RARE DISEASE
Glycogen storage disease due to acid maltase deficiency
Glycogen storage disease due to acid maltase deficiency
Glycogen storage disease due to acid maltase deficiency
Synonyms: Alpha-1,4-glucosidase acid deficiency, GSD due to acid maltase deficiency, GSD type 2, GSD type II, Glycogen storage disease type 2, Glycogen storage disease type II, Glycogenosis due to acid maltase deficiency, Glycogenosis type 2, Glycogenosis type II, Pompe disease
Synonyms: Alpha-1,4-glucosidase acid deficiency, GSD due to acid maltase deficiency, GSD type 2, GSD type II, Glycogen storage disease type 2, Glycogen storage disease type II, Glycogenosis due to acid maltase deficiency, Glycogenosis type 2, Glycogenosis type II, Pompe disease
Synonyms: Alpha-1,4-glucosidase acid deficiency, GSD due to acid maltase deficiency, GSD type 2, GSD type II, Glycogen storage disease type 2, Glycogen storage disease type II, Glycogenosis due to acid maltase deficiency, Glycogenosis type 2, Glycogenosis type II, Pompe disease
Drug discovery
31
drugs
With orphan designations
Overview
Glycogen storage disease due to acid maltase deficiency (Pompe disease) is an autosomal recessive lysosomal disorder caused by deficient acid α-glucosidase (GAA) activity, leading to pathological glycogen accumulation in cardiac, skeletal, and respiratory muscles. The clinical spectrum ranges from severe infantile-onset disease with hypertrophic cardiomyopathy and respiratory failure to late-onset forms presenting with progressive proximal myopathy and respiratory insufficiency without cardiac involvement [1][2][5]. Diagnostic confirmation requires GAA enzyme assay and genetic testing of GAA mutations [2][14].
Burden
Infantile-onset: Mortality <1 year without ERT; 83% 5-year survival with early treatment [2][10]
Late-onset: Progressive disability with 30% requiring wheelchair/ventilator within 15 years of diagnosis [5][14]
Economic impact: Annual ERT costs exceed $300,000 per patient, plus multidisciplinary care expenses [10][14]
Therapies
Enzyme replacement therapy (ERT):
Alglucosidase alfa (Myozyme®/Lumizyme®) improves survival in infantile-onset disease and delays progression in late-onset forms [3][9]
Next-generation ERT (avalglucosidase alfa, cipaglucosidase alfa + miglustat) shows non-inferior efficacy with enhanced cellular uptake [3][9]
Supportive care: Respiratory support (non-invasive ventilation), physical therapy, and cardiac monitoring [10][12]
Investigational approaches: Gene therapy and substrate reduction therapy in clinical trials [3][11]
Categories: rare cardiac diseases, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare transplant-related disorders
Research Papers
1,244 drug discovery papers about Glycogen storage disease due to acid maltase deficiency, with 4 first-in-class and 23 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,244 drug discovery papers about Glycogen storage disease due to acid maltase deficiency, with 4 first-in-class and 23 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
antibodies
2026-05-15 | Combined omalizumab and desensitization to control IgE-mediated hypersensitivity in enzyme replacement therapy for late-onset Pompe disease.
Pompe disease is a rare, progressive lysosomal storage disorder caused by acid α-glucosidase deficiency, leading to glycogen accumulation, proximal muscle weakness, and respiratory decline. Enzyme replacement therapy (ERT) significantly improves survival and stabilizes motor function, but IgE-mediated hypersensitivity reactions (HSRs) can critically compromise treatment, posing a major clinical challenge. Desensitization protocols allow temporary tolerance to ERT, yet breakthrough reactions may occur, necessitating adjunctive strategies such as omalizumab. We report a 40-year-old woman with late-onset Pompe disease who developed severe IgE-mediated HSRs to alglucosidase alfa after years of uneventful therapy. Basophil activation testing (BAT) and serum-specific IgE confirmed an IgE-mediated mechanism. A 15-step, 5-bag desensitization protocol allowed temporary tolerance, but breakthrough reactions required therapy interruption. Upon switching to avalglucosidase alfa, BAT demonstrated IgE cross-reactivity, and a new desensitization protocol was implemented. Initial infusions were complicated by recurrent HSRs. The addition of subcutaneous omalizumab (300 mg monthly), administered two days before ERT, enabled safe reintroduction. Moreover, therapy was resumed gradually, starting at 50% of the target dose and escalating stepwise to the full therapeutic dose, resulting in uninterrupted treatment. Follow-up showed stable neuromuscular and respiratory function, progressive decline in BAT reactivity, and improved quality of life. This case highlights the critical role of BAT in diagnosing and monitoring IgE-mediated HSRs, the efficacy of individualized desensitization protocols, and the utility of omalizumab as an adjunctive therapy in refractory cases. In rare diseases like Pompe, documenting such integrated allergological strategies provides practical guidance for maintaining access to life-prolonging therapy and offers a reproducible framework for managing complex allergic complications.
2026-01-26 | Insights into immunogenicity and therapeutic strategies to mitigate the immune response in infantile-onset Pompe disease: a comprehensive systematic literature review.
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). 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. 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. 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.
2025-09-02 | Novel transferrin receptor-mediated enzyme replacement therapy efficiently treats myogenic and neurogenic aspects of Pompe disease in mice.
Pompe disease (PD) is a multisystemic progressive disease caused by acid-alpha glucosidase (GAA) deficiency. Patients display a spectrum of phenotypes ranging from the severe, rapidly progressive infantile-onset PD (IOPD) form to the slower progressing late-onset PD (LOPD). Enzyme replacement therapies (ERTs) are the only approved treatments; they decrease mortality in IOPD while maintaining or improving motor and respiratory function in LOPD. These therapies do not cross the blood-brain barrier (BBB) and the long-term survival of ERT-treated IOPD patients revealed underlying neurological disease. We used PD as a model to evaluate delivery of GAA across the BBB using anti-transferrin receptor (TfR) antibodies and show robust glycogen clearance and reduced neuroinflammation in the CNS of mice with PD. Importantly, anti-TfR-GAA treatment resulted in superior glycogen clearance in skeletal muscle compared with two approved ERTs. Glyco-chemical exchange saturation transfer/nuclear overhauser effect magnetic resonance imaging successfully estimated glycogen content in Pompe mouse brains, providing a non-invasive and translational method to evaluate brain-penetrant therapies for PD. Moreover, hexose tetrasaccharide was elevated in the cerebrospinal fluid of diseased mice and mirrored CNS glycogen levels, suggesting it may be a promising CNS biomarker. These data support the theory that the neurogenic and myogenic manifestations of PD can be effectively treated by anti-TfR-GAA.
2025-05-01 | Assessing neurodegeneration in Pompe disease using a degeneration-specific neurofilament light chain (NF-L) antibody
Pompe disease (PD) is an autosomal recessive disorder in which mutations in the acid-alpha glucosidase ( Gaa ) gene result in impaired or absent GAA protein. Since GAA acts to degrade lysosomal glycogen, the impact is widespread glycogen accumulation. Neuronal glycogen accumulation is prominent and autopsy case reports and animal model data indicate that neurodegeneration occurs as the disease progresses. We recently described an antibody, MCA-6H63, that uniquely binds to a portion of NF-L during degeneration (PMID: 37091583). Here we tested the hypothesis that MCA-6H63 could be used to immunohistochemically identify degenerating neurons in PD. First, we evaluated the spinal cord of a human with late-onset PD who succumbed to cardiorespiratory failure at age 54. Positive staining was noted in the soma of neurons in the ventral horn of the spinal cord, fibers in the ventral roots, and in white matter tracts. However, in control experiments in which tissue was incubated in control IgG mouse antibody, staining was absent. We next evaluated the brainstem and spinal cord in the Gaa -/- mouse model of PD (age 10-12 mo). Positive MCA-6H63 staining was noted in the soma of neurons in the medulla and extensive labeling of white matter tracts. In the spinal cord, we observed sparse labeling of neuronal fibers, presumably dendrites. Lastly, we examined a unique mouse model (age 10-12 mo) with Gaa absent only in choline acetyltransferase (ChAT) positive neurons (ChAT-cre +/+ ▪Gaa +/- ▪eYFP +/+ ▪Flox-Gaa +/+ ). MCA-6H63 staining was also observed in distinct brainstem nuclei and in some white matter tracts. We conclude that MCA-6H63 staining in mouse and human CNS tissue verifies neurodegeneration in PD. Since axons contain more NF-L than perikaryon, future studies with MCA-6H63 in PD or other neurodegenerative conditions should focus on neural fibers (e.g., ventral root, peripheral nerve axons) as this may provide a useful surrogate tag for neuronal degeneration. Collectively, the data support the thesis that effective PD treatment strategies must ultimately mitigate neurodegeneration. Funding: R01HD052682 (DDF and BJB); 1K99NS133388-01A1(SR) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
2025-04-14 | Bone disease and osteoporosis associated with Pompe disease.
Pompe disease is a lysosomal storage disorder defined by a mutation in the GAA gene encoding alpha-1,4-glucosidase alpha (acid maltase). Pompe disease encompasses a range of clinical presentations that are broadly characterized as either classic infantile Pompe disease or late-onset Pompe disease (LOPD). LOPD is a milder manifestation of the disease that presents after the first year of life and is typically characterized by mild proximal muscle weakness and lack of cardiac involvement compared to the classic infantile form. The mainstay of treatment is enzyme replacement therapy (EnRT). Decreased bone mineral density (BMD) is frequently encountered in LOPD. While bone loss is thought to be due to mechanical unloading secondary to the progressive muscle weakness associated with the disease, there is a lack of tissue-level data in support of this mechanism. We describe a 60-yr-old female with LOPD managed with EnRT who presented with proximal muscle weakness and decreased BMD on dual-energy X-ray absorptiometry. Undecalcified bone histology showed low turnover osteoporosis, and treatment was initiated with romosozumab. Romosozumab specifically may provide a promising osteoporosis therapy for LOPD-associated osteoporosis. As a sclerostin inhibitor, it both inhibits bone resorption and promotes new bone formation. We additionally emphasize that bone biopsy should be considered as a useful diagnostic tool in the evaluation of osteoporosis associated with uncommon pathologies, since bone histology provides more specific tissue-level information over clinical and laboratory evaluation as well as substantive guidance for treatment.
small molecules
2026-09-19 | Enzyme replacement therapy (ERT) combined with transient low-dose methotrexate (TLD-MTX) results in age- and disease-dependent immune profile changes in Infantile- vs. late-onset Pompe disease patients.
Transient low-dose methotrexate (MTX) induces long-term immune tolerance to enzyme replacement therapy (ERT) in Pompe disease; however, the underlying immunological mechanisms remain unclear. We hypothesized that TLD-MTX would reduce immune activation and induce a regulatory phenotype in patients with Infantile-Onset Pompe Disease (IOPD) and Late-Onset Pompe Disease (LOPD) treated with ERT. We evaluated immune cell profile changes in patients treated with ERT+MTX using multiparameter flow cytometry on peripheral blood mononuclear cells collected at baseline and six months post-treatment. We analyzed 40 immune parameters in (1) thirteen unpaired samples from ERT+MTX-untreated (n=10) and -treated (n=3) IOPD patients and (2) six paired pre- and post-treatment samples from LOPD (n=6) patients. Linear regression analyses were used to assess correlations between immune parameters and disease activity measured by urinary glucose tetrasaccharide (Glc4; a breakdown product of glycogen). In IOPD, ERT+MTX-treated samples (median age: 12.3 months) showed reduced % CD16+ monocytes and increased classical CD14+CD16- monocytes, suggesting a shift toward a less activated immune profile. Untreated samples had higher % mature memory B cells and lower % plasmablasts, central memory CD4+ and CD8+ T cells, and TIGIT+ CD8+ T cells. In contrast, LOPD patients (median age: 51.5 years) exhibited decreased % B cells and increased % TIGIT+ CD4+ T cells after treatment. Baseline Glc4 levels were higher in IOPD than LOPD (42.5 vs. 7) and decreased in both groups following ERT+MTX. In untreated IOPD patients, Glc4 levels positively correlated with CD16+ monocytes, mature memory B cells, and terminally differentiated CD8+ T cells; these associations were not observed after treatment. In LOPD, T follicular regulatory cells correlated with Glc4 prior to treatment but not after, and no additional significant correlations were identified. These findings demonstrate distinct immune profiles before and after ERT+MTX treatment in IOPD and LOPD patients. In IOPD, reduced pro-inflammatory monocytes and memory T cells provide evidence to suggest decreased immune activation. In LOPD, increased TIGIT+ CD4+ T cells may reflect a regulatory mechanism contributing to immune tolerance.
2026-06-12 | TRPML1 agonists synergize with enzyme replacement therapy in fibroblasts from Pompe disease patients.
Pompe disease is a severe and progressive metabolic myopathy caused by pathogenic variants of the GAA gene, deficiency of acid alpha-glucosidase (GAA), and lysosomal glycogen storage. The current standard of treatment for PD is enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA). Despite significant success of ERT in correcting some disease manifestations, limitations of its efficacy have emerged, due to several factors. Poor expression or abnormal intracellular distribution of the cation-independent mannose-6-phosphate receptor (M6PR) at the plasma membrane of specific cells has been identified as one of these factors. Here, we investigated whether activation of Transient Receptor Potential Mucolipin 1 (TRPML1) synergizes with ERT. TRPML1 is a lysosomal ion channel that has been shown to induce multiple effects, including regulation of calcium homeostasis, stimulation of autophagy, activation of lysosomal biogenesis and exocytosis, enhancement of vesicle and membrane trafficking. We studied the effects of two TRPML1 agonists in cultured fibroblasts from Pompe disease patients. Specifically, we analyzed M6PR availability at the plasma membrane of control and mutant cells, level of correction of GAA activity by rhGAA, processing and lysosomal trafficking of the recombinant enzyme. Treatment with two TRPML1 agonist drugs increased M6PR total amounts and its availability at the plasma membrane and improved M6PR intracellular recycling. The improvements in M6PR distribution translated into better correction of GAA activity in cells incubated with rhGAA and in improved lysosomal trafficking and processing of the recombinant enzyme. These data provide in vitro proof-of-concept evidence supporting the combination of ERT with pharmacological manipulation of secondarily altered M6PR distribution as a strategy to obtain better exposure of cells to therapeutic enzymes.
2026-04-11 | Epigenetic modulation of the gut-muscle axis in pompe disease: Microbiota fingerprints to cellular and molecular pathomechanisms.
Inter-organ cross-talk is increasingly recognised as a fundamental determinant in the pathogenesis of neurodegenerative and neuromuscular disorders, modulating neuroinflammation, protein misfolding, and cellular dysfunction through systemic mediators such as cytokines, adipokines, and growth factors. In neuromuscular diseases, particularly Pompe disease, muscle degeneration is tightly linked to impaired autophagy and chronic inflammation. Recent evidence highlights the gut microbiota as a key regulator of innate and adaptive immune responses, exerting direct effects on skeletal muscle and supporting the existence of a gut-muscle axis. Dysbiosis has been proposed to influence myopathy progression, suggesting that modulation of the intestinal ecosystem may hold therapeutic relevance. Consequently, interventions employing probiotics, prebiotics, and targeted nutritional compounds have emerged as promising strategies to modulate immune activity, attenuate inflammation, and enhance autophagic efficiency, thereby contributing to the restoration of intestinal eubiosis and complementing enzyme replacement therapy. In parallel, epigenetic mechanisms are gaining prominence as additional modulators of pathogenic pathways, with the potential to influence microbiome composition and function. Collectively, these insights position the gut-muscle axis as a central regulatory node in Pompe disease and a compelling target for personalised nutritional and nutraceutical approaches. This review aims to provide a comprehensive examination of the gut-muscle axis and its implications in Pompe disease. Understanding how nutrient-induced changes in microbial gene expression may be harnessed to develop novel, synergistic therapeutic strategies could ultimately improve clinical outcomes and enhance the quality of life of affected individuals.
2026-04-10 | Restoration of lysosomal membrane integrity in cell models of Pompe disease depends on fatty acid synthase and its product palmitic acid.
BACKGROUND: Lysosomal storage disorders (LSDs) are rare inherited diseases caused by mutations in genes encoding lysosomal proteins, leading to substrate accumulation and lysosomal dysfunction. Whether this build-up compromises lysosomal membrane integrity remains an open question. In this study, we aimed to investigate the presence of lysosomal membrane damage in LSD cells and to identify mechanisms that could reveal potential strategies for improvement of lysosomal function. METHODS: Primary skin fibroblasts from patients with LSDs were used to evaluate lysosomal integrity and function. Lysosomal immunopurification enabled lipidomic and proteomic profiling, complemented by viral transduction for targeted protein expression at lysosomal membranes. Pharmacologic and metabolite treatments were applied in loss-of-function and rescue analyses. Microscopy-based approaches were used to assess lysosomal activity, membrane damage, and integrity. As a complementary model, we employed conditional mouse embryonic fibroblasts (MEFs) lacking class 3 phosphoinositide 3-kinase (PI3K-3), which exhibit lysosomal dysfunction and autophagy defects characteristic of LSDs. RESULTS: In Pompe disease, caused by mutations in the acid alpha-glucosidase gene, glycogen accumulation aggravates persistent lysosomal membrane damage. Moreover, using loss- and gain-of-function models of PI3K-3, we showed that its product, phosphoinositide-3-phosphate (PI3P), was essential for preserving lysosomal membrane integrity. Notably, Pompe patient fibroblasts exhibited chronic lysosomal damage, marked by increased galectin-3 (GAL-3) recruitment and reduced levels of lysosome-associated PI3K-3. Targeted restoration of PI3K-3 at lysosomal membranes rescued this defect and stabilized membrane integrity. Proteomic analyses following genetic or pharmacologic inhibition of PI3K-3 revealed a striking downregulation of fatty acid metabolism, including depletion of fatty acid synthase (FASN). We further demonstrated that PI3K-3 and FASN functionally interacted to maintain lysosomal integrity in Pompe cells. Supplementation with the FASN product palmitate reproduced the protective effect of PI3K-3 targeting, enhancing lysosomal proteolysis and restoring autophagic flux. Importantly, palmitate treatment also improved lysosomal function in fibroblasts from patients with Gaucher disease and type 2 neuronal ceroid lipofuscinosis, extending the relevance of this mechanism across LSDs. CONCLUSIONS: These findings in cell models of LSDs uncover a link between PI3K-3, fatty acid metabolism, and lysosomal membrane integrity. They provide a basis for future in vivo validation of PI3K-3 activation and metabolic modulation as adjuvant treatments to improve lysosomal function in LSDs.
2026-04-02 | Dietary and body composition profiles in Chinese pediatric late-onset Pompe disease: implications for nutritional management
Background Late-onset Pompe disease (LOPD) is characterized by glycogen accumulation, leading to progressive weakness and gastrointestinal involvement. This study aimed to investigate the dietary habits and body composition phenotype of pediatric patients and to assess their correlations with motor ability and gastrointestinal symptom burden. Methods In this study, body composition was assessed by bio-electrical impedance analysis (BIA), and dietary intake was quantified using a food-frequency questionnaire. Clinical outcomes comprised the Gastrointestinal Symptom Rating Scale (GSRS) and the 6-min walk test (6MWT). Associations between variables were examined by correlation analyses. Results This study enrolled 30 children with LOPD and 30 healthy controls. Compared with controls, patients with LOPD exhibited significantly lower body mass index (BMI), intracellular water (ICW), total body water (TBW), skeletal muscle mass (SMM), protein mass (PM), and basal metabolic rate (BMR) (all P < 0.05). Children with LOPD displayed a markedly lower daily frequency of fruit intake, and increased consumption of dairy products and eggs. Correlation analyses revealed that multiple body composition parameters (ICW, SMM, etc.) were positively associated with motor performance ( P < 0.05). For diet, soy product and dairy intakes correlated positively with 6-min walk distance ( r = 0.389, P = 0.045; r = 0.386, P = 0.048), while vegetable intake correlated negatively with gastrointestinal symptom severity ( r = −0.366, P = 0.047). Conclusion LOPD children exhibited pronounced alterations in body composition and dietary pattern. These findings support the integration of nutritional assessment and dietary intervention into the comprehensive management of pediatric LOPD.
proteins
2026-09-29 | GC801-enabled AAV gene therapy in a neonate with Pompe disease
We report a neonate with IOPD who had high pre-existing anti-AAV9 antibody titers, which precluded eligibility for AAV9-mediated gene therapy (GC301). Preconditioning with a single dose of the IgG-degrading enzyme GC801 (0.2 mg/kg) safely reduced serum IgG from 6.25 g/L to a nadir of 0.72 g/L within 5 days. This pharmacological window facilitated successful GC301 vector transduction, driving a robust increase in GAA activity to 19.38 mmol/L/16h by day 84. Crucially, no adverse events beyond the underlying IOPD were observed. Our findings support the potential utility of GC801 as an agent to overcome pre-existing humoral barriers in neonatal gene therapy candidates.
2026-09-21 | Infantile-Onset Pompe Disease: Current Therapeutic Landscape, Clinical Challenges, and Future Horizons
Infantile-onset Pompe disease (IOPD) is a type of Pompe disease (PD) whose typical form presents in the first months of life.It is the most severe form of the PD spectrum.The underlying metabolic disturbance leads to widespread muscle involvement, affecting both cardiac and skeletal tissues, which critically impairs motor and respiratory function.Because of that, without treatment, the disease quickly progresses and leads to death.The aim of this article is to present the potential of treatment options for IOPD that have been developed in recent years.Currently, enzyme replacement therapy (ERT) represents the cornerstone of management, aiming to improve cardiac function, support motor development, and extend overall survival.Advanced therapeutic formulations continue to be explored to enhance treatment outcomes.However, conventional ERT presents inherent limitations, including the logistical burden of lifelong intravenous infusions, potential treatmentlimiting immune responses, and restricted passage across the blood-brain barrier.Moreover, the challenges posed by ERT have encouraged the development of alternative and complementary treatment strategies.Therefore, novel approaches are currently being investigated.
2026-09-16 | Screening for potential late-onset Pompe disease patients among individuals with suspected sleep apnea: A prospective, multicenter observational Cohort Study in Japan (PSSAP-J Study).
Pompe disease is an autosomal recessive disorder caused by a deficiency of acid α-glucosidase (GAA) enzyme. This deficiency induces progressive glycogen accumulation, leading to weakness of the respiratory muscle, including the diaphragm. As established enzyme replacement therapy is available for Pompe disease, earlier detection of potential Late-Onset Pompe Disease (LOPD) and subsequent intervention would have a significant clinical impact. Our hypothesis was that sleep problems, including sleep-disordered breathing (SDB) and clinical symptoms, may indicate an early stage of LOPD, since decreased respiratory muscle activity often presents initially during sleep. The primary aim of the PSSAP-J study was to demonstrate a higher prevalence of LOPD in a sleep-laboratory-based population. Secondary aims included identifying predictive factors for LOPD from diagnostic polysomnography (PSG) findings and clinical symptoms. This prospective multicenter observational cohort study enrolled consecutive patients presenting to sleep laboratories for overnight PSG due to suspected SDB. All patients underwent a Dried Blood Spot (DBS) screening for GAA activity. Genetic analysis of the GAA gene was performed for confirmatory testing when indicated. A total of 724 participants were analyzed, although the COVID-19 pandemic prevented reaching the target sample size (n = 1,500). No definitive LOPD cases were confirmed among those who completed the confirmatory testing (prevalence 0%; 95% confidence interval [CI], 0.00%-0.51%). However, seven screen-positive patients declined confirmatory testing and were classified as indeterminate cases. Consequently, we could not definitively establish a higher prevalence or identify predictive factors for LOPD in this population. Although the primary study aims could not be confirmed due to the sample size shortfall and the presence of indeterminate cases, our findings highlight the importance for sleep physicians to maintain a high index of suspicion for underlying myopathies, such as LOPD, in clinical practice. UMIN000039191, UMIN Clinical Trials Registry ( http://www.umin.ac.jp/ctr ).
2026-08-23 | GAA engineered to improve cellular uptake enhances correction in a preclinical hematopoietic stem cell gene therapy model of Pompe disease.
Pompe disease (PD) is a severe autosomal-recessive lysosomal storage disorder in which deficiency of acid alpha-glucosidase (GAA) enzyme function results in glycogen accumulation and a spectrum of clinically severe neuromuscular disease. Enzyme replacement therapy is the standard of care for PD, although its efficacy is limited by inefficient uptake by cells in target organs. Autologous transplantation of hematopoietic stem cells (HSCs), genetically modified ex vivo with lentiviral vectors (LVVs), allows secretion and systemic delivery of lysosomal enzymes and has resulted in clinical correction of severe neurometabolic diseases. We evaluated the potential of HSC gene therapy to correct GAA deficiency in a murine model of PD. To improve lysosomal delivery, we engineered a novel GAA transgene by adding a peptide tag targeting the insulin-like growth factor 2 binding domain (vIGF2-GAA). Transplantation of Gaa -/- HSCs genetically modified to express vIGF2-GAA into Gaa -/- recipient mice resulted in sustained systemic levels of engineered GAA. Reduction of glycogen accumulation in muscle tissues and brain confirmed the superior activity of vIGF2-GAA compared to wild-type (WT) GAA, lowering urine glucose tetrasaccharide levels and correcting skeletal and cardiac phenotypes. These results demonstrate the therapeutic advantage of delivering engineered vIGF2-GAA and support the clinical translation of HSC gene therapy for PD.
2026-08-01 | Glycogen storage disease type II (Pompe disease) presenting with peripheral lymphadenopathy in a juvenile domestic shorthair cat
Abstract This report describes a 13‐month‐old, female, spayed domestic shorthair cat that had, at 8 months of age, an initial diagnosis of severe left ventricular concentric hypertrophy with differentials including juvenile hypertrophic cardiomyopathy, mitral valve dysplasia, infiltrative disease or, less likely, ventricular non‐compaction. On final emergency presentation, it had diffuse peripheral lymphadenopathy and bicytopenia. Postmortem transmission electron microscopy of formalin‐fixed heart tissue provided a definitive diagnosis. It revealed distended secondary lysosomes packed with glycogen beta particles, pathognomonic for glycogen storage disease type II.
gene therapies
2026-09-15 | Current Status of Cellular and Gene-Based Therapies for Congenital Metabolic Disorders: A Review.
Congenital metabolic disorders often lead to irreversible organ damage beginning during fetal life or shortly after birth. Advances in prenatal diagnostics have enabled earlier identification of these conditions, creating opportunities for prenatal therapeutic intervention. Preclinical studies have demonstrated that prenatal cell therapies can result in donor cell engraftment, enzyme production, and partial correction of metabolic defects in several disease models. The fetal environment may support immune tolerance and enhance treatment effectiveness. Limited clinical experience suggests that these approaches are feasible and may be beneficial in selected conditions, including lysosomal storage diseases and infantile-onset Pompe disease. In utero gene therapy has also shown long-term metabolic correction in animal models. However, important challenges remain, including limited engraftment, immune responses, vector safety, ethical concerns, and regulatory barriers. Prenatal cellular and gene-based therapies are promising but remain experimental. Current evidence is strongest for biological rationale and preclinical proof of concept; clinical benefit has not yet been established for most disorders. Further clinical studies are needed to determine their safety, efficacy, and future role in the treatment of congenital metabolic disorders. This article reviews the current status of prenatal fetal cellular and gene‑based therapeutic approaches for inborn errors of metabolism.
2026-09-08 | Genome Editing for Glycogen Storage Diseases.
Gene therapy has been developed for several glycogen storage diseases and has advanced into clinical trials. However, the limitations of these gene therapies with regard to stability following treatment early in life have led to the development of genome editing. Early results for genome editing in both glycogen storage disease type Ia and Pompe disease have demonstrated promising efficacy, and proof-of-concept studies as well as a clinical trial are underway. These studies will determine whether genome editing fulfills its promise with regard to stably treating glycogen storage diseases early in life.
2026-07-28 | Autophagy-Lysosomal Dysfunction as a Converging Mechanism of Cardiomyopathy in Lysosomal Storage Disorders: From Pathobiology to Targeted Therapy.
Cardiac disease is a leading cause of morbidity and early death across several lysosomal storage disorders (LSDs); however, the cardiomyopathies of Fabry, Pompe, and Danon disease are still largely treated as separate, substrate-specific disorders. We argue that they are better understood as variations on a single theme: the breakdown of the autophagy-lysosome system within cardiomyocytes. In the healthy heart, this system clears damaged proteins and organelles and is regulated by mTORC1 and the master regulator TFEB. Once lysosomal degradation or autophagosome-lysosome fusion fails, undegraded substrates and defective mitochondria accumulate, driving hypertrophy, interstitial fibrosis, and conduction disease. Danon disease, resulting from the loss of LAMP2, is the clearest example of a primary defect in autophagic flux, whereas the glycogen storage of Pompe disease and the globotriaosylceramide accumulation of Fabry disease impair flux through different upstream mechanisms that converge on the same downstream injury. The same framework extends to other storage disorders with cardiac involvement, such as mucopolysaccharidosis (MPS). We trace this shared pathobiology from molecule to bedside, examine biomarkers that reflect lysosomal and autophagic dysfunction rather than storage alone, and re-examine treatment in that light: why enzyme replacement therapy corrects substrate accumulation but leaves much of the autophagic and mitochondrial damage unresolved, and why gene therapy-particularly AAV9-LAMP2B for Danon disease-together with autophagy- and TFEB-directed strategies may help close that gap. Viewing these disorders through a single mechanistic lens reshapes how we monitor them and where future therapies should be directed.
2026-06-25 | A Comprehensive Update on Pompe Disease: From Existing Therapies to Emerging Curative Strategies
Pompe disease (PD) is a rare, autosomal recessive neuromuscular disorder caused by mutations in the gene encoding acid alpha-glucosidase (GAA). The resulting deficiency in GAA, a lysosomal enzyme, leads to the pathological accumulation of glycogen, primarily in cardiac and skeletal muscles. PD presents as a clinical continuum spanning two major phenotypes: infantile-onset Pompe disease (IOPD), the most severe form, typically characterized by onset before 12 months of age, rapid hypertrophic cardiomyopathy, and severe hypotonia; and late-onset Pompe disease (LOPD), which manifests between 12 months of age and adulthood, and is characterized by progressive axial and proximal muscle weakness and respiratory insufficiency. Enzyme replacement therapy (ERT), available since 2006, has improved survival, particularly in IOPD, but is limited by variable efficacy and limited penetration of the blood–brain barrier, necessitating new approaches. In this comprehensive review, we focus on advances in the understanding and management of PD. First, we explore recent diagnostic advances and the characterization of multisystem involvement in PD. Next, we critically discuss the advantages and limitations of current ERT approaches, and advances achieved with next-generation ERT (avalglucosidase alfa, cipaglucosidase alfa + miglustat). Finally, we summarize cutting-edge, potentially curative strategies, including substrate reduction therapy and novel experimental therapies (e.g., gene therapy) that seek to circumvent the limitations of ERT, provide durable effects, and potentially penetrate the central nervous system.
2026-04-03 | A genome-edited isogenic human embryonic stem cell model of pompe disease recapitulates cardiac and skeletal muscle pathology.
BACKGROUND: Pompe disease is an autosomal recessive lysosomal storage disorder caused by mutations in the GAA gene, leading to acid alpha-glucosidase deficiency and pathological glycogen accumulation, primarily in cardiac and skeletal muscle. While enzyme replacement therapy (ERT) has improved clinical outcomes, its limited efficacy especially in skeletal muscle underscores the need for improved disease models and novel therapeutic strategies. Induced pluripotent stem cells (iPSCs) from Pompe patients have facilitated mechanistic studies; however, their utility is restricted by limited patient sample availability. METHODS: To address this limitation, we employed CRISPR-Cas9 genome editing to disrupt GAA in a well-characterized human embryonic stem cell (hESC) line, BJNhem20, thereby generating a Pompe disease model independent of patient material. RESULTS: The edited hESC line exhibited markedly reduced GAA enzymatic activity while maintaining pluripotency and trilineage differentiation potential. Upon directed differentiation, cardiac and skeletal muscle cells displayed pronounced lysosome and glycogen accumulation. CONCLUSIONS: These findings demonstrate that genome-edited hESC for Pompe disease can recapitulate key pathological features, providing a robust and scalable platform for disease modelling and therapeutic screening. This approach offers a valuable alternative to patient-derived iPSCs for studying rare genetic disorders and for the development of targeted interventions.
other
2025-12-21 | Diaphragmatic pacing system from the point of view of the patients: 14 years of clinical experience and follow-up.
High cervical spinal diseases (C1-C4), resulting in paralysis of the respiratory muscles, makes the person dependent on invasive mechanical ventilation (IMV) for life support. Although effective from a ventilatory point of view, IMV is associated with increased morbidity and mortality; ventilated patients have higher rates of respiratory complications, a significant reduction in life expectancy, and above all, a serious psychological repercussion with estrangement from the world. Diaphragmatic pacing system (DPS) is a well-established technique capable of restoring paraphysiological ventilation. A narrative review of the case history and their follow-up of 13 patients dependent on life support ventilation who have been implanted since 2011 in the Neurocritical Care Unit of the Niguarda Hospital, Milan. Diaphragmatic pacing system was successful implanted in all the patients: of them 9 were affected by traumatic cervical SCI, 2 by Arnold Chiari sequelae, 1 due to a spontaneous ischemia. One patient with Pompe disease was included although his pathophysiology primarly affects the diaphragm instead the high cervical spine tract. During the 14 years follow-up, 92% of patients (12/13) used DPS and in 42 % of them (5/12 patients) we were able to be disconnected from IMV for at least 12 h. One of the patients (7.7%) was completely weaned from IMV and the tracheostomy was finally removed. One patient needed hospitalization for a respiratory complication. All the patients perceived their quality of life to be excellent or good. The long-term follow-up of 13 patients with DPS suggests that the implant could be a potential long-term alternative to IMV, particularly in terms of quality of life. The diaphragmatic stimulator protects from IMV associated respiratory complications, therefore reducing hospitalization. Allowing spontaneous breathing for a variable number of hours enables the caregiver to support the individual more effectively, facilitating their reintegration into daily social and work activities. Diaphragmatic pacing system does not eliminate the disability but allows for more independent years of life with a greater possibility of social reintegration.
2025-07-28 | Autophagy impairment is associated with enhanced satellite cell activation in muscle biopsies from younger late-onset Pompe disease patients.
Late-onset Pompe disease (LOPD) is caused by α-glucosidase (GAA) deficiency, leading to glycogen accumulation resulting in progressive muscular weakness and respiratory insufficiency. Glycogen overload, vacuolation, and autophagic accumulation are the histological hallmarks of the disease. However, markers capable of tracking the progression of LOPD across different disease stages remain insufficiently characterized. We performed a comprehensive myopathologic analysis of eleven LOPD muscle biopsies from untreated patients (age range 7-69 years) and compared them to eleven biopsies from histologically normal age-matched controls. The cohort was divided into two groups considering the age at muscle biopsy below or above 33 years: (1) younger LOPD and (2) older LOPD, respectively. We quantified periodic acid-Schiff-positive fibers, vacuolated fibers using a novel vacuolation severity score, autophagic markers, and satellite cell behavior. We observed prominent vacuolization, glycogen overload, and autophagic bodies in younger LOPD. Moreover, this group showed higher regenerative features accompanied by an increase in the percentages of active satellite cells compared to older LOPD. In conclusion, autophagy impairment correlates with enhanced satellite cell activation in muscle biopsies from younger LOPD patients. These findings suggest that stimulating satellite cell activity may hold therapeutic potential for addressing LOPD progression in its early stages.
2025-04-21 | Splicing correction by peptide-conjugated morpholinos as a novel treatment for late-onset Pompe disease.
Late-onset Pompe disease (LOPD) is overwhelmingly caused by a single mutation that disrupts splicing of acid-alpha glucosidase (GAA) and results in the accumulation of lysosomal glycogen in muscle cells leading to progressive muscle weakness in patients. Current therapeutics for LOPD do not meet the needs of patients and have largely been developed in mutant animal models lacking Gaa expression, which more closely mimic the less common infantile form of the disease. Here we design and evaluate peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) to target the causative mutation in GAA and correct pathogenic splicing in muscle tissue. We show PPMO compounds correct LOPD splicing in both patient induced pluripotent stem cell-derived muscle cells and in skeletal muscle tissue after intravenous dosing in a newly developed humanized LOPD animal model that recapitulates patient LOPD splicing.
2025-02-05 | Rescue of common and rare exon 2 skipping variants of the GAA gene using modified U1 snRNA.
Pompe disease (PD) is an autosomal recessive lysosomal storage disorder caused by the deficient activity of acid alpha glucosidase (GAA) enzyme due to mutations in the GAA gene. As a result, undigested glycogen accumulates within lysosomes causing their dysfunction. From a clinical point of view, the disease can be classified in infantile-onset (IO) and late-onset (LO) forms. The common GAA c.-32-13T>G variant, found in 40-70% of LO-PD alleles, is a leaky splicing mutation interfering with the correct GAA exon 2 recognition by the spliceosome leading to the production of non-functional GAA transcripts. In this study, we used modified, GAA-tailored U1 snRNAs to correct the aberrant splicing determined by the c.-32-13T>G and other GAA exon 2-skipping mutations. A set of constructs expressing 5 different engineered U1 snRNAs was generated. A functional splicing assay using a GAA hybrid minigene carrying different variants known to affect GAA exon 2 splicing was used to test the effect of engineered U1 snRNAs on exon 2 inclusion. The effect on endogenously expressed GAA transcript and GAA enzymatic activity was assessed by transfecting patient-derived fibroblasts bearing the common c.-32-13T>G with the best performing modified U1 snRNA. Modified U1-3, U1+1 and U1+6 snRNAs were all able to increase, in a dose-dependent manner, the inclusion of exon 2 within the transcript derived from the GAA minigene harbouring the c.-32-13T>G variant. The U1+1 was the most effective one (2,5 fold increase). Moreover, U1+1 snRNA partially rescued the correct splicing of GAA minigenes harbouring mutations that affect the 3'ss (c.-32-3C>G, c.-32-2A>G) and the 5'ss (c.546G>A, c.546G>C, c.546G>T). Notably, the treatment of patient-derived fibroblasts carrying the c.-32-13T>G mutation with the U1+1 snRNA increased the amount of normal GAA mRNA by 1,8 fold and the GAA enzymatic activity by 70%. we provide the proof-of-concept for the use of modified GAA-tailored U1 snRNAs, designed to potentiate the recognition of the GAA exon 2 5'ss, as therapeutic tools to correct the aberrant transcripts carrying variants that affect exon 2 splicing, including the common c.-32-13T>G variant.
2025-01-08 | Challenges in multinational rare disease clinical studies during COVID-19: regulatory assessment of cipaglucosidase alfa plus miglustat in adults with late-onset Pompe disease.
PROPEL (ATB200-03; NCT03729362) compared the efficacy and safety of cipaglucosidase alfa plus miglustat (cipa + mig), a two-component therapy for late-onset Pompe disease (LOPD), versus alglucosidase alfa plus placebo (alg + pbo). The primary endpoint was change in 6-min walk distance (6MWD) from baseline to week 52. During PROPEL, COVID-19 interrupted some planned study visits and assessment windows, leading to delayed visits, make-up assessments for patients who missed ≥ 3 successive infusions before planned assessments at weeks 38 and 52, and some advanced visits (end-of-study/early-termination visits). These were remapped to the respective planned visits. To evaluate if remapping may have overestimated treatment effects, we conducted post hoc analyses using a mixed-effect model for repeated measures based on actual time points of assessments. In this post hoc analysis, estimated mean treatment difference between cipa + mig and alg + pbo for change from baseline to week 52 in 6MWD was 11.7 m (95% confidence interval [CI] - 1.0 to 24.4; p = 0.072). In the original published analyses, between-group difference using last observation carried forward was 13.6 m (95% CI - 2.8 to 29.9; p = 0.071 [p value from separate non-parametric analysis of covariance]). Both statistical analysis approaches led to similar results and consistent conclusions, confirming the efficacy of cipa + mig for adults with LOPD. NCT03729362; trial start date: December 4, 2018.Trial registration number.
antibodies
2026-05-15 | Combined omalizumab and desensitization to control IgE-mediated hypersensitivity in enzyme replacement therapy for late-onset Pompe disease.
Pompe disease is a rare, progressive lysosomal storage disorder caused by acid α-glucosidase deficiency, leading to glycogen accumulation, proximal muscle weakness, and respiratory decline. Enzyme replacement therapy (ERT) significantly improves survival and stabilizes motor function, but IgE-mediated hypersensitivity reactions (HSRs) can critically compromise treatment, posing a major clinical challenge. Desensitization protocols allow temporary tolerance to ERT, yet breakthrough reactions may occur, necessitating adjunctive strategies such as omalizumab. We report a 40-year-old woman with late-onset Pompe disease who developed severe IgE-mediated HSRs to alglucosidase alfa after years of uneventful therapy. Basophil activation testing (BAT) and serum-specific IgE confirmed an IgE-mediated mechanism. A 15-step, 5-bag desensitization protocol allowed temporary tolerance, but breakthrough reactions required therapy interruption. Upon switching to avalglucosidase alfa, BAT demonstrated IgE cross-reactivity, and a new desensitization protocol was implemented. Initial infusions were complicated by recurrent HSRs. The addition of subcutaneous omalizumab (300 mg monthly), administered two days before ERT, enabled safe reintroduction. Moreover, therapy was resumed gradually, starting at 50% of the target dose and escalating stepwise to the full therapeutic dose, resulting in uninterrupted treatment. Follow-up showed stable neuromuscular and respiratory function, progressive decline in BAT reactivity, and improved quality of life. This case highlights the critical role of BAT in diagnosing and monitoring IgE-mediated HSRs, the efficacy of individualized desensitization protocols, and the utility of omalizumab as an adjunctive therapy in refractory cases. In rare diseases like Pompe, documenting such integrated allergological strategies provides practical guidance for maintaining access to life-prolonging therapy and offers a reproducible framework for managing complex allergic complications.
2026-01-26 | Insights into immunogenicity and therapeutic strategies to mitigate the immune response in infantile-onset Pompe disease: a comprehensive systematic literature review.
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). 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. 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. 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.
2025-09-02 | Novel transferrin receptor-mediated enzyme replacement therapy efficiently treats myogenic and neurogenic aspects of Pompe disease in mice.
Pompe disease (PD) is a multisystemic progressive disease caused by acid-alpha glucosidase (GAA) deficiency. Patients display a spectrum of phenotypes ranging from the severe, rapidly progressive infantile-onset PD (IOPD) form to the slower progressing late-onset PD (LOPD). Enzyme replacement therapies (ERTs) are the only approved treatments; they decrease mortality in IOPD while maintaining or improving motor and respiratory function in LOPD. These therapies do not cross the blood-brain barrier (BBB) and the long-term survival of ERT-treated IOPD patients revealed underlying neurological disease. We used PD as a model to evaluate delivery of GAA across the BBB using anti-transferrin receptor (TfR) antibodies and show robust glycogen clearance and reduced neuroinflammation in the CNS of mice with PD. Importantly, anti-TfR-GAA treatment resulted in superior glycogen clearance in skeletal muscle compared with two approved ERTs. Glyco-chemical exchange saturation transfer/nuclear overhauser effect magnetic resonance imaging successfully estimated glycogen content in Pompe mouse brains, providing a non-invasive and translational method to evaluate brain-penetrant therapies for PD. Moreover, hexose tetrasaccharide was elevated in the cerebrospinal fluid of diseased mice and mirrored CNS glycogen levels, suggesting it may be a promising CNS biomarker. These data support the theory that the neurogenic and myogenic manifestations of PD can be effectively treated by anti-TfR-GAA.
2025-05-01 | Assessing neurodegeneration in Pompe disease using a degeneration-specific neurofilament light chain (NF-L) antibody
Pompe disease (PD) is an autosomal recessive disorder in which mutations in the acid-alpha glucosidase ( Gaa ) gene result in impaired or absent GAA protein. Since GAA acts to degrade lysosomal glycogen, the impact is widespread glycogen accumulation. Neuronal glycogen accumulation is prominent and autopsy case reports and animal model data indicate that neurodegeneration occurs as the disease progresses. We recently described an antibody, MCA-6H63, that uniquely binds to a portion of NF-L during degeneration (PMID: 37091583). Here we tested the hypothesis that MCA-6H63 could be used to immunohistochemically identify degenerating neurons in PD. First, we evaluated the spinal cord of a human with late-onset PD who succumbed to cardiorespiratory failure at age 54. Positive staining was noted in the soma of neurons in the ventral horn of the spinal cord, fibers in the ventral roots, and in white matter tracts. However, in control experiments in which tissue was incubated in control IgG mouse antibody, staining was absent. We next evaluated the brainstem and spinal cord in the Gaa -/- mouse model of PD (age 10-12 mo). Positive MCA-6H63 staining was noted in the soma of neurons in the medulla and extensive labeling of white matter tracts. In the spinal cord, we observed sparse labeling of neuronal fibers, presumably dendrites. Lastly, we examined a unique mouse model (age 10-12 mo) with Gaa absent only in choline acetyltransferase (ChAT) positive neurons (ChAT-cre +/+ ▪Gaa +/- ▪eYFP +/+ ▪Flox-Gaa +/+ ). MCA-6H63 staining was also observed in distinct brainstem nuclei and in some white matter tracts. We conclude that MCA-6H63 staining in mouse and human CNS tissue verifies neurodegeneration in PD. Since axons contain more NF-L than perikaryon, future studies with MCA-6H63 in PD or other neurodegenerative conditions should focus on neural fibers (e.g., ventral root, peripheral nerve axons) as this may provide a useful surrogate tag for neuronal degeneration. Collectively, the data support the thesis that effective PD treatment strategies must ultimately mitigate neurodegeneration. Funding: R01HD052682 (DDF and BJB); 1K99NS133388-01A1(SR) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
2025-04-14 | Bone disease and osteoporosis associated with Pompe disease.
Pompe disease is a lysosomal storage disorder defined by a mutation in the GAA gene encoding alpha-1,4-glucosidase alpha (acid maltase). Pompe disease encompasses a range of clinical presentations that are broadly characterized as either classic infantile Pompe disease or late-onset Pompe disease (LOPD). LOPD is a milder manifestation of the disease that presents after the first year of life and is typically characterized by mild proximal muscle weakness and lack of cardiac involvement compared to the classic infantile form. The mainstay of treatment is enzyme replacement therapy (EnRT). Decreased bone mineral density (BMD) is frequently encountered in LOPD. While bone loss is thought to be due to mechanical unloading secondary to the progressive muscle weakness associated with the disease, there is a lack of tissue-level data in support of this mechanism. We describe a 60-yr-old female with LOPD managed with EnRT who presented with proximal muscle weakness and decreased BMD on dual-energy X-ray absorptiometry. Undecalcified bone histology showed low turnover osteoporosis, and treatment was initiated with romosozumab. Romosozumab specifically may provide a promising osteoporosis therapy for LOPD-associated osteoporosis. As a sclerostin inhibitor, it both inhibits bone resorption and promotes new bone formation. We additionally emphasize that bone biopsy should be considered as a useful diagnostic tool in the evaluation of osteoporosis associated with uncommon pathologies, since bone histology provides more specific tissue-level information over clinical and laboratory evaluation as well as substantive guidance for treatment.
small molecules
2026-09-19 | Enzyme replacement therapy (ERT) combined with transient low-dose methotrexate (TLD-MTX) results in age- and disease-dependent immune profile changes in Infantile- vs. late-onset Pompe disease patients.
Transient low-dose methotrexate (MTX) induces long-term immune tolerance to enzyme replacement therapy (ERT) in Pompe disease; however, the underlying immunological mechanisms remain unclear. We hypothesized that TLD-MTX would reduce immune activation and induce a regulatory phenotype in patients with Infantile-Onset Pompe Disease (IOPD) and Late-Onset Pompe Disease (LOPD) treated with ERT. We evaluated immune cell profile changes in patients treated with ERT+MTX using multiparameter flow cytometry on peripheral blood mononuclear cells collected at baseline and six months post-treatment. We analyzed 40 immune parameters in (1) thirteen unpaired samples from ERT+MTX-untreated (n=10) and -treated (n=3) IOPD patients and (2) six paired pre- and post-treatment samples from LOPD (n=6) patients. Linear regression analyses were used to assess correlations between immune parameters and disease activity measured by urinary glucose tetrasaccharide (Glc4; a breakdown product of glycogen). In IOPD, ERT+MTX-treated samples (median age: 12.3 months) showed reduced % CD16+ monocytes and increased classical CD14+CD16- monocytes, suggesting a shift toward a less activated immune profile. Untreated samples had higher % mature memory B cells and lower % plasmablasts, central memory CD4+ and CD8+ T cells, and TIGIT+ CD8+ T cells. In contrast, LOPD patients (median age: 51.5 years) exhibited decreased % B cells and increased % TIGIT+ CD4+ T cells after treatment. Baseline Glc4 levels were higher in IOPD than LOPD (42.5 vs. 7) and decreased in both groups following ERT+MTX. In untreated IOPD patients, Glc4 levels positively correlated with CD16+ monocytes, mature memory B cells, and terminally differentiated CD8+ T cells; these associations were not observed after treatment. In LOPD, T follicular regulatory cells correlated with Glc4 prior to treatment but not after, and no additional significant correlations were identified. These findings demonstrate distinct immune profiles before and after ERT+MTX treatment in IOPD and LOPD patients. In IOPD, reduced pro-inflammatory monocytes and memory T cells provide evidence to suggest decreased immune activation. In LOPD, increased TIGIT+ CD4+ T cells may reflect a regulatory mechanism contributing to immune tolerance.
2026-06-12 | TRPML1 agonists synergize with enzyme replacement therapy in fibroblasts from Pompe disease patients.
Pompe disease is a severe and progressive metabolic myopathy caused by pathogenic variants of the GAA gene, deficiency of acid alpha-glucosidase (GAA), and lysosomal glycogen storage. The current standard of treatment for PD is enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA). Despite significant success of ERT in correcting some disease manifestations, limitations of its efficacy have emerged, due to several factors. Poor expression or abnormal intracellular distribution of the cation-independent mannose-6-phosphate receptor (M6PR) at the plasma membrane of specific cells has been identified as one of these factors. Here, we investigated whether activation of Transient Receptor Potential Mucolipin 1 (TRPML1) synergizes with ERT. TRPML1 is a lysosomal ion channel that has been shown to induce multiple effects, including regulation of calcium homeostasis, stimulation of autophagy, activation of lysosomal biogenesis and exocytosis, enhancement of vesicle and membrane trafficking. We studied the effects of two TRPML1 agonists in cultured fibroblasts from Pompe disease patients. Specifically, we analyzed M6PR availability at the plasma membrane of control and mutant cells, level of correction of GAA activity by rhGAA, processing and lysosomal trafficking of the recombinant enzyme. Treatment with two TRPML1 agonist drugs increased M6PR total amounts and its availability at the plasma membrane and improved M6PR intracellular recycling. The improvements in M6PR distribution translated into better correction of GAA activity in cells incubated with rhGAA and in improved lysosomal trafficking and processing of the recombinant enzyme. These data provide in vitro proof-of-concept evidence supporting the combination of ERT with pharmacological manipulation of secondarily altered M6PR distribution as a strategy to obtain better exposure of cells to therapeutic enzymes.
2026-04-11 | Epigenetic modulation of the gut-muscle axis in pompe disease: Microbiota fingerprints to cellular and molecular pathomechanisms.
Inter-organ cross-talk is increasingly recognised as a fundamental determinant in the pathogenesis of neurodegenerative and neuromuscular disorders, modulating neuroinflammation, protein misfolding, and cellular dysfunction through systemic mediators such as cytokines, adipokines, and growth factors. In neuromuscular diseases, particularly Pompe disease, muscle degeneration is tightly linked to impaired autophagy and chronic inflammation. Recent evidence highlights the gut microbiota as a key regulator of innate and adaptive immune responses, exerting direct effects on skeletal muscle and supporting the existence of a gut-muscle axis. Dysbiosis has been proposed to influence myopathy progression, suggesting that modulation of the intestinal ecosystem may hold therapeutic relevance. Consequently, interventions employing probiotics, prebiotics, and targeted nutritional compounds have emerged as promising strategies to modulate immune activity, attenuate inflammation, and enhance autophagic efficiency, thereby contributing to the restoration of intestinal eubiosis and complementing enzyme replacement therapy. In parallel, epigenetic mechanisms are gaining prominence as additional modulators of pathogenic pathways, with the potential to influence microbiome composition and function. Collectively, these insights position the gut-muscle axis as a central regulatory node in Pompe disease and a compelling target for personalised nutritional and nutraceutical approaches. This review aims to provide a comprehensive examination of the gut-muscle axis and its implications in Pompe disease. Understanding how nutrient-induced changes in microbial gene expression may be harnessed to develop novel, synergistic therapeutic strategies could ultimately improve clinical outcomes and enhance the quality of life of affected individuals.
2026-04-10 | Restoration of lysosomal membrane integrity in cell models of Pompe disease depends on fatty acid synthase and its product palmitic acid.
BACKGROUND: Lysosomal storage disorders (LSDs) are rare inherited diseases caused by mutations in genes encoding lysosomal proteins, leading to substrate accumulation and lysosomal dysfunction. Whether this build-up compromises lysosomal membrane integrity remains an open question. In this study, we aimed to investigate the presence of lysosomal membrane damage in LSD cells and to identify mechanisms that could reveal potential strategies for improvement of lysosomal function. METHODS: Primary skin fibroblasts from patients with LSDs were used to evaluate lysosomal integrity and function. Lysosomal immunopurification enabled lipidomic and proteomic profiling, complemented by viral transduction for targeted protein expression at lysosomal membranes. Pharmacologic and metabolite treatments were applied in loss-of-function and rescue analyses. Microscopy-based approaches were used to assess lysosomal activity, membrane damage, and integrity. As a complementary model, we employed conditional mouse embryonic fibroblasts (MEFs) lacking class 3 phosphoinositide 3-kinase (PI3K-3), which exhibit lysosomal dysfunction and autophagy defects characteristic of LSDs. RESULTS: In Pompe disease, caused by mutations in the acid alpha-glucosidase gene, glycogen accumulation aggravates persistent lysosomal membrane damage. Moreover, using loss- and gain-of-function models of PI3K-3, we showed that its product, phosphoinositide-3-phosphate (PI3P), was essential for preserving lysosomal membrane integrity. Notably, Pompe patient fibroblasts exhibited chronic lysosomal damage, marked by increased galectin-3 (GAL-3) recruitment and reduced levels of lysosome-associated PI3K-3. Targeted restoration of PI3K-3 at lysosomal membranes rescued this defect and stabilized membrane integrity. Proteomic analyses following genetic or pharmacologic inhibition of PI3K-3 revealed a striking downregulation of fatty acid metabolism, including depletion of fatty acid synthase (FASN). We further demonstrated that PI3K-3 and FASN functionally interacted to maintain lysosomal integrity in Pompe cells. Supplementation with the FASN product palmitate reproduced the protective effect of PI3K-3 targeting, enhancing lysosomal proteolysis and restoring autophagic flux. Importantly, palmitate treatment also improved lysosomal function in fibroblasts from patients with Gaucher disease and type 2 neuronal ceroid lipofuscinosis, extending the relevance of this mechanism across LSDs. CONCLUSIONS: These findings in cell models of LSDs uncover a link between PI3K-3, fatty acid metabolism, and lysosomal membrane integrity. They provide a basis for future in vivo validation of PI3K-3 activation and metabolic modulation as adjuvant treatments to improve lysosomal function in LSDs.
2026-04-02 | Dietary and body composition profiles in Chinese pediatric late-onset Pompe disease: implications for nutritional management
Background Late-onset Pompe disease (LOPD) is characterized by glycogen accumulation, leading to progressive weakness and gastrointestinal involvement. This study aimed to investigate the dietary habits and body composition phenotype of pediatric patients and to assess their correlations with motor ability and gastrointestinal symptom burden. Methods In this study, body composition was assessed by bio-electrical impedance analysis (BIA), and dietary intake was quantified using a food-frequency questionnaire. Clinical outcomes comprised the Gastrointestinal Symptom Rating Scale (GSRS) and the 6-min walk test (6MWT). Associations between variables were examined by correlation analyses. Results This study enrolled 30 children with LOPD and 30 healthy controls. Compared with controls, patients with LOPD exhibited significantly lower body mass index (BMI), intracellular water (ICW), total body water (TBW), skeletal muscle mass (SMM), protein mass (PM), and basal metabolic rate (BMR) (all P < 0.05). Children with LOPD displayed a markedly lower daily frequency of fruit intake, and increased consumption of dairy products and eggs. Correlation analyses revealed that multiple body composition parameters (ICW, SMM, etc.) were positively associated with motor performance ( P < 0.05). For diet, soy product and dairy intakes correlated positively with 6-min walk distance ( r = 0.389, P = 0.045; r = 0.386, P = 0.048), while vegetable intake correlated negatively with gastrointestinal symptom severity ( r = −0.366, P = 0.047). Conclusion LOPD children exhibited pronounced alterations in body composition and dietary pattern. These findings support the integration of nutritional assessment and dietary intervention into the comprehensive management of pediatric LOPD.
proteins
2026-09-29 | GC801-enabled AAV gene therapy in a neonate with Pompe disease
We report a neonate with IOPD who had high pre-existing anti-AAV9 antibody titers, which precluded eligibility for AAV9-mediated gene therapy (GC301). Preconditioning with a single dose of the IgG-degrading enzyme GC801 (0.2 mg/kg) safely reduced serum IgG from 6.25 g/L to a nadir of 0.72 g/L within 5 days. This pharmacological window facilitated successful GC301 vector transduction, driving a robust increase in GAA activity to 19.38 mmol/L/16h by day 84. Crucially, no adverse events beyond the underlying IOPD were observed. Our findings support the potential utility of GC801 as an agent to overcome pre-existing humoral barriers in neonatal gene therapy candidates.
2026-09-21 | Infantile-Onset Pompe Disease: Current Therapeutic Landscape, Clinical Challenges, and Future Horizons
Infantile-onset Pompe disease (IOPD) is a type of Pompe disease (PD) whose typical form presents in the first months of life.It is the most severe form of the PD spectrum.The underlying metabolic disturbance leads to widespread muscle involvement, affecting both cardiac and skeletal tissues, which critically impairs motor and respiratory function.Because of that, without treatment, the disease quickly progresses and leads to death.The aim of this article is to present the potential of treatment options for IOPD that have been developed in recent years.Currently, enzyme replacement therapy (ERT) represents the cornerstone of management, aiming to improve cardiac function, support motor development, and extend overall survival.Advanced therapeutic formulations continue to be explored to enhance treatment outcomes.However, conventional ERT presents inherent limitations, including the logistical burden of lifelong intravenous infusions, potential treatmentlimiting immune responses, and restricted passage across the blood-brain barrier.Moreover, the challenges posed by ERT have encouraged the development of alternative and complementary treatment strategies.Therefore, novel approaches are currently being investigated.
2026-09-16 | Screening for potential late-onset Pompe disease patients among individuals with suspected sleep apnea: A prospective, multicenter observational Cohort Study in Japan (PSSAP-J Study).
Pompe disease is an autosomal recessive disorder caused by a deficiency of acid α-glucosidase (GAA) enzyme. This deficiency induces progressive glycogen accumulation, leading to weakness of the respiratory muscle, including the diaphragm. As established enzyme replacement therapy is available for Pompe disease, earlier detection of potential Late-Onset Pompe Disease (LOPD) and subsequent intervention would have a significant clinical impact. Our hypothesis was that sleep problems, including sleep-disordered breathing (SDB) and clinical symptoms, may indicate an early stage of LOPD, since decreased respiratory muscle activity often presents initially during sleep. The primary aim of the PSSAP-J study was to demonstrate a higher prevalence of LOPD in a sleep-laboratory-based population. Secondary aims included identifying predictive factors for LOPD from diagnostic polysomnography (PSG) findings and clinical symptoms. This prospective multicenter observational cohort study enrolled consecutive patients presenting to sleep laboratories for overnight PSG due to suspected SDB. All patients underwent a Dried Blood Spot (DBS) screening for GAA activity. Genetic analysis of the GAA gene was performed for confirmatory testing when indicated. A total of 724 participants were analyzed, although the COVID-19 pandemic prevented reaching the target sample size (n = 1,500). No definitive LOPD cases were confirmed among those who completed the confirmatory testing (prevalence 0%; 95% confidence interval [CI], 0.00%-0.51%). However, seven screen-positive patients declined confirmatory testing and were classified as indeterminate cases. Consequently, we could not definitively establish a higher prevalence or identify predictive factors for LOPD in this population. Although the primary study aims could not be confirmed due to the sample size shortfall and the presence of indeterminate cases, our findings highlight the importance for sleep physicians to maintain a high index of suspicion for underlying myopathies, such as LOPD, in clinical practice. UMIN000039191, UMIN Clinical Trials Registry ( http://www.umin.ac.jp/ctr ).
2026-08-23 | GAA engineered to improve cellular uptake enhances correction in a preclinical hematopoietic stem cell gene therapy model of Pompe disease.
Pompe disease (PD) is a severe autosomal-recessive lysosomal storage disorder in which deficiency of acid alpha-glucosidase (GAA) enzyme function results in glycogen accumulation and a spectrum of clinically severe neuromuscular disease. Enzyme replacement therapy is the standard of care for PD, although its efficacy is limited by inefficient uptake by cells in target organs. Autologous transplantation of hematopoietic stem cells (HSCs), genetically modified ex vivo with lentiviral vectors (LVVs), allows secretion and systemic delivery of lysosomal enzymes and has resulted in clinical correction of severe neurometabolic diseases. We evaluated the potential of HSC gene therapy to correct GAA deficiency in a murine model of PD. To improve lysosomal delivery, we engineered a novel GAA transgene by adding a peptide tag targeting the insulin-like growth factor 2 binding domain (vIGF2-GAA). Transplantation of Gaa -/- HSCs genetically modified to express vIGF2-GAA into Gaa -/- recipient mice resulted in sustained systemic levels of engineered GAA. Reduction of glycogen accumulation in muscle tissues and brain confirmed the superior activity of vIGF2-GAA compared to wild-type (WT) GAA, lowering urine glucose tetrasaccharide levels and correcting skeletal and cardiac phenotypes. These results demonstrate the therapeutic advantage of delivering engineered vIGF2-GAA and support the clinical translation of HSC gene therapy for PD.
2026-08-01 | Glycogen storage disease type II (Pompe disease) presenting with peripheral lymphadenopathy in a juvenile domestic shorthair cat
Abstract This report describes a 13‐month‐old, female, spayed domestic shorthair cat that had, at 8 months of age, an initial diagnosis of severe left ventricular concentric hypertrophy with differentials including juvenile hypertrophic cardiomyopathy, mitral valve dysplasia, infiltrative disease or, less likely, ventricular non‐compaction. On final emergency presentation, it had diffuse peripheral lymphadenopathy and bicytopenia. Postmortem transmission electron microscopy of formalin‐fixed heart tissue provided a definitive diagnosis. It revealed distended secondary lysosomes packed with glycogen beta particles, pathognomonic for glycogen storage disease type II.
gene therapies
2026-09-15 | Current Status of Cellular and Gene-Based Therapies for Congenital Metabolic Disorders: A Review.
Congenital metabolic disorders often lead to irreversible organ damage beginning during fetal life or shortly after birth. Advances in prenatal diagnostics have enabled earlier identification of these conditions, creating opportunities for prenatal therapeutic intervention. Preclinical studies have demonstrated that prenatal cell therapies can result in donor cell engraftment, enzyme production, and partial correction of metabolic defects in several disease models. The fetal environment may support immune tolerance and enhance treatment effectiveness. Limited clinical experience suggests that these approaches are feasible and may be beneficial in selected conditions, including lysosomal storage diseases and infantile-onset Pompe disease. In utero gene therapy has also shown long-term metabolic correction in animal models. However, important challenges remain, including limited engraftment, immune responses, vector safety, ethical concerns, and regulatory barriers. Prenatal cellular and gene-based therapies are promising but remain experimental. Current evidence is strongest for biological rationale and preclinical proof of concept; clinical benefit has not yet been established for most disorders. Further clinical studies are needed to determine their safety, efficacy, and future role in the treatment of congenital metabolic disorders. This article reviews the current status of prenatal fetal cellular and gene‑based therapeutic approaches for inborn errors of metabolism.
2026-09-08 | Genome Editing for Glycogen Storage Diseases.
Gene therapy has been developed for several glycogen storage diseases and has advanced into clinical trials. However, the limitations of these gene therapies with regard to stability following treatment early in life have led to the development of genome editing. Early results for genome editing in both glycogen storage disease type Ia and Pompe disease have demonstrated promising efficacy, and proof-of-concept studies as well as a clinical trial are underway. These studies will determine whether genome editing fulfills its promise with regard to stably treating glycogen storage diseases early in life.
2026-07-28 | Autophagy-Lysosomal Dysfunction as a Converging Mechanism of Cardiomyopathy in Lysosomal Storage Disorders: From Pathobiology to Targeted Therapy.
Cardiac disease is a leading cause of morbidity and early death across several lysosomal storage disorders (LSDs); however, the cardiomyopathies of Fabry, Pompe, and Danon disease are still largely treated as separate, substrate-specific disorders. We argue that they are better understood as variations on a single theme: the breakdown of the autophagy-lysosome system within cardiomyocytes. In the healthy heart, this system clears damaged proteins and organelles and is regulated by mTORC1 and the master regulator TFEB. Once lysosomal degradation or autophagosome-lysosome fusion fails, undegraded substrates and defective mitochondria accumulate, driving hypertrophy, interstitial fibrosis, and conduction disease. Danon disease, resulting from the loss of LAMP2, is the clearest example of a primary defect in autophagic flux, whereas the glycogen storage of Pompe disease and the globotriaosylceramide accumulation of Fabry disease impair flux through different upstream mechanisms that converge on the same downstream injury. The same framework extends to other storage disorders with cardiac involvement, such as mucopolysaccharidosis (MPS). We trace this shared pathobiology from molecule to bedside, examine biomarkers that reflect lysosomal and autophagic dysfunction rather than storage alone, and re-examine treatment in that light: why enzyme replacement therapy corrects substrate accumulation but leaves much of the autophagic and mitochondrial damage unresolved, and why gene therapy-particularly AAV9-LAMP2B for Danon disease-together with autophagy- and TFEB-directed strategies may help close that gap. Viewing these disorders through a single mechanistic lens reshapes how we monitor them and where future therapies should be directed.
2026-06-25 | A Comprehensive Update on Pompe Disease: From Existing Therapies to Emerging Curative Strategies
Pompe disease (PD) is a rare, autosomal recessive neuromuscular disorder caused by mutations in the gene encoding acid alpha-glucosidase (GAA). The resulting deficiency in GAA, a lysosomal enzyme, leads to the pathological accumulation of glycogen, primarily in cardiac and skeletal muscles. PD presents as a clinical continuum spanning two major phenotypes: infantile-onset Pompe disease (IOPD), the most severe form, typically characterized by onset before 12 months of age, rapid hypertrophic cardiomyopathy, and severe hypotonia; and late-onset Pompe disease (LOPD), which manifests between 12 months of age and adulthood, and is characterized by progressive axial and proximal muscle weakness and respiratory insufficiency. Enzyme replacement therapy (ERT), available since 2006, has improved survival, particularly in IOPD, but is limited by variable efficacy and limited penetration of the blood–brain barrier, necessitating new approaches. In this comprehensive review, we focus on advances in the understanding and management of PD. First, we explore recent diagnostic advances and the characterization of multisystem involvement in PD. Next, we critically discuss the advantages and limitations of current ERT approaches, and advances achieved with next-generation ERT (avalglucosidase alfa, cipaglucosidase alfa + miglustat). Finally, we summarize cutting-edge, potentially curative strategies, including substrate reduction therapy and novel experimental therapies (e.g., gene therapy) that seek to circumvent the limitations of ERT, provide durable effects, and potentially penetrate the central nervous system.
2026-04-03 | A genome-edited isogenic human embryonic stem cell model of pompe disease recapitulates cardiac and skeletal muscle pathology.
BACKGROUND: Pompe disease is an autosomal recessive lysosomal storage disorder caused by mutations in the GAA gene, leading to acid alpha-glucosidase deficiency and pathological glycogen accumulation, primarily in cardiac and skeletal muscle. While enzyme replacement therapy (ERT) has improved clinical outcomes, its limited efficacy especially in skeletal muscle underscores the need for improved disease models and novel therapeutic strategies. Induced pluripotent stem cells (iPSCs) from Pompe patients have facilitated mechanistic studies; however, their utility is restricted by limited patient sample availability. METHODS: To address this limitation, we employed CRISPR-Cas9 genome editing to disrupt GAA in a well-characterized human embryonic stem cell (hESC) line, BJNhem20, thereby generating a Pompe disease model independent of patient material. RESULTS: The edited hESC line exhibited markedly reduced GAA enzymatic activity while maintaining pluripotency and trilineage differentiation potential. Upon directed differentiation, cardiac and skeletal muscle cells displayed pronounced lysosome and glycogen accumulation. CONCLUSIONS: These findings demonstrate that genome-edited hESC for Pompe disease can recapitulate key pathological features, providing a robust and scalable platform for disease modelling and therapeutic screening. This approach offers a valuable alternative to patient-derived iPSCs for studying rare genetic disorders and for the development of targeted interventions.
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2025-12-21 | Diaphragmatic pacing system from the point of view of the patients: 14 years of clinical experience and follow-up.
High cervical spinal diseases (C1-C4), resulting in paralysis of the respiratory muscles, makes the person dependent on invasive mechanical ventilation (IMV) for life support. Although effective from a ventilatory point of view, IMV is associated with increased morbidity and mortality; ventilated patients have higher rates of respiratory complications, a significant reduction in life expectancy, and above all, a serious psychological repercussion with estrangement from the world. Diaphragmatic pacing system (DPS) is a well-established technique capable of restoring paraphysiological ventilation. A narrative review of the case history and their follow-up of 13 patients dependent on life support ventilation who have been implanted since 2011 in the Neurocritical Care Unit of the Niguarda Hospital, Milan. Diaphragmatic pacing system was successful implanted in all the patients: of them 9 were affected by traumatic cervical SCI, 2 by Arnold Chiari sequelae, 1 due to a spontaneous ischemia. One patient with Pompe disease was included although his pathophysiology primarly affects the diaphragm instead the high cervical spine tract. During the 14 years follow-up, 92% of patients (12/13) used DPS and in 42 % of them (5/12 patients) we were able to be disconnected from IMV for at least 12 h. One of the patients (7.7%) was completely weaned from IMV and the tracheostomy was finally removed. One patient needed hospitalization for a respiratory complication. All the patients perceived their quality of life to be excellent or good. The long-term follow-up of 13 patients with DPS suggests that the implant could be a potential long-term alternative to IMV, particularly in terms of quality of life. The diaphragmatic stimulator protects from IMV associated respiratory complications, therefore reducing hospitalization. Allowing spontaneous breathing for a variable number of hours enables the caregiver to support the individual more effectively, facilitating their reintegration into daily social and work activities. Diaphragmatic pacing system does not eliminate the disability but allows for more independent years of life with a greater possibility of social reintegration.
2025-07-28 | Autophagy impairment is associated with enhanced satellite cell activation in muscle biopsies from younger late-onset Pompe disease patients.
Late-onset Pompe disease (LOPD) is caused by α-glucosidase (GAA) deficiency, leading to glycogen accumulation resulting in progressive muscular weakness and respiratory insufficiency. Glycogen overload, vacuolation, and autophagic accumulation are the histological hallmarks of the disease. However, markers capable of tracking the progression of LOPD across different disease stages remain insufficiently characterized. We performed a comprehensive myopathologic analysis of eleven LOPD muscle biopsies from untreated patients (age range 7-69 years) and compared them to eleven biopsies from histologically normal age-matched controls. The cohort was divided into two groups considering the age at muscle biopsy below or above 33 years: (1) younger LOPD and (2) older LOPD, respectively. We quantified periodic acid-Schiff-positive fibers, vacuolated fibers using a novel vacuolation severity score, autophagic markers, and satellite cell behavior. We observed prominent vacuolization, glycogen overload, and autophagic bodies in younger LOPD. Moreover, this group showed higher regenerative features accompanied by an increase in the percentages of active satellite cells compared to older LOPD. In conclusion, autophagy impairment correlates with enhanced satellite cell activation in muscle biopsies from younger LOPD patients. These findings suggest that stimulating satellite cell activity may hold therapeutic potential for addressing LOPD progression in its early stages.
2025-04-21 | Splicing correction by peptide-conjugated morpholinos as a novel treatment for late-onset Pompe disease.
Late-onset Pompe disease (LOPD) is overwhelmingly caused by a single mutation that disrupts splicing of acid-alpha glucosidase (GAA) and results in the accumulation of lysosomal glycogen in muscle cells leading to progressive muscle weakness in patients. Current therapeutics for LOPD do not meet the needs of patients and have largely been developed in mutant animal models lacking Gaa expression, which more closely mimic the less common infantile form of the disease. Here we design and evaluate peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) to target the causative mutation in GAA and correct pathogenic splicing in muscle tissue. We show PPMO compounds correct LOPD splicing in both patient induced pluripotent stem cell-derived muscle cells and in skeletal muscle tissue after intravenous dosing in a newly developed humanized LOPD animal model that recapitulates patient LOPD splicing.
2025-02-05 | Rescue of common and rare exon 2 skipping variants of the GAA gene using modified U1 snRNA.
Pompe disease (PD) is an autosomal recessive lysosomal storage disorder caused by the deficient activity of acid alpha glucosidase (GAA) enzyme due to mutations in the GAA gene. As a result, undigested glycogen accumulates within lysosomes causing their dysfunction. From a clinical point of view, the disease can be classified in infantile-onset (IO) and late-onset (LO) forms. The common GAA c.-32-13T>G variant, found in 40-70% of LO-PD alleles, is a leaky splicing mutation interfering with the correct GAA exon 2 recognition by the spliceosome leading to the production of non-functional GAA transcripts. In this study, we used modified, GAA-tailored U1 snRNAs to correct the aberrant splicing determined by the c.-32-13T>G and other GAA exon 2-skipping mutations. A set of constructs expressing 5 different engineered U1 snRNAs was generated. A functional splicing assay using a GAA hybrid minigene carrying different variants known to affect GAA exon 2 splicing was used to test the effect of engineered U1 snRNAs on exon 2 inclusion. The effect on endogenously expressed GAA transcript and GAA enzymatic activity was assessed by transfecting patient-derived fibroblasts bearing the common c.-32-13T>G with the best performing modified U1 snRNA. Modified U1-3, U1+1 and U1+6 snRNAs were all able to increase, in a dose-dependent manner, the inclusion of exon 2 within the transcript derived from the GAA minigene harbouring the c.-32-13T>G variant. The U1+1 was the most effective one (2,5 fold increase). Moreover, U1+1 snRNA partially rescued the correct splicing of GAA minigenes harbouring mutations that affect the 3'ss (c.-32-3C>G, c.-32-2A>G) and the 5'ss (c.546G>A, c.546G>C, c.546G>T). Notably, the treatment of patient-derived fibroblasts carrying the c.-32-13T>G mutation with the U1+1 snRNA increased the amount of normal GAA mRNA by 1,8 fold and the GAA enzymatic activity by 70%. we provide the proof-of-concept for the use of modified GAA-tailored U1 snRNAs, designed to potentiate the recognition of the GAA exon 2 5'ss, as therapeutic tools to correct the aberrant transcripts carrying variants that affect exon 2 splicing, including the common c.-32-13T>G variant.
2025-01-08 | Challenges in multinational rare disease clinical studies during COVID-19: regulatory assessment of cipaglucosidase alfa plus miglustat in adults with late-onset Pompe disease.
PROPEL (ATB200-03; NCT03729362) compared the efficacy and safety of cipaglucosidase alfa plus miglustat (cipa + mig), a two-component therapy for late-onset Pompe disease (LOPD), versus alglucosidase alfa plus placebo (alg + pbo). The primary endpoint was change in 6-min walk distance (6MWD) from baseline to week 52. During PROPEL, COVID-19 interrupted some planned study visits and assessment windows, leading to delayed visits, make-up assessments for patients who missed ≥ 3 successive infusions before planned assessments at weeks 38 and 52, and some advanced visits (end-of-study/early-termination visits). These were remapped to the respective planned visits. To evaluate if remapping may have overestimated treatment effects, we conducted post hoc analyses using a mixed-effect model for repeated measures based on actual time points of assessments. In this post hoc analysis, estimated mean treatment difference between cipa + mig and alg + pbo for change from baseline to week 52 in 6MWD was 11.7 m (95% confidence interval [CI] - 1.0 to 24.4; p = 0.072). In the original published analyses, between-group difference using last observation carried forward was 13.6 m (95% CI - 2.8 to 29.9; p = 0.071 [p value from separate non-parametric analysis of covariance]). Both statistical analysis approaches led to similar results and consistent conclusions, confirming the efficacy of cipa + mig for adults with LOPD. NCT03729362; trial start date: December 4, 2018.Trial registration number.
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Drug Discovery Landscape
31 orphan drug designations for Glycogen storage disease due to acid maltase deficiency, including 3 approved therapies.
31 orphan drug designations for Glycogen storage disease due to acid maltase deficiency, including 3 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
non-replicating single stranded recombinant adeno-associated viral vector with a thyroxine hormone binding globulin (THBG) promoter expressing the modified human acid alpha-glucosidase gene (hGAA) | gene therapies | FDA | AskBio Inc. | |
recombinant adeno-associated virus serotype 9 vector expressing codon optimized human GAA gene | gene therapies | FDA | Beijing Genecradle Therapeutics Co., Ltd. | |
Autologous CD34+ cells transduced with a lentiviral vector containing the human GAA gene | gene therapies | EMA | — | Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC) |
selective inhibitor of GYS1 | proteins | FDA | Shionogi Inc. | |
CD71 Binding Centyrin-GYS1 siRNA | RNAs | FDA | Aro Biotherapeutics Company | |
Adeno-associated viral vector expressing acid alpha-glucosidase gene | gene therapies | EMA | Astellas Pharma Europe B.V. | |
recombinant adeno-associated viral vector serotype 8 encoding human acid alpha-glucosidase | gene therapies | FDA | Astellas Gene Therapies, Inc. | |
Vanglusagene ensiparvovec | gene therapies | EMA | Spark Therapeutics Ireland Limited | |
recombinant adeno-associated viral (AAV) vector that contains a bio-engineered capsid (AAV-Spark100) and a codon-optimized expression cassette to drive expression of a secretable form of human acid a-glucosidase (GAA) | gene therapies | FDA | Genentech, Inc., a Member of the Roche Group | |
Miglustat [Opfolda] | small molecules | EMA | Amicus Therapeutics Europe Limited | |
clervonafusp alfa | proteins | FDA | Valerion Therapeutics, LLC | |
Adeno-associated viral vector expressing acid alpha-glucosidase gene | gene therapies | EMA | [INACTIVE] AskBio France | |
Alglucosidase alfa [Pombiliti] | proteins | EMA | Amicus Therapeutics Europe Limited | |
cipaglucosidase alfa-atga and miglustat [Pombiliti and Opfolda] | proteins | FDA | Approved | Amicus Therapeutics, Inc. |
Non-replicating recombinant adeno-associated viral vector expressing the human acid alpha-glucosidase gene | gene therapies | FDA | Asklepios Biopharmaceutics, Inc | |
clenbuterol | small molecules | FDA | Avenue Therapeutics, Inc. | |
Recombinant human acid alpha-glucosidase conjugated with mannose-6-phosphate analogues | proteins | EMA | — | NanoMedSyn |
clenbuterol | proteins | FDA | Duke University Medical Center | |
Avalglucosidase alfa [Nexviadyme] | proteins | EMA | Sanofi B.V. | |
avalglucosidase alfa-ngpt [Nexviazyme] | proteins | FDA | Approved | Genzyme Corporation, a Sanofi Company |
Recombinant adeno-associated viral vector containing human acid alfa-glucosidase-gene | gene therapies | EMA | Sarepta Therapeutics Ireland Limited | |
Glycosylation independent lysosomal targeting tagged recombinant human acid alpha glucosidase | proteins | EMA | BioMarin International Limited | |
reveglucosidase alfa | proteins | FDA | BioMarin Pharmaceutical, Inc. | |
Triheptanoin | small molecules | FDA | — | Baylor Research Institute |
RECOMBINANT ADENO-ASSOCIATED VIRAL VECTOR CONTAINING THE HUMAN ACID ALFA-GLUCOSIDASE GENE | gene therapies | EMA | TMC Pharma Services Limited | |
duvoglustat hydrochloride | small molecules | FDA | Amicus Therapeutics, Inc | |
Adeno-associated viral vector expressing human acid alpha glucosidase gene | gene therapies | FDA | Audentes Therapeutics, Inc. | |
Alglucosidase alfa [Myozyme] | proteins | EMA | Approved | [INACTIVE] Sanofi B.V. |
Recombinant human highly phosphorylated acid alpha-glucosidase | proteins | FDA | — | Novazyme Pharmaceuticals, Inc. |
Recombinant human acid alpha-glucosidase; alglucosidase alfa [1. Myozyme 2. Lumizyme] | proteins | FDA | Approved | Genzyme Corporation |
Human acid precursor alpha-glucosidase, recombinant | proteins | FDA | Pharming/Genzyme LLC |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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