, Bhambhani V, Hopkin RJ, et al. Transforming the clinical outcome in CRIM-negative infantile Pompe disease identified via newborn screening: the benefits of early treatment with enzyme replacement therapy and immune tolerance induction. Genet Med. (2021) 23:845–55. doi: 10.1038/s41436-020-01080-y

PubMed Abstract | Crossref Full Text | Google Scholar

38. Banugaria SG, Prater SN, McGann JK, Feldman JD, Tannenbaum JA, Bailey C, et al. Bortezomib in the rapid reduction of high sustained antibody titers in disorders treated with therapeutic protein: lessons learned from Pompe disease. Genet Med. (2013) 15:123–31. doi: 10.1038/gim.2012.110

PubMed Abstract | Crossref Full Text | Google Scholar

39. Poelman E, Hoogeveen-Westerveld M, van den Hout JMP, Bredius RGM, Lankester AC, Driessen GJA, et al. Effects of immunomodulation in classic infantile Pompe patients with high antibody titers. Orphanet J Rare Dis. (2019) 14:71. doi: 10.1186/s13023-019-1039-z

PubMed Abstract | Crossref Full Text | Google Scholar

40. Banugaria SG, Patel TT, Mackey J, Das S, Amalfitano A, Rosenberg AS, et al. Persistence of high sustained antibodies to enzyme replacement therapy despite extensive immunomodulatory therapy in an infant with Pompe disease: need for agents to target antibody-secreting plasma cells. Mol Genet Metab. (2012) 105:677–80. doi: 10.1016/j.ymgme.2012.01.019

PubMed Abstract | Crossref Full Text | Google Scholar

41. Elder ME, Nayak S, Collins SW, Lawson LA, Kelley JS, Herzog RW, et al. B-Cell depletion and immunomodulation before initiation of enzyme replacement therapy blocks the immune response to acid alpha-glucosidase in infantile-onset Pompe disease. J Pediatr. (2013) 163:847–54 e1. doi: 10.1016/j.jpeds.2013.03.002

PubMed Abstract | Crossref Full Text | Google Scholar

42. Khallaf HHA, Propst J, Geffrard S, Botha E, and Pervaiz MA. CRIM-negative pompe disease patients with satisfactory clinical outcomes on enzyme replacement therapy. JIMD Rep. (2013) 9:133–7. doi: 10.1007/8904_2012_192

PubMed Abstract | Crossref Full Text | Google Scholar

43. Corti M, Elder M, Falk D, Lawson L, Smith B, Nayak S, et al. B-cell depletion is protective against anti-AAV capsid immune response: A human subject case study. Mol Ther Methods Clin Dev. (2014) 1:14033–. doi: 10.1038/mtm.2014.33

PubMed Abstract | Crossref Full Text | Google Scholar

44. Markic J, Polic B, Stricevic L, Metlicic V, Kuzmanic-Samija R, Kovacevic T, et al. Effects of immune modulation therapy in the first Croatian infant diagnosed with Pompe disease: a 3-year follow-up study. Wien Klin Wochenschr. (2014) 126:133–7. doi: 10.1007/s00508-013-0475-3

PubMed Abstract | Crossref Full Text | Google Scholar

45. Broomfield A, Davison J, Fletcher J, Finnegan N, Wood M, Hensman P, et al. The UK experience of enzyme replacement therapy in patients with infantile onset Pompe disease. Mol Genet Metab. (2015) 114:S24–5. doi: 10.1016/j.ymgme.2014.12.037

Crossref Full Text | Google Scholar

46. Chien YH, Lee NC, Chen CA, Tsai FJ, Tsai WH, Shieh JY, et al. Long-term prognosis of patients with infantile-onset Pompe disease diagnosed by newborn screening and treated since birth. J Pediatr. (2015) 166:985–91 e1-2. doi: 10.1016/j.jpeds.2014.10.068

PubMed Abstract | Crossref Full Text | Google Scholar

47. Berrier KL, Kazi ZB, Prater SN, Bali DS, Goldstein J, Stefanescu MC, et al. CRIM-negative infantile Pompe disease: characterization of immune responses in patients treated with ERT monotherapy. Genet Med. (2015) 17:912–8. doi: 10.1038/gim.2015.6

PubMed Abstract | Crossref Full Text | Google Scholar

48. Sheets KB, Kazi Z, DeArmey S, Lisi E, Stenger E, and Kishnani PS. Discordant clinical responses in CRIM-positive IPD siblings demonstrate need for prophylactic ITI in the naive setting. Mol Genet Metab. (2015) 114:S22. doi: 10.1016/j.ymgme.2014.12.030

Crossref Full Text | Google Scholar

49. Gupta N, Kazi ZB, Nampoothiri S, Jagdeesh S, Kabra M, Puri RD, et al. Clinical and molecular disease spectrum and outcomes in patients with infantile-onset pompe disease. J Pediatr. (2020) 216:44–50 e5. doi: 10.1016/j.jpeds.2019.08.058

PubMed Abstract | Crossref Full Text | Google Scholar

50. Messinger YH, Mendelsohn NJ, Rhead W, Dimmock D, Hershkovitz E, Champion M, et al. Successful immune tolerance induction to enzyme replacement therapy in CRIM-negative infantile Pompe disease. Genet Med. (2012) 14:135–42. doi: 10.1038/gim.2011.4

PubMed Abstract | Crossref Full Text | Google Scholar

51. Mandel H, Bar-Joseph G, Lorber A, Khoury A, Natan D, Eldad DJ, et al. Enzyme replacement therapy in Pompe disease in Northern Israel - A six year follow-up. Mol Genet Metab. (2009) 98:81.

Google Scholar

52. Hunley TE, Corzo D, Dudek M, Kishnani P, Amalfitano A, Chen YT, et al. Nephrotic syndrome complicating alpha-glucosidase replacement therapy for Pompe disease. Pediatrics. (2004) 114:e532–5. doi: 10.1542/peds.2003-0988-L

PubMed Abstract | Crossref Full Text | Google Scholar

53. Chien YH, Chiang SC, Zhang XK, Keutzer J, Lee NC, Huang AC, et al. Early detection of Pompe disease by newborn screening is feasible: results from the Taiwan screening program. Pediatrics. (2008) 122:e39–45. doi: 10.1542/peds.2007-2222

PubMed Abstract | Crossref Full Text | Google Scholar

54. U.S. Food and Drug Administration. Drug approval package(2006). Available online at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/125141s000_MyozymeTOC.cfm#:~:text=Approval%20Date%3A%2004%2F28%2F2006 (Accessed January 17, 2024).

Google Scholar

55. Rhead W, Wells C, Margolis D, and Kishnani P. Immune-modulation therapy in a CRIM negative Pompe disease patient blocks antibody formation towards Myozyme, reverses cardiomyopathy, and prolongs survival. Mol Genet Metab. (2009) 96:S37. doi: 10.1016/j.ymgme.2008.11.116

Crossref Full Text | Google Scholar

56. Kronn DF, Day-Salvatore D, Hwu WL, Jones SA, Nakamura K, Okuyama T, et al. Management of confirmed newborn-screened patients with pompe disease across the disease spectrum. Pediatrics. (2017) 140:S24–s45. doi: 10.1542/peds.2016-0280E

PubMed Abstract | Crossref Full Text | Google Scholar

57. Abbott M-A, Prater SN, Banugaria SG, Richards SM, Young SP, Rosenberg AS, et al. Atypical immunologic response in a patient with CRIM-negative Pompe disease. Mol Genet Metab. (2011) 104:583–6. doi: 10.1016/j.ymgme.2011.08.003

PubMed Abstract | Crossref Full Text | Google Scholar

58. Broomfield A, Fletcher J, Hensman P, Wright R, Prunty H, Pavaine J, et al. Rapidly progressive white matter involvement in early childhood: the expanding phenotype of infantile onset pompe? JIMD Rep. (2018) 39:55–62. doi: 10.1007/8904_2017_46

PubMed Abstract | Crossref Full Text | Google Scholar

59. Cohen JL, Desai A, Li C, Huggins E, Cooper G, Bhambhani V, et al. Early diagnosis and treatment of infantile-onset Pompe disease via newborn screen. Mol Genet Metab. (2021) 132:S26–7. doi: 10.1016/j.ymgme.2020.12.044

Crossref Full Text | Google Scholar

60. Cohen JL, Chakraborty P, Fung-Kee-Fung K, Schwab ME, Bali D, Young SP, et al. In utero enzyme-replacement therapy for infantile-onset pompe's disease. N Engl J Med. (2022) 387:2150–8. doi: 10.1056/NEJMoa2200587

PubMed Abstract | Crossref Full Text | Google Scholar

61. Broomfield A, Fletcher J, Davison J, Finnegan N, Fenton M, Chikermane A, et al. Response of 33 UK patients with infantile-onset Pompe disease to enzyme replacement therapy. J Inherit Metab Dis. (2016) 39:261–71. doi: 10.1007/s10545-015-9898-5

PubMed Abstract | Crossref Full Text | Google Scholar

62. Bali DS, Goldstein JL, Rehder C, Kazi ZB, Berrier KL, Dai J, et al. Clinical laboratory experience of blood CRIM testing in infantile pompe disease. Mol Genet Metab Rep. (2015) 5:76–9. doi: 10.1016/j.ymgmr.2015.10.012

PubMed Abstract | Crossref Full Text | Google Scholar

63. Wang Z, Okamoto P, and Keutzer J. A new assay for fast, reliable CRIM status determination in infantile-onset Pompe disease. Mol Genet Metab. (2014) 111:92–100. doi: 10.1016/j.ymgme.2013.08.010

PubMed Abstract | Crossref Full Text | Google Scholar

64. Sanofi. Myozyme® (alglucosidase alfa). Summary of Product Characteristics. Available online at: https://www.ema.europa.eu/en/documents/product-information/myozyme-epar-product-information_en.pdf (Accessed January 17, 2024).

Google Scholar

65. Sanofi. Lumizyme® (alglucosidase alfa). Prescribing informationSanofi (2020). Available online at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/125291lbl.pdf.

Google Scholar

66. Sanofi. NEXVIAZYME (avalglucosidase alfa-ngpt) for injection, for intravenous use. Available online at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761194s000lbl.pdf (Accessed February 27, 2025).

Google Scholar

67. Pompe variant database(2024). Available online at: https://www.pompevariantdatabase.nl/pompe_mutations_list.php?orderby=aMut_ID1 (Accessed January 17, 2024).

Google Scholar

68. Berkeley drosophila genome project. Available online at: https://www.fruitfly.org/seq_tools/splice.html (Accessed January 17, 2024).

Google Scholar

69. Chiang SC, Chien YH, Chang KL, Lee NC, and Hwu WL. The timely needs for infantile onset pompe disease newborn screening-practice in Taiwan. Int J Neonatal Screen. (2020) 6:30. doi: 10.3390/ijns6020030

PubMed Abstract | Crossref Full Text | Google Scholar

70. Desai AK, Kazi ZB, Bali DS, and Kishnani PS. Characterization of immune response in Cross-Reactive Immunological Material (CRIM)-positive infantile Pompe disease patients treated with enzyme replacement therapy. Mol Genet Metab Rep. (2019) 20:100475. doi: 10.1016/j.ymgmr.2019.100475

PubMed Abstract | Crossref Full Text | Google Scholar

71. Curelaru S, Desai AK, Fink D, Zehavi Y, Kishnani PS, and Spiegel R. A favorable outcome in an infantile-onset Pompe patient with cross reactive immunological material (CRIM) negative disease with high dose enzyme replacement therapy and adjusted immunomodulation. Mol Genet Metab Rep. (2022) 32:100893. doi: 10.1016/j.ymgmr.2022.100893

PubMed Abstract | Crossref Full Text | Google Scholar

72. Vucko ER. A case study of infantile Pompe: Clinical outcomes of early treatment in the first year of life. Mol Genet Metab. (2017) 120:S134–5. doi: 10.1016/j.ymgme.2016.11.355

Crossref Full Text | Google Scholar

73. Poelman E, van den Dorpel JJA, Hoogeveen-Westerveld M, van den Hout JMP, van der Giessen LJ, van der Beek N, et al. Effects of higher and more frequent dosing of alglucosidase alfa and immunomodulation on long-term clinical outcome of classic infantile Pompe patients. J Inherit Metab Dis. (2020) 43:1243–53. doi: 10.1002/jimd.12268

PubMed Abstract | Crossref Full Text | Google Scholar

74. Yang CF, Liao TE, Chu YL, Chen LZ, Huang LY, Yang TF, et al. Long-term outcomes of very early treated infantile-onset Pompe disease with short-term steroid premedication: experiences from a nationwide newborn screening programme. J Med Genet. (2023) 60:430–9. doi: 10.1136/jmg-2022-108675

PubMed Abstract | Crossref Full Text | Google Scholar

75. Stenger EO, Kazi Z, Lisi E, Gambello MJ, and Kishnani P. Immune tolerance strategies in siblings with infantile pompe disease-advantages for a preemptive approach to high-sustained antibody titers. Mol Genet Metab Rep. (2015) 4:30–4. doi: 10.1016/j.ymgmr.2015.05.004

PubMed Abstract | Crossref Full Text | Google Scholar

76. Rairikar M, Kazi ZB, Desai A, Walters C, Rosenberg A, and Kishnani PS. High dose IVIG successfully reduces high rhGAA IgG antibody titers in a CRIM-negative infantile Pompe disease patient. Mol Genet Metab. (2017) 122:76–9. doi: 10.1016/j.ymgme.2017.05.006

PubMed Abstract | Crossref Full Text | Google Scholar

77. McPheron M and Sapp K. eP026: Newborn screening for Pompe disease: The Indiana experience. Genet Med. (2022) 24:S17–8. doi: 10.1016/j.gim.2022.01.064

Crossref Full Text | Google Scholar

78. Pascarella A, Gueraldi D, Polo G, Rubert L, Cazzorla C, Giuliani A, et al. Long term follow-up of patients diagnosed by Pompe Disease newborn screening. J Inherited Metab Disease. (2019) 42:240–1.

Google Scholar

79. Poelman E, Hoogeveen–Westerveld M, Kroos-de Haan M, van den Hout J, Bronsema K, van de Merbel N, et al. Antibody formation to enzyme replacement therapy in classic infantile pompe disease: Effects of immunomodulation in naive patients. Neuromuscular Disord. (2017) 27:S162. doi: 10.1016/j.nmd.2017.06.250

Crossref Full Text | Google Scholar

80. Poelman E, Hoogeveen-Westerveld M, Kroos-de Haan MA, van den Hout JMP, Bronsema KJ, van de Merbel NC, et al. High sustained antibody titers in patients with classic infantile pompe disease following immunomodulation at start of enzyme replacement therapy. J Pediatr. (2018) 195:236–243 e3. doi: 10.1016/j.jpeds.2017.11.046

PubMed Abstract | Crossref Full Text | Google Scholar

81. Gupta P, Shayota BJ, Desai AK, Kiblawi F, Myridakis D, Messina J, et al. A race against time-changing the natural history of CRIM negative infantile pompe disease. Front Immunol. (2020) 11:1929. doi: 10.3389/fimmu.2020.01929

PubMed Abstract | Crossref Full Text | Google Scholar

82. Owens P, Wong M, Bhattacharya K, and Ellaway C. Infantile-onset Pompe disease: A case series highlighting early clinical features, spectrum of disease severity and treatment response. J Paediatr Child Health. (2018) 54:1255–61. doi: 10.1111/jpc.14070

PubMed Abstract | Crossref Full Text | Google Scholar

83. Mandel H, Bali D, Kishnani PS, Bar-Joseph G, Lorber A, Khoury A, et al. Treatment outcome of pompe disease infants with negative cross-reactive immunologic material from Israel and gaza. Clin Ther. (2011) 33:S17. doi: 10.1016/j.clinthera.2011.05.058

Crossref Full Text | Google Scholar

84. Pascual-Pascual SI, Nascimento A, Fernandez-Llamazares CM, Medrano-Lopez C, Villalobos-Pinto E, Martinez-Moreno M, et al. Clinical guidelines for infantile-onset Pompe disease. Rev Neurol. (2016) 63:269–79. doi: 10.33588/rn.6306.2016232

Crossref Full Text | Google Scholar

85. Gragnaniello V, Deodato F, Gasperini S, Donati MA, Canessa C, Fecarotta S, et al. Immune responses to alglucosidase in infantile Pompe disease: recommendations from an Italian pediatric expert panel. Ital J Pediatr. (2022) 48:41. doi: 10.1186/s13052-022-01219-4

PubMed Abstract | Crossref Full Text | Google Scholar

86. Slonim AE, Bulone L, Ritz S, Goldberg T, Chen A, and Martiniuk F. Identification of two subtypes of infantile acid Maltase deficiency. J Pediatr. (2000) 137:283–5. doi: 10.1067/mpd.2000.107112

PubMed Abstract | Crossref Full Text | Google Scholar

87. de Vries JM, van der Beek NA, Kroos MA, Ozkan L, van Doorn PA, Richards SM, et al. High antibody titer in an adult with Pompe disease affects treatment with alglucosidase alfa. Mol Genet Metab. (2010) 101:338–45. doi: 10.1016/j.ymgme.2010.08.009

PubMed Abstract | Crossref Full Text | Google Scholar

88. De Groot AS, Desai AK, Lelias S, Miah SMS, Terry FE, Khan S, et al. Immune tolerance-adjusted personalized immunogenicity prediction for pompe disease. Front Immunol. (2021) 12:636731. doi: 10.3389/fimmu.2021.636731

PubMed Abstract | Crossref Full Text | Google Scholar

89. Gragnaniello V, Pijnappel P, Burlina AP, In 't Groen SLM, Gueraldi D, Cazzorla C, et al. Newborn screening for Pompe disease in Italy: Long-term results and future challenges. Mol Genet Metab Rep. (2022) 33:100929. doi: 10.1016/j.ymgmr.2022.100929

PubMed Abstract | Crossref Full Text | Google Scholar

90. Nicolino M, Byrne B, Wraith JE, Leslie N, Mandel H, Freyer DR, et al. Clinical outcomes after long-term treatment with alglucosidase alfa in infants and children with advanced Pompe disease. Genet Med. (2009) 11:210–9. doi: 10.1097/GIM.0b013e31819d0996

PubMed Abstract | Crossref Full Text | Google Scholar

91. Sarah B, Giovanna B, Emanuela K, Nadi N, Jose V, and Alberto P. Clinical efficacy of the enzyme replacement therapy in patients with late-onset Pompe disease: a systematic review and a meta-analysis. J Neurol. (2022) 269:733–41. doi: 10.1007/s00415-021-10526-5

PubMed Abstract | Crossref Full Text | Google Scholar

92. de Las Heras J, Cano A, Vinuesa A, Montes M, Unceta Suarez M, Arza A, et al. Importance of timely treatment initiation in infantile-onset pompe disease, a single-centre experience. Children (Basel). (2021) 8:1026. doi: 10.3390/children8111026

PubMed Abstract | Crossref Full Text | Google Scholar

93. Desai AK, Smith PB, Yi JS, Rosenberg AS, Burt TD, and Kishnani PS. Immunophenotype associated with high sustained antibody titers against enzyme replacement therapy in infantile-onset Pompe disease. Front Immunol. (2023) 14:1301912. doi: 10.3389/fimmu.2023.1301912

PubMed Abstract | Crossref Full Text | Google Scholar

94. Kim KH, Desai AK, Vucko ER, Boggs T, Kishnani PS, and Burton BK. Development of high sustained anti-drug antibody titers and corresponding clinical decline in a late-onset Pompe disease patient after 11+ years on enzyme replacement therapy. Mol Genet Metab Rep. (2023) 36:100981. doi: 10.1016/j.ymgmr.2023.100981

PubMed Abstract | Crossref Full Text | Google Scholar

95. Hasanoğlu A. Abstracts of the annual symposium of the society for the study of inborn errors of metabolism. Birmingham, United Kingdom. September 4-7, 2012. J Inherit Metab Dis. (2012) 35 Suppl 1:S1–182. doi: 10.1007/s10545-012-9512-z

PubMed Abstract | Crossref Full Text | Google Scholar

96. Kazi ZB, Prater SN, Kobori JA, Viskochil D, Bailey C, Gera R, et al. Durable and sustained immune tolerance to ERT in Pompe disease with entrenched immune responses. JCI Insight. (2016) 1:e86821. doi: 10.1172/jci.insight.86821

PubMed Abstract | Crossref Full Text | Google Scholar