Stimulation of Respiratory Motor Output and Ventilation in a Murine Model of Pompe Disease by Ampakines

ElMallah, Mai K.; Pagliardini, Silvia; Turner, Scott A.; Cerreta, Anthony J.; Falk, Darin J.; Byrne, Barry J.; Greer, John J.; Fuller, David D.

doi:10.1165/rcmb.2014-0374oc

Cited by 42 publications

(62 citation statements)

References 56 publications

(98 reference statements)

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“…Despite the significant improvement in ventilator‐free survival in CRIM‐positive patients with Pompe disease, there continues to be evidence of respiratory insufficiency. The respiratory system is affected in Pompe disease with glycogen accumulation occurring in the diaphragm, 3 the tongue, 35 the tracheal smooth muscle, 36 and in the respiratory motor neurons 35,37 . In this current case series, there is a variable course with some patients showing an annual decline in FVC and others showing an improvement.…”

Section: Discussionmentioning

confidence: 62%

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: 62%

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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“…1A). In contrast, PAS staining revealed prototypical Pompe motoneuron histopathology (DeRuisseau et al, 2009; ElMallah et al, 2014; ElMallah et al, 2015; Lee et al, 2011) throughout the Gaa −/− hypoglossal nucleus. Thus, hypoglossal motoneurons were robustly PAS positive in Gaa −/− medullary sections, with a swollen soma including numerous vacuoles (Fig.…”

Section: Resultsmentioning

confidence: 81%

Neuropathology in respiratory-related motoneurons in young Pompe (Gaa) mice

Turner

Hoyt

ElMallah

et al. 2016

Respiratory Physiology & Neurobiology

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Respiratory and/or lingual dysfunction are among the first motor symptoms in Pompe disease, a disorder resulting from absence or dysfunction of the lysosomal enzyme acid α-glucosidase (GAA). Here, we histologically evaluated the medulla, cervical and thoracic spinal cords in 6 weeks old asymptomatic Pompe (Gaa−/−) mice to determine if neuropathology in respiratory motor regions has an early onset. Periodic acid-Schiff (PAS) staining indicated glycogen accumulation was exclusively occurring in Gaa−/− hypoglossal, mid-cervical and upper thoracic motoneurons. Markers of DNA damage (Tunel) and ongoing apoptosis (Cleaved Caspase 3) did not co-localize with PAS staining, but were prominent in a medullary region which included the nucleus tractus solitarius, and also in the thoracic spinal dorsal horn. We conclude that respiratory-related motoneurons are particularly susceptible to GAA deficiency and that neuronal glycogen accumulation and neurodegeneration may occur independently in early stage disease. The data support early therapeutic intervention in Pompe disease.

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“…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%

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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Stimulation of Respiratory Motor Output and Ventilation in a Murine Model of Pompe Disease by Ampakines

Cited by 42 publications

References 56 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

Neuropathology in respiratory-related motoneurons in young Pompe (Gaa) mice

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

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