Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance Induction

Han, Sang-oh; Ronzitti, Giuseppe; Arnson, Benjamin; Leborgne, Christian; Li, Songtao; Mingozzi, Federico; Koeberl, Dwight D.

doi:10.1016/j.omtm.2019.04.005

Cited by 8 publications

(13 citation statements)

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“…In conclusion, this study is the first to report the respiratory function of CRIM‐positive patients with IPD who commenced ERT in the first year of life. In preparation for upcoming clinical trials involving novel ERTs and gene therapy, 55,56 this respiratory function information provides a baseline so we can better evaluate the impact of future therapies.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary outcome measures in long‐term survivors of infantile Pompe disease on enzyme replacement therapy: A case series

ElMallah

Desai

Nading

et al. 2020

Pediatric Pulmonology

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

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Section: Discussionmentioning

confidence: 99%

Pulmonary outcome measures in long‐term survivors of infantile Pompe disease on enzyme replacement therapy: A case series

ElMallah

Desai

Nading

et al. 2020

Pediatric Pulmonology

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“…During inspiration, the primary muscle in use is the diaphragm which is controlled by phrenic motor neurons. The diaphragm of Pompe mice have accumulation of glycogen and decreased contractile force when stimulated [36,37,42,[46][47][48]50,51,53,[55][56][57][58][59]. In addition, the phrenic nerves have a decreased ability to stimulate the diaphragm due to glycogen accumulation in the phrenic motor neuron cell bodies and axons, neurodegeneration of the phrenic motor neurons, and denervation of the diaphragm [40,43,45,48,51,[60][61][62].…”

Section: Discussionmentioning

confidence: 99%

“…Gaa -/-mice on both the B6/129 and the pure 129SVE background lack GAA protein and GAA activity in the diaphragm [50][51][52][53][54]. As a result, the diaphragms of these Gaa -/-mice and the mice created by Bijvoet et al have significant glycogen accumulation as demonstrated by positive periodic acid-Schiff (PAS+) staining and mass spectrometry [36,37,46,47,50,51,[53][54][55][56][57]. Mass spectrometry provides evidence that Gaa -/-mice are born with glycogen accumulation in the diaphragm that progressively increases throughout life [55].…”

Section: Diaphragm and Phrenic Motor Neuron Pathologymentioning

confidence: 99%

“…Similarly, the model developed by Raben et al, in which exon 6 is disrupted, has progressive accumulation of lysosomal glycogen in the muscles and motor neurons but does not display obvious muscle wasting and weakness until 8-9 months of age [37]. Several researchers have back-crossed this Gaa -/-to pure backgrounds, either 129SVE [38][39][40][41][42][43][44][45] or C57BL/6 [46,47]. The Gaa -/-mouse on the pure 129SVE background is thought to have less severe respiratory deficits as compared to the Gaa -/-mouse on the mixed B6/129 background [39,42,48], however, overall respiratory function has not been assessed in the Gaa -/-mouse on the C57BL/6 background.…”

Section: Introductionmentioning

confidence: 99%

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The Respiratory Phenotype of Pompe Disease Rodent Models

Fusco¹,

McCall²,

Dhindsa³

et al. 2020

Preprint

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Pompe disease is a glycogen storage disease caused by a deficiency in acid α-glucosidase (GAA) – a hydrolase necessary for the degradation of lysosomal glycogen. This deficiency in GAA results in muscle and neuronal glycogen accumulation, which causes respiratory insufficiency. Pompe disease rodent models provide a means of assessing respiratory pathology and are important for pre-clinical studies of novel therapies that aim to treat respiratory dysfunction and improve quality of life. This review aims to compile and summarize existing manuscripts which characterize the respiratory phenotype of Pompe rodent models. Manuscripts included in this review were selected utilizing specific search terms and exclusion criteria. Analysis of these findings demonstrate that Pompe disease rodent models have respiratory physiological defects as well as pathologies in the diaphragm, tongue, phrenic and hypoglossal motor nucleus, phrenic and hypoglossal nerves, neuromuscular junctions, and airway smooth muscle and higher order respiratory control centers. Overall, the culmination of these pathologies contributes to severe respiratory dysfunction, underscoring the importance of characterizing the respiratory phenotype while developing effective therapies for patients.

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“…GAA activity was increased in the liver following both ERT and AAV administration, and glycogen content was reduced in both the myocardium and diaphragm. Following the identification of the minimum effective dose (8 x 10 10 vg/kg), Hann et al confirmed that the administration of low dose AAV2/8-LSPhGAA prevents the humoral responses to GAA and that the liver expression of GAA provides cross-correction in distant organs by virtue of continuous secretion of GAA from the liver [123].…”

Section: Liver-directed Gaa Expressionmentioning

confidence: 99%

Advancements in AAV-mediated Gene Therapy for Pompe Disease

Salabarria

Nair

Clément

et al. 2020

JND

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Pompe disease (glycogen storage disease type II) is caused by mutations in acid ␣-glucosidase (GAA) resulting in lysosomal pathology and impairment of the muscular and cardio-pulmonary systems. Enzyme replacement therapy (ERT), the only approved therapy for Pompe disease, improves muscle function by reducing glycogen accumulation but this approach entails several limitations including a short drug half-life and an antibody response that results in reduced efficacy. To address these limitations, new treatments such as gene therapy are under development to increase the intrinsic ability of the affected cells to produce GAA. Key components to gene therapy strategies include the choice of vector, promoter, and the route of administration. The efficacy of gene therapy depends on the ability of the vector to drive gene expression in the target tissue and also on the recipient's immune tolerance to the transgene protein. In this review, we discuss the preclinical and clinical studies that are paving the way for the development of a gene therapy strategy for patients with early and late onset Pompe disease as well as some of the challenges for advancing gene therapy.

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Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance Induction

Cited by 8 publications

References 0 publications

Pulmonary outcome measures in long‐term survivors of infantile Pompe disease on enzyme replacement therapy: A case series

Pulmonary outcome measures in long‐term survivors of infantile Pompe disease on enzyme replacement therapy: A case series

The Respiratory Phenotype of Pompe Disease Rodent Models

Advancements in AAV-mediated Gene Therapy for Pompe Disease

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