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Gene therapy with an adeno-associated virus serotype 8 (AAV8) vector (AAV8-LSPhGAA) could eliminate the need for enzyme replacement therapy (ERT) by creating a liver depot for acid α-glucosidase (GAA) production. We report initial safety and bioactivity of the first dose (1.6 × 10 12 vector genomes/kg) cohort (n = 3) in a 52-week open-label, single-dose, dose-escalation study (NCT03533673) in patients with late-onset Pompe disease (LOPD). Subjects discontinued biweekly ERT after week 26 based on the detection of elevated serum GAA activity and the absence of clinically significant declines per protocol. Prednisone (60 mg/day) was administered as immunoprophylaxis through week 4, followed by an 11-week taper. All subjects demonstrated sustained serum GAA activities from 101% to 235% of baseline trough activity 2 weeks following the preceding ERT dose. There were no treatment-related serious adverse events. No subject had anti-capsid T cell responses that decreased transgene expression. Muscle biopsy at week 24 revealed unchanged muscle glycogen content in two of three subjects. At week 52, muscle GAA activity for the cohort was significantly increased (p < 0.05). Overall, these initial data support the safety and bioactivity of AAV8-LSPhGAA, the safety of withdrawing ERT, successful immunoprophylaxis, and justify continued clinical development of AAV8-LSPhGAA therapy in Pompe disease., Competing Interests: Declaration of interests D.D.K. and P.S.K. have developed the technology that is being used in the study. If the technology is commercially successful in the future, the developers and Duke University may benefit financially. D.D.K. has served as a consultant for Sangamo Therapeutics and for Genzyme Sanofi, Amicus, and Vertex; has received grant support from Viking Therapeutics, Genzyme Sanofi, Roivant Rare Diseases, and Amicus; and has equity in Askbio, which is developing gene therapy for Pompe disease. E.C.S. received salary support for his role as PI on this study. S.H. is an employee of Askbio. L.E.C. has received honoraria from Genzyme Sanofi, has participated in research supported by Genzyme Sanofi, Valerion, Biomarin, and by Roivant Sciences; and is a member of the Pompe Registry North American Board of Advisors Genzyme Sanofi. D.B. has received research grant support and travel funds from Genzyme Sanofi, Baebies Inc., Biomarin, Alexion Inc., SOBI biopharma, and JCR biopharma. P.S.K. has received research/grant support from Genzyme Sanofi and Valerion Therapeutics. She received consulting fees and honoraria from Genzyme Sanofi, Amicus Therapeutics, and Vertex. She is a member of the Pompe and Gaucher Disease Registry Advisory Board for Genzyme Sanofi and on the Amicus Scientific advisory board., (Copyright © 2023 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Purpose: Enzyme replacement therapy (ERT) with recombinant human acid-α glucosidase (rhGAA) at standard dose of 20 mg/kg every other week is insufficient to halt the long-term progression of myopathy in Pompe disease., Methods: We conducted a retrospective study on infantile-onset Pompe disease (IPD) and late-onset Pompe disease (LOPD) patients with onset before age 5 years, ≥12 months of treatment with standard dose ERT, and rhGAA immunogenic tolerance prior to dose escalation. Long-term follow-up of up to 18 years was obtained. We obtained physical therapy, lingual strength, biochemical, and pulmonary assessments as dose was escalated., Results: Eleven patients with IPD (n = 7) or LOPD (n = 4) were treated with higher doses of up to 40 mg/kg weekly. There were improvements in gross motor function measure in 9/10 patients, in lingual strength in 6/6 patients, and in pulmonary function in 4/11. Significant reductions in urinary glucose tetrasaccharide, creatine kinase, aspartate aminotransferase, and alanine aminotransferase were observed at 40 mg/kg weekly compared with lower doses (p < 0.05). No safety or immunogenicity concerns were observed at higher doses., Conclusion: Higher rhGAA doses are safe, improve gross motor outcomes, lingual strength, pulmonary function measures, and biochemical markers in early-onset Pompe disease, and should be considered in patients with clinical and functional decline.

Objectives: To report the respiratory function of school-aged children with infantile Pompe disease (IPD) who started enzyme replacement therapy (ERT) in infancy and early childhood., Study Design: This is a retrospective chart review of pulmonary function tests of: (a) patients with IPD 5 to 18 years of age, (b) who were not ventilator dependent, and (c) were able to perform upright and supine spirometry. Subjects were divided into a younger (5-9 years) and older cohort (10-18 years) for the analysis. Upright and supine forced vital capacity (FVC), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP) were analyzed., Results: Fourteen patients, all cross-reactive immunologic material (CRIM)-positive, met the inclusion criteria and were included in this study. Mean upright and supine FVC were 70.3% and 64.9% predicted, respectively, in the 5- to 9-year-old cohort; and 61.5% and 52.5% predicted, respectively, in the 10- to 18-year-old group. Individual patient trends showed stability in FVC overtime in six of the 14 patients. MIPs and MEPs were consistent with inspiratory and expiratory muscle weakness in the younger and older age group but did not decline with age., Conclusion: Data from this cohort of CRIM-positive patients with IPD showed that ERT is able to maintain respiratory function in a subgroup of patients whereas others had a steady decline. There was a statistically significant decline in FVC from the upright to a supine position in both the younger and older age groups of CRIM-positive ERT-treated patients. Before ERT, patients with IPD were unable to maintain independent ventilation beyond the first few years of life., (© 2020 Wiley Periodicals, Inc.)

Infantile Pompe disease is a rare, metabolic disorder due to deficiency of the enzyme acid α-glucosidase that degrades lysosomal glycogen. The deficiency leads to multisystem dysfunction. Neuromuscular weakness due to metabolic myopathy is present, which predisposes children to sleep-disordered breathing. With the advent of enzyme replacement therapy (ERT), children are living longer, and there is a new natural history that is emerging. In a prior paper on our cohort of infantile Pompe disease patients, we reported a high incidence of both hypoventilation and obstructive sleep apnea (OSA). In this retrospective study, we analyzed longitudinal nocturnal polysomnography results from 10 patients with infantile-onset Pompe disease, all of which were on enzyme replacement therapy for a mean of 34.9 months at the time of follow-up study. Patients demonstrated relative stability in sleep disordered breathing, with a trend towards improvement in both OSA and central sleep apnea. ERT may help in the treatment of sleep apnea in this cohort., (© 2015 Wiley Periodicals, Inc.)

Emerging phenotypes in long-term survivors with Pompe disease on standard enzyme replacement therapy (ERT) (alglucosidase alfa 20 mg/kg/2 weeks) can include patients with worsening motor function. Whether higher doses of ERT improve skeletal function in these patients has not been systematically studied. This exploratory, randomized, open-label, 52-week study examined the safety and efficacy of 2 ERT regimens of alglucosidase alfa (20 mg/kg/week or 40 mg/kg/2 weeks) in 13 patients with Pompe disease and clinical decline or a lack of improvement on standard ERT: late-onset (n = 4), infantile-onset (n = 9). Cross-reactive immunologic material assay-negative patients were excluded. Eleven of 13 patients completed the study. Trends for improvement were seen in total gross motor function, but not mobility; however, 6 (late-onset, 2; infantile-onset, 4) of 11 patients (55%) who met the entry criteria of motor decline (late-onset, 4; infantile-onset, 7) showed improvement in motor and/or mobility skills. No between-regimen differences in efficacy emerged. Two case studies highlight the benefits of increased ERT dose in patients with Pompe disease experiencing clinical decline. Both alternative regimens were generally well tolerated. This study was limited by the small sample size, which is not uncommon for small clinical studies of rare diseases. Additionally, the study did not include direct assessment of muscle pathology, which may have identified potential causes of decreased response to ERT. Results were inconclusive but suggest that increased ERT dose may be beneficial in some patients with Pompe disease experiencing motor decline. Controlled studies are needed to clarify the benefits and risks of this strategy., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To report the ophthalmologic and histologic findings in a series of children with infantile Pompe disease treated with enzyme replacement therapy (ERT)., Methods: Records of children with infantile Pompe disease treated with ERT who had at least one complete ophthalmic examination and the ocular histopathology of children with infantile Pompe disease who were treated with ERT were reviewed. The patients' clinical history, including external ocular examination, ocular alignment and motility, dilated fundus examination, and cycloplegic refraction, was evaluated. A literature review was performed for ophthalmologic findings in infantile Pompe disease using PubMed., Results: The clinical findings of 13 children were included and the ocular histopathology of 3 children with infantile Pompe disease who were treated with ERT were reviewed. Forty-six percent (6 of 13) had bilateral ptosis, 23% (3 of 13) had strabismus, 62% (8 of 13) had myopia, and 69% (9 of 13) had astigmatism. On histologic examination, there was vacuolar myopathy affecting the extraocular muscles, ciliary body, and iris smooth muscle and glycogen accumulation in corneal endothelial, lens epithelium, and retinal ganglion cells, and within lysosomes of scleral fibroblasts., Conclusions: It is important that ophthalmic providers are aware of the high prevalence of myopia, astigmatism, and ptosis in children with infantile Pompe disease treated with ERT because they are potentially amblyogenic but treatable factors., (Copyright 2014, SLACK Incorporated.)

Infantile Pompe disease is a rare, autosomal recessive disorder due to deficiency of the enzyme acid α-glucosidase that degrades lysosomal glycogen. Clinical features of diffuse hypotonia, cardiomyopathy, and weakness are present within the first days to months of life in patients with classic infantile Pompe disease. Progression of the disease often leads to respiratory failure. Although sleep apnea is reported in late-onset Pompe disease, sleep pathology is not well characterized in infantile disease. In this retrospective study, we analyzed nocturnal polysomnography results from 17 patients with infantile-onset Pompe disease. Obstructive sleep apnea and hypoventilation were common among this cohort, even in those that did not have symptoms of sleep-disordered breathing. All patients with infantile-onset Pompe disease should undergo polysomnography as a routine part of their care., (© 2013 Wiley Periodicals, Inc.)

Objective: Pompe disease is a neuromuscular disorder that was progressive and fatal prior to enzyme replacement therapy (ERT). The advent of treatment has made early recognition imperative. Electrodiagnostic (EDx) studies represent a valuable diagnostic tool in Pompe disease, but there has been little contemporary data., Methods: The records of 29 patients with Pompe disease who had undergone EDx evaluation at Duke University Medical Center from 1999 to 2010 were reviewed., Results: Seventeen children and twelve adults comprised the group. The clinical characteristics of both groups did not differ from expected. Needle electromyography demonstrated spontaneous activity (SA) in 80% of children and 83% of adults. Myotonic discharges were found in 53% of children and 72% of adults, often isolated to the paraspinal muscles in adults. Eight patients had EDx studies performed after ERT with 3 showing improvement after therapy, despite clinical improvement in 6 of 8., Conclusions: EDx studies remain a helpful tool in diagnosing Pompe disease, but do not appear to be sensitive for monitoring response to ERT based upon this limited sample., Significance: Paraspinal examination is necessary in adults with symptoms suggestive of Pompe disease, as abnormalities may be isolated to this region. Standard EDx studies are not sufficient to monitor early response to ERT and further research on potential biomarkers is needed., (Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Purpose: Pompe disease (PD) is a progressive metabolic myopathy for which the only available treatment is alglucosidase alfa (Myozyme®). Enzyme replacement therapy (ERT) has improved ventilator-free survival, and cardiac and motor functions in patients with infantile PD. However, for an adequate response to occur, a large amount of enzymes must be infused. In some patients, this may be problematic due to infusion-associated reactions (IARs) occurring in approximately 50% of patients receiving alglucosidase alfa infusions. Whilst the majority of these reactions are mild, life threatening hypersensitivity reactions may occur in some patients. In these patients desensitization is indicated to enable continued ERT safely. Infants and young children with PD and significant infusion reactions pose unique management challenges because of their young age, limited communication skills, variable presentation and underlying cardiomyopathy., Methods/subjects: In 2 patients with PD who experienced significant ERT-related reactions: an infant (IgE positive) and a young child (IgE negative), we implemented a desensitization protocol, that started by administering a reduced dose of alglucosidase alfa (10 mg/kg weekly) instead of the standard (20 mg/kg bi-weekly) using serial micro-dilutions that were individually prepared and delivered in a highly regulated manner based on patients' clinical manifestations and tolerance., Results: Successful desensitization was achieved in both patients, allowing them to eventually continue to receive the full dose of ERT safely., Conclusion: Therapeutic demands in infants and young children with PD need to be tailored according to the patient presentation, and underlying cardiac and fluid-volume status. Desensitization allowed both patients to continue alglucosidase alfa treatment at the recommended dose without prolonged interruption of therapy, or further reactions., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Pompe disease (acid α-glucosidase deficiency) is one of several lysosomal storage diseases amenable to treatment with enzyme replacement therapy (ERT). While echocardiography (echo) has been the standard method to evaluate the cardiac response to ERT, cardiac magnetic resonance imaging (CMR) has the advantage of a better tissue definition and characterization of myocardial fibrosis. However, CMR for Pompe disease is not frequently performed due to a high risk of sedation. We report the first use of CMR in a feasible protocol to quantify left ventricular (LV) mass, function, and the presence of myocardial fibrosis in the Pompe population., Methods: Children with Pompe disease on ERT were assessed with transthoracic echo and CMR over a 3 year period at a single institution. Echocardiography was performed using standard techniques without sedation. CMR was performed using retrospectively gated and real-time imaging, with and without sedation. LV mass indexed to body surface area (LVMI) and ejection fraction (EF) were measured by both echo and CMR, and evaluated for change over time. Myocardial fibrosis was assessed by CMR with delayed enhancement imaging 5-10 min after gadolinium contrast using single shot inversion recovery sequences with inversion time set to null the signal from normal myocardium., Results: Seventeen CMR scans were successfully performed in 10 subjects with Pompe disease (median age at first CMR is 9 months, range 1-38 months, 80% male), with sedation only performed in 4 studies. There was a median interval of 5 months (range 0-34 months) from the start of ERT to first CMR (baseline). At baseline, the median indexed LVMI by CMR (140.0 g/m(2), range 43.8-334.0) tended to be lower than that assessed by echo (median 204.0 g/m(2), range 52.0-385.0), but did not reach statistical significance. At baseline, CMR EF was similar to that assessed by echo (55% vs. 55%). Overall, there was no significant decrease in CMR measured LVMI over time (CMR median LVMI at baseline 94 g/m(2) (range 43.8-334) vs. CMR median at most recent study 44.5 g/m(2) (range 34-303), p=0.44). In 5 patients with serial CMR scans over time, LVMI decreased in 2, was similar in 2, and increased in 1 patient with high sustained antibodies to exogenous enzyme. Delayed enhancement was noted in only l separate patient who also had high sustained antibodies to exogenous enzyme., Conclusion: CMR is an imaging tool that is feasible to use to serially follow LVMI and EF in children with Pompe disease on ERT. Real-time imaging is adequate for quantification purposes in these patients and minimizes the need for sedation. Quantitative CMR LVMI is generally lower than echo derived LVMI. Delayed enhancement appears to be a rare finding by CMR in Pompe disease. A further follow-up is necessary to better understand the long term effects of ERT in infantile Pompe survivors, especially those with high sustained antibody titers or advanced cardiac disease at treatment outset., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: Pompe disease (glycogen storage disease type II or acid maltase deficiency) is an autosomal recessive disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). Classic infantile-onset disease, characterized by cardiomegaly and profound weakness, leads to death in the first year of life from cardiorespiratory failure. Reversal of cardiomyopathy and improved motor function have been shown in clinical trials of rhGAA enzyme replacement therapy (ERT) with alglucosidase alfa (Myozyme), recently approved for clinical use. Increased survival potentially unmasks long-term complications of this previously lethal disease, including risk of skeletal fracture, recently identified at our institution and not previously reported in children with Pompe disease., Objective: To report the risk of fracture in children with Pompe disease with increased survival with ERT., Materials and Methods: We present four cases of fracture in patients with classic infantile Pompe disease treated with ERT at our institution, and review a study database for additional reports of fracture in this population., Results: We review 19 fractures in 14 children with Pompe disease on ERT., Conclusion: Radiologists should be familiar with and vigilant for the association of fractures and increased survival on ERT in children with Pompe disease. We discuss potential mechanisms, implications for radiographic surveillance, potential intervention, and needs for further research.