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BACKGROUND: A major challenge to adeno-associated virus (AAV)-mediated gene therapy is the presence of anti-AAV capsid neutralizing antibodies (NAbs), which can block viral vector transduction even at very low titers. In the present study, we examined the ability of a combination immunosuppression (IS) treatment with bortezomib and a mouse-specific CD20 monoclonal antibody to suppress anti-AAV NAbs and enable readministration of AAV vectors of the same capsid in mice. METHODS: An AAV8 vector (AAV8-CB-hGAA) that ubiquitously expresses human α-glucosidase was used for initial gene therapy and a second AAV8 vector (AAV8-LSP-hSEAP) that contains a liver-specific promoter to express human secreted embryonic alkaline phosphatase (hSEAP) was used for AAV readministration. Plasma samples were used for determination of anti-AAV8 NAb titers. Cells isolated from whole blood, spleen, and bone marrow were analyzed for B-cell depletion by flow cytometry. The efficiency of AAV readministration was determined by the secretion of hSEAP in blood. RESULTS: In näive mice, an 8-week IS treatment along with AAV8-CB-hGAA injection effectively depleted CD19+ B220+ B cells from blood, spleen, and bone marrow and prevented the formation of anti-AAV8 NAbs. Following administration of AAV8-LSP-hSEAP, increasing levels of hSEAP were detected in blood for up to 6 weeks, indicating successful AAV readministration. In mice pre-immunized with AAV8-CB-hGAA, comparison of IS treatment for 8, 12, 16, and 20 weeks revealed that the 16-week IS treatment demonstrated the highest plasma hSEAP level following AAV8-LSP-hSEAP readministration. CONCLUSIONS: Our data suggest that this combination treatment is an effective IS approach that will allow retreatment of patients with AAV-mediated gene therapy. A combination IS treatment with bortezomib and a mouse-specific CD20 monoclonal antibody effectively suppressed anti-AAV NAbs in naïve mice and in mice with pre-existing antibodies, allowing successful readministration of the same AAV capsid vector.
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Anticorpos Neutralizantes , Doença de Depósito de Glicogênio Tipo II , Humanos , Camundongos , Animais , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Capsídeo , Anticorpos Antivirais , Vetores Genéticos/genética , Retratamento , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Dependovirus/genéticaRESUMO
PURPOSE: To assess the magnitude of benefit to early treatment initiation, enabled by newborn screening or prenatal diagnosis, in patients with cross-reactive immunological material (CRIM)-negative infantile Pompe disease (IPD), treated with enzyme replacement therapy (ERT) and prophylactic immune tolerance induction (ITI) with rituximab, methotrexate, and intravenous immunoglobulin (IVIG). METHODS: A total of 41 CRIM-negative IPD patients were evaluated. Among patients who were treated with ERT + ITI (n = 30), those who were invasive ventilator-free at baseline and had ≥6 months of follow-up were stratified based on age at treatment initiation: (1) early (≤4 weeks), (2) intermediate (>4 and ≤15 weeks), and (3) late (>15 weeks). A historical cohort of 11 CRIM-negative patients with IPD treated with ERT monotherapy served as an additional comparator group. RESULTS: Twenty patients were included; five, seven, and eight in early, intermediate, and late treatment groups, respectively. Genotypes were similar across the three groups. Early-treated patients showed significant improvements in left ventricular mass index, motor and pulmonary outcomes, as well as biomarkers creatine kinase and urinary glucose tetrasaccharide, compared with those treated later. CONCLUSION: Our preliminary data suggest that early treatment with ERT + ITI can transform the long-term CRIM-negative IPD phenotype, which represents the most severe end of the Pompe disease spectrum.
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Doença de Depósito de Glicogênio Tipo II , Terapia de Reposição de Enzimas , Feminino , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II/genética , Humanos , Tolerância Imunológica , Recém-Nascido , Triagem Neonatal , Gravidez , Resultado do Tratamento , alfa-Glucosidases/genética , alfa-Glucosidases/uso terapêuticoRESUMO
Immune modulation with rituximab, methotrexate, and intravenous immunoglobulin (IVIG) has shown great success in inducing immune tolerance in a large cohort of enzyme replacement therapy (ERT)-naïve infantile Pompe disease patients. Antibody-dependent cellular cytotoxicity, the principal mechanism by which rituximab depletes B-cells, requires CD20 binding by Fab'2 of rituximab on B-cells and the concomitant binding of its Fc region to Fc receptors on effector cells or to complement. To protect patients against microbial infections when using rituximab, IVIG was added to the immunomodulation regimen used in Pompe disease. Administration of IVIG can saturate neonatal Fc receptors (FcRn), which recycle endogenous as well as administered polyclonal/monoclonal antibodies via the binding of the Fc moiety to FcRn. As such, the administration of IVIG prior to rituximab, a chimeric mouse-human monoclonal antibody, may sharply reduce the half-life of rituximab and in turn, its efficacy. Based on this understanding, it is vital to understand the optimal timing of IVIG administration in relation to rituximab administration for the purposes of inducing immune tolerance.
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Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Imunoglobulinas Intravenosas/administração & dosagem , Fatores Imunológicos/administração & dosagem , Rituximab/administração & dosagem , Doença de Depósito de Glicogênio Tipo II/imunologia , Humanos , Tolerância Imunológica/efeitos dos fármacos , Resultado do TratamentoRESUMO
PURPOSE: To investigate immune tolerance induction with transient low-dose methotrexate (TLD-MTX) initiated with recombinant human acid α-glucosidase (rhGAA), in treatment-naïve cross-reactive immunologic material (CRIM)-positive infantile-onset Pompe disease (IOPD) patients. METHODS: Newly diagnosed IOPD patients received subcutaneous or oral 0.4 mg/kg TLD-MTX for 3 cycles (3 doses/cycle) with the first 3 rhGAA infusions. Anti-rhGAA IgG titers, classified as high-sustained (HSAT; ≥51,200, ≥2 times after 6 months), sustained intermediate (SIT; ≥12,800 and <51,200 within 12 months), or low (LT; ≤6400 within 12 months), were compared with those of 37 CRIM-positive IOPD historic comparators receiving rhGAA alone. RESULTS: Fourteen IOPD TLD-MTX recipients at the median age of 3.8 months (range, 0.7-13.5 months) had a median last titer of 150 (range, 0-51,200) at median rhGAA duration ~83 weeks (range, 36-122 weeks). One IOPD patient (7.1%) developed titers in the SIT range and one patient (7.1%) developed titers in the HSAT range. Twelve of the 14 patients (85.7%) that received TLD-MTX remained LT, versus 5/37 HSAT (peak 51,200-409,600), 7/37 SIT (12,800-51,000), and 23/37 LT (200-12,800) among comparators. CONCLUSION: Results of TLD-MTX coinitiated with rhGAA are encouraging and merit a larger longitudinal study.
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Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II/imunologia , Tolerância Imunológica/genética , Metotrexato/administração & dosagem , Idade de Início , Reações Cruzadas/imunologia , Terapia de Reposição de Enzimas , Feminino , Doença de Depósito de Glicogênio Tipo II/genética , Doença de Depósito de Glicogênio Tipo II/patologia , Humanos , Lactente , Recém-Nascido , Masculino , alfa-Glucosidases/administração & dosagem , alfa-Glucosidases/genéticaRESUMO
Patients with Pompe disease have realized significant medical benefits due to enzyme replacement therapy (ERT) infusions with alglucosidase alfa. However, regular infusions are time-consuming. Utilizing recommended infusion rates, infusion duration is 3h 45min for a patient receiving the standard dose of 20mg/kg, not including additional time needed for preparation of ERT, assessment of vital signs, intravenous access, and post-infusion monitoring. Recent studies have demonstrated increased effectiveness of higher dose of ERT (40mg/kg) in infantile-onset Pompe disease (IOPD), which increases the infusion duration to 6h 36min. Increased infusion durations compound the psychosocial burden on patients and families and potentially further disrupt family activities and obligations. We developed a stepwise infusion rate escalation protocol to administer higher dose ERT safely while decreasing infusion duration, which has been implemented in 15 patients to date. Reported here in detail are five patients with IOPD on 40mg/kg/weekly ERT in whom infusion duration was decreased with individualized, stepwise rate escalation. All patients tolerated rate escalations above the recommended rates without experiencing any infusion associated reactions and experienced a reduction in infusion duration by 1h and 24min with a corresponding increase in reported satisfaction. Our experience with ERT rate escalation is presented. SYNOPSIS: A careful stepwise method of enzyme replacement therapy (ERT) rate escalation can safely reduce infusion duration in patients with Pompe disease.
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Terapia de Reposição de Enzimas , Doença de Depósito de Glicogênio Tipo II/terapia , alfa-Glucosidases/administração & dosagem , Adolescente , Criança , Pré-Escolar , Esquema de Medicação , Feminino , Doença de Depósito de Glicogênio Tipo II/enzimologia , Doença de Depósito de Glicogênio Tipo II/psicologia , Humanos , Lactente , Infusões Intravenosas , Masculino , PrognósticoRESUMO
BACKGROUND: Pompe disease is an autosomal recessive disorder caused by deficiency of the lysosomal glycogen-hydrolyzing enzyme acid α-glucosidase (GAA). The adult-onset form, late-onset Pompe disease (LOPD), has been characterized by glycogen accumulation primarily in skeletal, cardiac, and smooth muscles, causing weakness of the proximal limb girdle and respiratory muscles. However, increased scientific study of LOPD continues to enhance understanding of an evolving phenotype. PURPOSE: To expand our understanding of the evolving phenotype of LOPD since the approval of enzyme replacement therapy (ERT) with alglucosidase alfa (Myozyme™/Lumizyme™) in 2006. METHODS: All articles were included in the review that provided data on the charactertistics of LOPD identified via the PubMed database published since the approval of ERT in 2006. All signs and symptoms of the disease that were reported in the literature were identified and included in the review. RESULTS: We provide a comprehensive review of the evolving phenotype of LOPD. Our findings support and extend the knowledge of the multisystemic nature of the disease. CONCLUSIONS: With the advent of ERT and the concurrent increase in the scientific study of LOPD, the condition once primarily conceptualized as a limb-girdle muscle disease with prominent respiratory involvement is increasingly recognized to be a condition that results in signs and symptoms across body systems and structures.
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Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II/patologia , Músculos Respiratórios/patologia , alfa-Glucosidases/uso terapêutico , Adulto , Idade de Início , Terapia de Reposição de Enzimas/métodos , Feminino , Humanos , Masculino , Fenótipo , Músculos Respiratórios/efeitos dos fármacos , Resultado do Tratamento , alfa-Glucosidases/farmacologiaRESUMO
OBJECTIVE: Newborn screening (NBS) has led to early diagnosis and early initiation of treatment for infantile onset Pompe Disease (IOPD). However, guidelines for management of late onset Pompe disease (LOPD) via NBS, especially with the IVS c.-32-13T>G are not clear. This IVS variant is noted in 68-90% cases with LOPD and has been presumed to result in "adult" disease in compound heterozygosity, with a few cases with earlier onset and a mild to no phenotype in homozygosity. Our study evaluates newborns with LOPD having IVS variant with a diligent multidisciplinary approach to determine if they have an early presentation. METHODS: Seven children with LOPD identified by NBS with IVS variant (3 compound heterozygous, and 4 homozygous) were evaluated with clinical, biochemical (CK, AST, ALT, and urinary Glc4), cardiac evaluation, physical therapy (PT), occupational, and speech/language therapy. RESULTS: All seven patients demonstrated motor involvement by age 6months; the three patients with c.-32-13 T>G variant in compound heterozygosity had symptoms as neonates. Patients with c.-32-13 T>G variant in compound heterozygosity had more involvement with persistent hyperCKemia, elevated AST and ALT, swallowing difficulties, limb-girdle weakness, delayed motor milestones, and were initiated on ERT. The patients with c.-32-13T>G variant in homozygosity had normal laboratory parameters, and presented with very subtle yet LOPD specific signs, identified only by meticulous assessments. CONCLUSION: This patient cohort represents the first carefully phenotyped cohort of infants with LOPD with the "late-onset" GAA variant c.-32-13T>G detected by NBS in the USA. It emphasizes not only the opportunity for early detection of skeletal and other muscle involvement in infants with c.-32-13T>G variant but also a high probability of overlooking or underestimating the significance of clinically present and detectable features. It can thus serve as a valuable contribution in the development of evaluation and treatment algorithms for infants with LOPD.
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Glucana 1,4-alfa-Glucosidase/genética , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/genética , Fenótipo , Algoritmos , Pré-Escolar , Estudos de Coortes , Diagnóstico Precoce , Terapia de Reposição de Enzimas , Feminino , Variação Genética , Doença de Depósito de Glicogênio Tipo II/terapia , Heterozigoto , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Triagem Neonatal/métodosRESUMO
Introduction: High sustained anti-rhGAA antibody titers (HSAT; ≥12,800) are directly linked to reduced efficacy of enzyme replacement therapy (ERT) and subsequent clinical deterioration in infantile-onset Pompe disease (IOPD). We have previously demonstrated the safety and effectiveness of a bortezomib-based immune-tolerance induction (ITI) regimen (bortezomib, rituximab, methotrexate, and IVIG) in eliminating HSAT. Methods: Here, we describe two IOPD cases (patients 6 and 8) who developed HSAT at 8 and 10 weeks on ERT despite transient low-dose methotrexate ITI administration in the ERT-naïve setting and were treated with a bortezomib-based ITI regimen, and we compare their courses to a series of six historical patients (patients 1-5, and 7) with a similar presentation who exemplify our evolving approach to treatment. Results: In total, patients 6 and 8 received 16 and 8 doses of bortezomib (4 doses=1 cycle) respectively reducing titers from 25,600 to seronegative, but differences in the course of their therapy were instructive regarding the optimal approach to initial treatment of HSAT; specifically, patient 6 was treated initially with only a single course of bortezomib rescue therapy, while patient 8 received two back-to-back courses. Patient 8 received IVIG therapy throughout the immunosuppression whereas patient 6 received IVIG therapy and was switched to subcutaneous IgG replacement. Patient 6 had a transient reduction in anti-rhGAA antibodies, after receiving a single initial cycle of bortezomib, but had a recurrence of high anti-rhGAA antibody titer after 160 weeks that required 3 additional cycles of bortezomib to ultimately achieve tolerance. In contrast, patient 8 achieved tolerance after being given two consecutive cycles of bortezomib during their initial treatment and had B cell recovery by week 54. Since the reduction in anti-rhGAA antibodies, both patients are doing well clinically, and have decreasing ALT, AST, and CK. No major infections leading to interruption of treatment were observed in either patient. The bortezomib-based ITI was safe and well-tolerated, and patients continue to receive ERT at 40 mg/kg/week. Discussion: These case studies and our previous experience suggest that to achieve an effective reduction of anti-rhGAA antibodies in the setting of HSAT, bortezomib should be initiated at the earliest sign of high anti-rhGAA antibodies with a minimum of two consecutive cycles as shown in the case of patient 8. It is important to note that, despite initiation of ERT at age 2.3 weeks, patient 8 quickly developed HSAT. We recommend close monitoring of anti-rhGAA antibodies and early intervention with ITI as soon as significantly elevated anti-rhGAA antibody titers are noted.
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Doença de Depósito de Glicogênio Tipo II , Humanos , Recém-Nascido , Bortezomib/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Imunoglobulinas Intravenosas/uso terapêutico , Imunomodulação , Metotrexato/uso terapêutico , Resultado do TratamentoRESUMO
Introduction: Pompe disease, a lysosomal storage disorder, is characterized by acid α-glucosidase (GAA) deficiency and categorized into two main subtypes: infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). The primary treatment, enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), faces challenges due to immunogenic responses, including the production of anti-drug antibody (ADA), which can diminish therapeutic efficacy. This study aims to assess the effectiveness of immune tolerance induction (ITI) therapy in cross-reactive immunologic material (CRIM)-positive Pompe disease patients with established high ADA levels. Method: In a single-center, open-label prospective study, we assessed ITI therapy's efficacy in Pompe disease patients, both IOPD and LOPD, with persistently elevated ADA titers (≥1:12,800) and clinical decline. The ITI regimen comprised bortezomib, rituximab, methotrexate, and intravenous immunoglobulin. Biochemical data, biomarkers, ADA titers, immune status, and respiratory and motor function were monitored over six months before and after ITI. Results: This study enrolled eight patients (5 IOPD and 3 LOPD). After a 6-month ITI course, median ADA titers significantly decreased from 1:12,800 (range 1:12,800-1:51,200) to 1:1,600 (range 1:400-1:12,800), with sustained immune tolerance persisting up to 4.5 years in some cases. Serum CK levels were mostly stable or decreased, stable urinary glucose tetrasaccharide levels were maintained in four patients, and no notable deterioration in respiratory or ambulatory status was noted. Adverse events included two treatable infection episodes and transient symptoms like numbness and diarrhea. Conclusion: ITI therapy effectively reduces ADA levels in CRIM-positive Pompe disease patients with established high ADA titers, underscoring the importance of ADA monitoring and timely ITI initiation. The findings advocate for personalized immunogenicity risk assessments to enhance clinical outcomes. In some cases, prolonged immune suppression may be necessary, highlighting the need for further studies to optimize ITI strategies for Pompe disease treatment. ClinicalTrials.gov NCT02525172; https://clinicaltrials.gov/study/NCT02525172.
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Terapia de Reposição de Enzimas , Doença de Depósito de Glicogênio Tipo II , Tolerância Imunológica , alfa-Glucosidases , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , alfa-Glucosidases/uso terapêutico , alfa-Glucosidases/imunologia , alfa-Glucosidases/administração & dosagem , Terapia de Reposição de Enzimas/efeitos adversos , Terapia de Reposição de Enzimas/métodos , Doença de Depósito de Glicogênio Tipo II/imunologia , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II/terapia , Imunoglobulinas Intravenosas/uso terapêutico , Imunoglobulinas Intravenosas/administração & dosagem , Metotrexato/uso terapêutico , Metotrexato/administração & dosagem , Estudos Prospectivos , Rituximab/uso terapêutico , Rituximab/efeitos adversos , Rituximab/administração & dosagem , Resultado do TratamentoRESUMO
A late-onset Pompe disease patient developed high sustained antibody titers (HSAT) of ≥51,200 after 11+ years on alglucosidase alfa and previous tolerance. There was a corresponding worsening of motor function and rise in urinary glucose tetrasaccharide (Glc4). Following immunomodulation therapy, HSAT were eliminated with improved clinical outcomes and biomarker trends. This report highlights the importance of continued surveillance of antibody titers and biomarkers, the negative impact of HSAT, and improved outcomes with immunomodulation therapy.
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Introduction: The efficacy of enzyme replacement therapy (ERT) with alglucosidase alfa for infantile-onset Pompe disease (IOPD) is limited in some patients due to the development of high and sustained antibody titers (HSAT; ≥12,800). Methods: We carried out detailed immunophenotyping of IOPD patients (n=40), including analysis of circulating cell populations by flow cytometry and plasma cytokines by multiplex array, to determine whether patients with HSAT have unique immunological characteristics compared to those with low titers (LT; <12,800). Results: Compared to patients with LT, patients who develop HSAT were skewed toward a type 2 immune profile, with an increased frequency of Th2 cells that was positively correlated with levels of Th2 (IL-4, IL-5, IL-13) and pro-inflammatory (IL-6, TNF-α, MIP-1α, MIP-1ß) cytokines. B cells were increased in HSAT patients with a decreased fraction of unswitched memory B cells. Plasma GM-CSF concentrations were lower on average in HSAT patients, while CXCL11 was elevated. Finally, using principal components analysis, we derived an HSAT Signature Score that successfully stratified patients according to their antibody titers. Discussion: The immune profiles revealed in this study not only identify potential biomarkers of patients that developed HSAT but also provide insights into the pathophysiology of HSAT that will ultimately lead to improved immunotherapy strategies.
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Doença de Depósito de Glicogênio Tipo II , Humanos , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Imunofenotipagem , Terapia de Reposição de Enzimas , Citocinas , Linfócitos BRESUMO
The survival of infantile-onset Pompe disease (IOPD) patients has improved dramatically since the introduction of enzyme replacement therapy (ERT) with a1glucosidase alfa. However, long-term IOPD survivors on ERT demonstrate motor deficits indicating that current therapy cannot completely prevent disease progression in skeletal muscle. We hypothesized that in IOPD, skeletal muscle endomysial stroma and capillaries would show consistent changes that could impede the movement of infused ERT from blood to muscle fibers. We retrospectively examined 9 skeletal muscle biopsies from 6 treated IOPD patients using light and electron microscopy. We found consistent ultrastructural endomysial stromal and capillary changes. The endomysial interstitium was expanded by lysosomal material, glycosomes/glycogen, cellular debris, and organelles, some exocytosed by viable muscle fibers and some released on fiber lysis. Endomysial scavenger cells phagocytosed this material. Mature fibrillary collagen was seen in the endomysium, and both muscle fibers and endomysial capillaries showed basal laminar reduplication and/or expansion. Capillary endothelial cells showed hypertrophy and degeneration, with narrowing of the vascular lumen. Ultrastructurally defined stromal and vascular changes likely constitute obstacles to movement of infused ERT from capillary lumen to muscle fiber sarcolemma, contributing to the incomplete efficacy of infused ERT in skeletal muscle. Our observations can inform approaches to overcoming these barriers to therapy.
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Doença de Depósito de Glicogênio Tipo II , Humanos , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II/patologia , alfa-Glucosidases/uso terapêutico , Estudos Retrospectivos , Capilares/patologia , Células Endoteliais/patologia , Músculo Esquelético/patologia , AnticorposRESUMO
Infantile onset Pompe disease (IOPD) is a rare devastating disease that presents in early infancy with rapidly progressive hypertrophic cardiomyopathy, severe generalized myopathy and death within the first year of life. The emergence of enzyme replacement therapy (ERT) with recombinant human acid alpha glucosidase (rhGAA) has improved the natural course of IOPD with a significant impact on cardiomyopathy but has a more limited effect on the progression of myopathy and consequently the later deterioration of the disease. Possible reasons for reduced ERT efficacy include insufficient enzyme, partial targeting of skeletal muscle and the development of IgG rhGAA antibodies especially in patients who are cross-reactive immunological material (CRIM) negative. We report a CRIM-negative IOPD female patient who started treatment upon diagnosis at 4.5 months with ERT at 20 mg/kg every other week and a course of combined immunomodulation with rituximab, methotrexate and IVIG according to the published Duke protocol and increased ERT within a month to 40 mg/kg/week. Despite initial good clinical response to ERT and immunomodulation, monthly monitoring identified a gradual increase of serum antibody titers to rhGAA necessitating a second course of immunomodulation with bortezomib and maintenance rituximab and methotrexate. A gradual reduction in frequency of immunotherapy was instituted and over a period of 14 months was discontinued. Serum anti-rhGAA antibody titers remained negative for 5 months since cessation of immunomodulation and the patient is now immune tolerant with recovery of CD19. At the age of 30 months the patient is walking independently and has normal cardiac function and anatomy. We recommend initiating ERT at 40 mg/kg/week in CRIM-negative IOPD patients, concomitant with immunomodulation and monthly monitoring of serum anti-rhGAA IgG titers upon confirmation of the diagnosis.
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Infantile-onset Pompe disease (IOPD) is a glycogen storage disease caused by a deficiency of acid alpha-glucosidase (GAA). Treatment with recombinant human GAA (rhGAA, alglucosidase alfa) enzyme replacement therapy (ERT) significantly improves clinical outcomes; however, many IOPD children treated with rhGAA develop anti-drug antibodies (ADA) that render the therapy ineffective. Antibodies to rhGAA are driven by T cell responses to sequences in rhGAA that differ from the individuals' native GAA (nGAA). The goal of this study was to develop a tool for personalized immunogenicity risk assessment (PIMA) that quantifies T cell epitopes that differ between nGAA and rhGAA using information about an individual's native GAA gene and their HLA DR haplotype, and to use this information to predict the risk of developing ADA. Four versions of PIMA have been developed. They use EpiMatrix, a computational tool for T cell epitope identification, combined with an HLA-restricted epitope-specific scoring feature (iTEM), to assess ADA risk. One version of PIMA also integrates JanusMatrix, a Treg epitope prediction tool to identify putative immunomodulatory (regulatory) T cell epitopes in self-proteins. Using the JanusMatrix-adjusted version of PIMA in a logistic regression model with data from 48 cross-reactive immunological material (CRIM)-positive IOPD subjects, those with scores greater than 10 were 4-fold more likely to develop ADA (p<0.03) than those that had scores less than 10. We also confirmed the hypothesis that some GAA epitopes are immunomodulatory. Twenty-one epitopes were tested, of which four were determined to have an immunomodulatory effect on T effector response in vitro. The implementation of PIMA V3J on a secure-access website would allow clinicians to input the individual HLA DR haplotype of their IOPD patient and the GAA pathogenic variants associated with each GAA allele to calculate the patient's relative risk of developing ADA, enhancing clinical decision-making prior to initiating treatment with ERT. A better understanding of immunogenicity risk will allow the implementation of targeted immunomodulatory approaches in ERT-naïve settings, especially in CRIM-positive patients, which may in turn improve the overall clinical outcomes by minimizing the development of ADA. The PIMA approach may also be useful for other types of enzyme or factor replacement therapies.
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Biologia Computacional/métodos , Doença de Depósito de Glicogênio Tipo II/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , alfa-Glucosidases/metabolismo , Terapia de Reposição de Enzimas , Mapeamento de Epitopos , Feminino , Antígenos HLA-DR/genética , Humanos , Tolerância Imunológica , Lactente , Masculino , Medicina de Precisão , Prognóstico , Análise de Regressão , Risco , alfa-Glucosidases/genética , alfa-Glucosidases/imunologiaRESUMO
OBJECTIVES: To report the respiratory function of school-aged children with infantile Pompe disease (IPD) who started enzyme replacement therapy (ERT) in infancy and early childhood. STUDY DESIGN: This is a retrospective chart review of pulmonary function tests of: (a) patients with IPD 5 to 18 years of age, (b) who were not ventilator dependent, and (c) were able to perform upright and supine spirometry. Subjects were divided into a younger (5-9 years) and older cohort (10-18 years) for the analysis. Upright and supine forced vital capacity (FVC), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP) were analyzed. RESULTS: Fourteen patients, all cross-reactive immunologic material (CRIM)-positive, met the inclusion criteria and were included in this study. Mean upright and supine FVC were 70.3% and 64.9% predicted, respectively, in the 5- to 9-year-old cohort; and 61.5% and 52.5% predicted, respectively, in the 10- to 18-year-old group. Individual patient trends showed stability in FVC overtime in six of the 14 patients. MIPs and MEPs were consistent with inspiratory and expiratory muscle weakness in the younger and older age group but did not decline with age. CONCLUSION: Data from this cohort of CRIM-positive patients with IPD showed that ERT is able to maintain respiratory function in a subgroup of patients whereas others had a steady decline. There was a statistically significant decline in FVC from the upright to a supine position in both the younger and older age groups of CRIM-positive ERT-treated patients. Before ERT, patients with IPD were unable to maintain independent ventilation beyond the first few years of life.
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Terapia de Reposição de Enzimas , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Adolescente , Adulto , Criança , Feminino , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Humanos , Masculino , Testes de Função Respiratória , Sobreviventes , Resultado do Tratamento , Adulto JovemRESUMO
Immune tolerance induction (ITI) with a short-course of rituximab, methotrexate, and/or IVIG in the enzyme replacement therapy (ERT)-naïve setting has prolonged survival and improved clinical outcomes in patients with infantile Pompe disease (IPD) lacking endogenous acid-alpha glucosidase (GAA), known as cross-reactive immunologic material (CRIM)-negative. In the context of cancer therapy, rituximab administration results in sustained B-cell depletion in 83% of patients for up to 26-39 weeks with B-cell reconstitution beginning at approximately 26 weeks post-treatment. The impact of rituximab on serum immunoglobulin levels is not well studied, available data suggest that rituximab can cause persistently low immunoglobulin levels and adversely impact vaccine responses. Data on a cohort of IPD patients who received a short-course of ITI with rituximab, methotrexate, and IVIG in the ERT-naïve setting and had ≥6 months of follow-up were retrospectively studied. B-cell quantitation, ANC, AST, ALT, immunization history, and vaccine titers after B-cell reconstitution were reviewed. Data were collected for 34 IPD patients (25 CRIM-negative and 9 CRIM-positive) with a median age at ERT initiation of 3.5 months (0.1-11.0 months). B-cell reconstitution, as measured by normalization of CD19%, was seen in all patients (n = 33) at a median time of 17 weeks range (11-55 weeks) post-rituximab. All maintained normal CD19% with the longest follow-up being 248 weeks post-rituximab. 30/34 (88%) maintained negative/low anti-rhGAA antibody titers, even with complete B-cell reconstitution. Infections during immunosuppression were reported in five CRIM-negative IPD patients, all resolved satisfactorily on antibiotics. There were no serious sequelae or deaths. Of the 31 evaluable patients, 27 were up to date on age-appropriate immunizations. Vaccine titers were available for 12 patients after B-cell reconstitution and adequate humoral response was observed in all except an inadequate response to the Pneumococcal vaccine (n = 2). These data show the benefits of short-course prophylactic ITI in IPD both in terms of safety and efficacy. Data presented here are from the youngest cohort of patients treated with rituximab and expands the evidence of its safety in the pediatric population.
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Terapia de Reposição de Enzimas , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Tolerância Imunológica/efeitos dos fármacos , Imunoglobulinas Intravenosas/administração & dosagem , Imunossupressores/administração & dosagem , Metotrexato/administração & dosagem , Rituximab/administração & dosagem , alfa-Glucosidases/uso terapêutico , Anticorpos/sangue , Criança , Pré-Escolar , Quimioterapia Combinada , Terapia de Reposição de Enzimas/efeitos adversos , Feminino , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/enzimologia , Doença de Depósito de Glicogênio Tipo II/imunologia , Humanos , Imunoglobulinas Intravenosas/efeitos adversos , Imunossupressores/efeitos adversos , Lactente , Masculino , Metotrexato/efeitos adversos , Estudos Retrospectivos , Rituximab/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , alfa-Glucosidases/efeitos adversos , alfa-Glucosidases/imunologiaRESUMO
We report the clinical course of the first prenatally diagnosed cross-reactive immunologic material (CRIM)-negative infantile Pompe disease (IPD) patient [homozygous for c.2560C>T (p.Arg854X) variant in the GAA gene] to undergo prophylactic immune tolerance induction (ITI) and enzyme replacement therapy (ERT) within the first 2 days of life. Both parents were found to be carriers of the c.2560C>T (p.Arg854X) variant through prenatal carrier screening. Fetal echocardiogram at 31 weeks of gestation showed left ventricular hypertrophy. An echocardiogram on the 1st day of life revealed marked biventricular hypertrophy. Physical exam was significant for macroglossia and hypotonia. A short course of Prophylactic ITI with rituximab, methotrexate, and intravenous immunoglobulin (IVIG) in conjunction with ERT at a dose of 20 mg/kg every other week was started on day 2 of life. The patient completed the ITI protocol safely and complete B-cell recovery, based on CD19 count, was noted by 3 months of age. The patient never developed anti-rhGAA IgG antibodies to ERT. Vaccinations were initiated at 9 months of age, with adequate response noted. Complete recovery of cardiac function and left ventricular mass was seen by 11 weeks of age. At 8 months of age, the patient developmentally measured at 75-90% on the Alberta Infant Motor Scale, walked at 11 months and continues to develop age-appropriately at 50 months of age based on the Early Learning Accomplishment Profile. ERT dosing was increased to 40 mg/kg every 2 weeks at 32 months of age and frequency increased to 40 mg/kg every week at 47 months of age. Patient continues to have undetectable antibody titers, most recently at age 50 months and urine Hex4 has remained normal. To our knowledge, this is the first report of successful early ERT and ITI in a prenatally diagnosed CRIM-negative IPD patient and the youngest IPD patient to receive ITI safely. With the addition of Pompe disease to the Recommended Uniform Screening Panel(RUSP) and its addition to multiple state newborn screening programs, our case highlights the benefits of early diagnosis and timely initiation of treatment in babies with Pompe disease, who represent the most severe end of the disease spectrum.
Assuntos
Intervenção Médica Precoce , Terapia de Reposição de Enzimas , Doença de Depósito de Glicogênio Tipo II/terapia , Tolerância Imunológica/efeitos dos fármacos , Imunossupressores/administração & dosagem , alfa-Glucosidases/uso terapêutico , Anticorpos/sangue , Feminino , Predisposição Genética para Doença , Testes Genéticos , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/genética , Doença de Depósito de Glicogênio Tipo II/imunologia , Humanos , Recém-Nascido , Mutação , Fenótipo , Diagnóstico Pré-Natal , Resultado do Tratamento , alfa-Glucosidases/genética , alfa-Glucosidases/imunologiaRESUMO
Pompe disease is an autosomal recessive disorder caused by a deficiency of acid alpha-glucosidase resulting in intralysosomal glycogen accumulation in multiple tissue types, especially cardiac, skeletal, and smooth muscle. Enzyme replacement therapy (ERT) with alglucosidase alfa has led to improved clinical outcomes and prolonged survival in patients with Pompe disease. While ERT has changed the natural course of Pompe disease, with many long-term survivors, several factors affect the response to ERT. Previous studies in Pompe disease have shown that IgG antibodies to ERT can lead to a decline in muscle strength, pulmonary function, and overall and ventilator-free survival. Additionally, antibody responses to ERT can also cause hypersensitivity reactions. Various strategies to prevent or eliminate the IgG antibody response have been attempted in patients with Pompe disease. A detailed literature search was performed to compile data regarding the consequences of IgG antibodies, clinical approaches to prevent or eliminate IgG antibodies in patients with Pompe disease, and to expand our understanding of new modalities being developed in non-clinical settings. All qualifying articles describing the impact of IgG antibodies on the response to ERT, immunomodulation in patients with Pompe disease, and non-clinical settings identified via a PubMed database search were included in the review. Here, we provide a comprehensive review of combination- and single-agent therapies that have been investigated in the context of immune tolerance induction to ERT in Pompe disease to date. Immunomodulation strategies that successfully induce immune tolerance to ERT have improved overall survival, especially reflected in the decreased number of ventilator-dependent or deceased cross-reactive immunologic material (CRIM)-negative infantile Pompe disease (IPD) patients due to development of IgG antibodies when treated with ERT alone. Immunomodulation in CRIM-positive patients at the time they receive ERT also results in a decrease in the development of IgG antibodies compared to cases treated with ERT alone. Lessons learned from current approaches, alongside results from trials of novel immunomodulation strategies, may provide important insights into the development of next-generation therapies.
RESUMO
Enzyme replacement therapy (ERT) with rhGAA has improved clinical outcomes in infantile Pompe disease (IPD). A subset of CRIM-positive IPD patients develop high and sustained antibody titers (HSAT; ≥51,200) and/or sustained intermediate titer (SIT; ≥12,800 and <51,200), similar to CRIM-negative patients. To date there has been no systematic study to analyze the extent of IgG antibody response in CRIM-positive IPD. Such data would be critical and could serve as a comparator group for potential immune modulation approaches. A retrospective analysis of the dataset from the original rhGAA clinical trials final reports was conducted. CRIM-positive patients who received ERT monotherapy and had >6â¯months of antibody titer data available, were included in the study. Patients were classified based on their longitudinal antibody titers into HSAT, SIT, and low titer (LT; <12,800) groups. Of the 37 patients that met inclusion criteria, five (13%), seven (19%), and 25 (68%) developed HSAT, SIT, and LT, respectively. Median peak titers were 204,800 (51,200-409,600), 25,600 (12,800-51,200), and 800 (200-12,800) for HSAT, SIT, and LT groups, respectively. Median last titers were 102,400 (51,200-409,600), 1600 (200-25,600), and 400 (0-12,800) at median time since ERT initiation of 94â¯weeks (64-155â¯weeks), 104â¯weeks (86-144â¯weeks), and 130â¯weeks (38-182â¯weeks) for HSAT, SIT, and LT groups, respectively. 32% (12/37) of CRIM-positive IPD patients developed HSAT/SIT which may lead to limited ERT response and clinical decline. Further Studies are needed to identify CRIM-positive IPD patients at risk of developing HSAT/SIT, especially with the addition of Pompe disease to the newborn screening.
RESUMO
BACKGROUND: Cross-reactive immunological material-negative (CRIM-negative) infantile Pompe disease (IPD) patients develop an immune response against enzyme replacement therapy (ERT) with alglucosidase alfa that nullifies ERT efficacy. Prophylactic immune tolerance induction (ITI) with rituximab, methotrexate, and IVIG successfully prevents development of deleterious rhGAA IgG antibodies; however, safety, likelihood of success, and long-term efficacy of ITI in a larger cohort remain unknown. METHODS: Clinical data were analyzed for 19 CRIM-negative IPD patients who received ITI with rituximab, methotrexate, and IVIG in the ERT-naive setting (ERT+ITI) and compared to a historical cohort of 10 CRIM-negative IPD patients on ERT monotherapy. RESULTS: ITI was safely tolerated, although infections were reported in 4 patients. Fourteen (74%) ERT+ITI patients were alive, with a median age of 44.2 months at their final assessment. The eldest survivor was 103.9 months old, with 100.2 months of follow-up after initiation of ERT+ITI. Death (n = 5) occurred at a median age of 29.2 months and was unrelated to the administration of ITI. Fifteen patients either did not seroconvert (n = 8) or maintained low titers (n = 7; defined as titers of ≤6,400 throughout the course of ERT) following ERT+ITI. Only one patient developed high and sustained antibody titers (defined as titers of ≥51,200 at or beyond 6 months on ERT). Left ventricular mass index (LVMI) decreased from a median of 248.5 g/m2 at baseline to 76.8 g/m2 at a median time from ERT+ITI initiation to 59 weeks. ERT+ITI significantly improved overall survival (P = 0.001), eliminated/reduced antibodies at values of ≤6,400 at week 52 on ERT (P = 0.0004), and improved LVMI at week 52 on ERT (P = 0.02) when compared with ERT monotherapy. CONCLUSION: Evidence from this international cohort of CRIM-negative IPD patients further supports the safety, feasibility, and efficacy of ITI in the prevention of immune responses to ERT. TRIAL REGISTRATION: Clinicaltrials.gov NCT01665326. FUNDING: This research was supported in part by the Lysosomal Disease Network, a part of NIH Rare Diseases Clinical Research Network, and by a grant from Genzyme, a Sanofi company.