Systemic Delivery of AAVB1-<i>GAA</i>Clears Glycogen and Prolongs Survival in a Mouse Model of Pompe Disease

Keeler, Allison M.; Zieger, Marina; Todeasa, Sophia H.; McCall, Angela L; Gifford, Jennifer C.; Birsak, Samantha; Choudhury, Sourav; Byrne, Barry J.; Sena‐Esteves, Miguel; ElMallah, Mai K.

doi:10.1089/hum.2018.016

Cited by 34 publications

(54 citation statements)

References 54 publications

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“…Here, we show that stress conditions can result in persistent respiratory muscle defects. Lipid accumulation was seen in the muscles of respiration and we surmise that, similar to other disorders of excess substance accumulation, the excess fat accumulation impacts muscle contraction . Therefore, future therapeutic studies using the VLCAD −/− mouse model should evaluate impacts of the intervention on respiratory insufficiency and restrictive lung disease.…”

Section: Resultsmentioning

confidence: 69%

“…However, the respiratory rate could be corrected to WT levels by providing an alternative energy source, in this case therapeutic treatment with dextrose. The peak inspiratory flow and peak expiratory flow reflect inspiratory and expiratory muscle strength, primarily in the diaphragm and intercostals . Interestingly, the peak inspiratory and expiratory flows were not improved following dextrose administration.…”

Section: Discussionmentioning

confidence: 99%

“…Genomic DNA extraction and quantitative‐PCR . DNA was extracted and quantified as previously described . See Supporting Information for details.…”

Section: Methodsmentioning

confidence: 99%

“…These studies determined the impact of VLCADD on ventilation. Ventilation was quantified using whole‐body plethysmography in unrestrained, unanesthetized mice as previously described . See Supporting Information for details.…”

Section: Methodsmentioning

confidence: 99%

“…The peak inspiratory flow and peak expiratory flow reflect inspiratory and expiratory muscle strength, primarily in the diaphragm and intercostals. 14,15,18 Interestingly, the peak inspiratory and expiratory flows were not improved following dextrose administration. Thus, the normalization of the respiratory rate is most likely because of energy rescue, whereas the lack of response in the peak inspiratory and expiratory flows and tidal volumes is most likely a reflection of persistent muscular pathology.…”

Section: Impact Of Vlcadd On Breathingmentioning

confidence: 96%

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AAV9 gene replacement therapy for respiratory insufficiency in very‐long chain acyl‐CoA dehydrogenase deficiency

Zieger

Keeler

Flotte

et al. 2019

J of Inher Metab Disea

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Very‐long chain acyl‐CoA dehydrogenase (VLCAD) deficiency (VLCADD) is an autosomal recessive disorder of fatty acid oxidation. Fatty acids are a major source of energy during catabolic stress, so the absence of VLCAD can result in a metabolic crises and respiratory insufficiency. The etiology of this respiratory insufficiency is unclear. Thus, our aims were: (1) to characterize respiratory pathophysiology in VLCADD mice (VLCAD−/−), and (2) to determine if AAV9‐mediated gene therapy improves respiratory function. For the first aim, VLCAD−/− and wild‐type (WT) mice underwent an exercise/fast “stress protocol” and awake spontaneous breathing was evaluated using whole‐body plethysmography (WBP) both at baseline and during a hypercapnic respiratory challenge (FiO2: 0.21; FiCO2: 0.07; nitrogen balance). During hypercapnia, VLCAD −/− mice had a significantly lower frequency, tidal volume, minute ventilation, and peak inspiratory and expiratory flow, all of which indicate respiratory insufficiency. Histologically, the cardiac and respiratory muscles of stressed VLCAD −/− animals had an accumulation of intramyocellular lipids. For the second aim, a single systemic injection of AAV9‐VLCAD gene therapy improved this respiratory pathology by normalizing breathing frequency and enhancing peak inspiratory flow. In addition, following gene therapy, there was a moderate reduction of lipid accumulation in the respiratory muscles. Furthermore, VLCAD protein expression was robust in cardiac and respiratory muscle. This was confirmed by immuno‐staining with anti‐human VLCAD antibody. In summary, stress with exercise and fasting induces respiratory insufficiency in VLCAD−/− mice and a single injection with AAV9‐VLCAD gene therapy ameliorates breathing.

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Section: Resultsmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

“…Genomic DNA extraction and quantitative‐PCR . DNA was extracted and quantified as previously described . See Supporting Information for details.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Impact Of Vlcadd On Breathingmentioning

confidence: 96%

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AAV9 gene replacement therapy for respiratory insufficiency in very‐long chain acyl‐CoA dehydrogenase deficiency

Zieger

Keeler

Flotte

et al. 2019

J of Inher Metab Disea

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Gene therapy for glycogen storage diseases

Koeberl

Koch

Lim

et al. 2023

J of Inher Metab Disea

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Glycogen storage disorders (GSDs) are inherited disorders of metabolism resulting from the deficiency of individual enzymes involved in the synthesis, transport, and degradation of glycogen. This literature review summarizes the development of gene therapy for the GSDs. The abnormal accumulation of glycogen and deficiency of glucose production in GSDs lead to unique symptoms based upon the enzyme step and tissues involved, such as liver and kidney involvement associated with severe hypoglycemia during fasting and the risk of long‐term complications including hepatic adenoma/carcinoma and end stage kidney disease in GSD Ia from glucose‐6‐phosphatase deficiency, and cardiac/skeletal/smooth muscle involvement associated with myopathy +/− cardiomyopathy and the risk for cardiorespiratory failure in Pompe disease. These symptoms are present to a variable degree in animal models for the GSDs, which have been utilized to evaluate new therapies including gene therapy and genome editing. Gene therapy for Pompe disease and GSD Ia has progressed to Phase I and Phase III clinical trials, respectively, and are evaluating the safety and bioactivity of adeno‐associated virus vectors. Clinical research to understand the natural history and progression of the GSDs provides invaluable outcome measures that serve as endpoints to evaluate benefits in clinical trials. While promising, gene therapy and genome editing face challenges with regard to clinical implementation, including immune responses and toxicities that have been revealed during clinical trials of gene therapy that are underway. Gene therapy for the glycogen storage diseases is under development, addressing an unmet need for specific, stable therapy for these conditions.

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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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Systemic Delivery of AAVB1-GAAClears Glycogen and Prolongs Survival in a Mouse Model of Pompe Disease

Cited by 34 publications

References 54 publications

AAV9 gene replacement therapy for respiratory insufficiency in very‐long chain acyl‐CoA dehydrogenase deficiency

AAV9 gene replacement therapy for respiratory insufficiency in very‐long chain acyl‐CoA dehydrogenase deficiency

Gene therapy for glycogen storage diseases

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

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