ポンペ病

BACKGROUND: 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. PURPOSE: 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. METHODS: 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. RESULT: 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. CONCLUSION: 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. CLINICAL TRIAL REGISTRATION: UMIN000039191, UMIN Clinical Trials Registry ( http://www.umin.ac.jp/ctr ).

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.

BACKGROUND: The impact of anti‑drug antibodies (ADAs) on the bioavailability of recombinant human acid α-glucosidase (rhGAA) in classic infantile Pompe disease remains incompletely understood. OBJECTIVE: The aim of this study was to investigate the effects of ADAs on the bioavailability of rhGAA in classic infantile Pompe disease. METHODS: We analyzed 15 pharmacokinetic (PK) curves from 13 patients receiving rhGAA. High titers were defined as ≥ 1:31250. Alpha-glucosidase activity in plasma was measured using protein A beads to precipitate ADA-bound rhGAA, and sepharose as control. Neutralizing effects were assessed in fibroblasts and culture medium after incubation with patient sera and a fixed amount of rhGAA. Peak activity (Cmax) and area under the curve (AUC) were calculated by non-compartmental analysis. RESULTS: rhGAA bioavailability was affected in six of nine high-titer patients (n = 1, 1:31,250; n = 5, ≥ 1:156,250). AUC was reduced by 11-52% in the protein A assay compared with sepharose (n = 5). Fibroblast uptake studies demonstrated neutralizing effects with intracellular enzyme activity reduced to 47-71% (n = 5). No ADA effect was detectable in three patients. At the group level, high-ADA patients showed significantly lower Cmax in both assays and a lower AUC in the protein A assay compared with non-high-ADA patients. Slower infusion schemes, as management for infusion-associated reactions, correlated inversely with Cmax (R = - 0.64), but not AUC. Immunomodulation eliminated the effects of ADAs, as shown in two patients. CONCLUSIONS: High ADAs have heterogenous effects on rhGAA bioavailability. Titers ≥1:156,250, mostly, had a measurable effect, capturing up to > 50% of infused rhGAA. A high titer, per se, did not imply neutralizing effects. Where available, functional assays, including PK curves and uptake studies, may contribute to characterize ADA effects.