The role of immune tolerance induction in restoration of the efficacy of ERT in Pompe disease.

Pompe disease is a lysosomal storage disorder caused by deficiency in the enzyme acid α-glucosidase (GAA). Pompe disease is characterized by the accumulation of glycogen, predominantly in muscle tissue, leading to progressive muscle weakness, loss of motor, respiratory, and, in the infantile-onset form, cardiac function. Disease progression is highly variable depending on phenotype, but premature death due to respiratory complications occurs in most patients. Beginning in 2006, approved alglucosidase alfa enzyme replacement therapies [recombinant human (rh) GAA] have been available to treat Pompe patients. Treatment of classic infantile-onset patients, who manifest the severest form of the disease, with alglucosidase alfa (Myozyme®) has led to extended survival and an evolving understanding of the pathophysiology and course of the disease. Moreover, such treatment has brought to light the role of the immune response in abrogating the efficacy of rhGAA in classic infantile-onset patients with severe genetic mutations. Thus, optimization of treatment for such patients includes development and utilization of strategies to prevent or eliminate immune responses, including modulating the immune system (prophylactic and therapeutic immune tolerance induction regimens) and engineering the enzyme to be less immunogenic and more effective. Future research is also critical for evaluating and mitigating novel disease-associated pathologies uncovered by prolonged survival of infantile-onset patients including development of novel therapeutics, and for protein design strategies to increase delivery of enzyme replacement therapy to critical target tissues. Such efforts would be greatly bolstered by further development of predictive animal models and biomarkers to facilitate clinical trials and patient management. Published 2012. This article is a U.S. Government work and is in the public domain in the USA.

Lacaná E ，Yao LP ，Pariser AR ，Rosenberg AS ... -  《-》

The new era of Pompe disease: advances in the detection, understanding of the phenotypic spectrum, pathophysiology, and management.

Pompe disease is an autosomal recessive neuromuscular disorder marked by progressive muscle weakness due to lysosomal buildup of glycogen. Presentation is described as a spectrum, varying by age of onset, organ involvement, and degree of myopathy. Given the phenotypic variability, Pompe disease is broadly classified into an infantile form and a late onset (juvenile, childhood, adult onset) form. Prior to the advent of enzyme replacement therapy (ERT) with alglucosidase alfa and approval for human use in 2006, the natural history was limited due to death before age 2 years for infantile onset cases and significant morbidity and early mortality for late onset Pompe disease (LOPD). ERT with alglucosidase alfa redefined the once fatal outcome in infantile Pompe, establishing an emergent phenotype. Treatment in late onset patients resulted in improved outcomes, enhancing understanding of the phenotype, presentation, and extent of organ involvement. This Issue of the Seminars seeks to enumerate the recent advancements in the field of Pompe disease, including newborn screening, novel therapeutic targets, new insights in the pathophysiology including role of autophagy, and impacts of long-term disease burden and CNS glycogen accumulation on cognition in infantile survivors. It also addresses immunological challenges and the critical role of immunomodulation in ERT treatment outcome. Other topics discussed include the role of biomarkers in monitoring disease progression and treatment responses, the role of genotype in defining phenotype and treatment response, better insights into the clinical presentations in LOPD and finally the importance of a multidisciplinary approach to care with the role of physical therapy as an example. Many gaps in our scientific understanding of this disease still remain; however, we hope the next decade will bring new knowledge and therapies to the horizon.

Kishnani PS ，Beckemeyer AA ，Mendelsohn NJ 《-》

Infantile Pompe disease on ERT: update on clinical presentation, musculoskeletal management, and exercise considerations.

Enzyme replacement therapy (ERT) with alglucosidase alpha, approved by the FDA in 2006, has expanded possibilities for individuals with Pompe disease (glycogen storage disease type II, GSDII, or acid maltase deficiency). Children with infantile Pompe disease are surviving beyond infancy, some achieving independent walking and functional levels never before possible. Individuals with late-onset Pompe disease are experiencing motor and respiratory improvement and/or stabilization with slower progression of impairments. A new phenotype is emerging for those with infantile Pompe disease treated with ERT. This new phenotype appears to be distinct from the late-onset phenotype rather than a shift from infantile to late-onset phenotype that might be expected from a simple diminution of symptoms with ERT. Questions arise regarding the etiology of the distinct distribution of weakness in this new phenotype, with increasing questions regarding exercise and musculoskeletal management. Answers require an increased understanding of the muscle pathology in Pompe disease, how that muscle pathology may be impacted by ERT, and the potential impact of, and need for, other clinical interventions. This article reviews the current state of knowledge regarding the pathology of muscle involvement in Pompe disease and the potential change in muscle pathology with ERT; the newly emerging musculoskeletal and gross motor phenotype of infantile Pompe disease treated with ERT; updated recommendations regarding musculoskeletal management in Pompe disease, particularly in children now surviving longer with residual weakness impacting development and integrity of the musculoskeletal system; and the potential impact and role of exercise in infantile Pompe survivors treated with ERT.

Case LE ，Beckemeyer AA ，Kishnani PS 《-》

New therapeutic approaches for Pompe disease: enzyme replacement therapy and beyond.

Kishnani PS ，Beckemeyer AA 《-》

Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapy.

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. 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. 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. 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.

Chen HA ，Hsu RH ，Fang CY ，Desai AK ，Lee NC ，Hwu WL ，Tsai FJ ，Kishnani PS ，Chien YH ... -  《Frontiers in Immunology》