scholarly journals The Respiratory Phenotype of Pompe Disease Rodent Models

2020 ◽  
Author(s):  
Anna Fusco ◽  
Angela McCall ◽  
Justin Dhindsa ◽  
Lucy Zheng ◽  
Aidan Bailey ◽  
...  
Keyword(s):  
Pompe Disease ◽  
Neuromuscular Junctions ◽  
Respiratory Control ◽  
Glycogen Storage ◽  
Motor Nucleus ◽  
Rodent Models ◽  
Respiratory Dysfunction ◽  
Glycogen Accumulation ◽  
Search Terms ◽  
Respiratory Pathology

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.

scholarly journals The Respiratory Phenotype of Pompe Disease Mouse Models

2020 ◽  
Vol 21 (6) ◽  
pp. 2256
Author(s):  
Anna F. Fusco ◽  
Angela L. McCall ◽  
Justin S. Dhindsa ◽  
Lucy Zheng ◽  
Aidan Bailey ◽  
...  
Keyword(s):  
Mouse Models ◽  
Pompe Disease ◽  
Neuromuscular Junctions ◽  
Respiratory Control ◽  
Glycogen Storage ◽  
Respiratory Dysfunction ◽  
Glycogen Accumulation ◽  
Search Terms ◽  
Respiratory Pathology

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 mouse 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 that characterize the respiratory phenotype of Pompe mouse models. Manuscripts included in this review were selected utilizing specific search terms and exclusion criteria. Analysis of these findings demonstrate that Pompe disease mouse models have respiratory physiological defects as well as pathologies in the diaphragm, tongue, higher-order respiratory control centers, phrenic and hypoglossal motor nuclei, phrenic and hypoglossal nerves, neuromuscular junctions, and airway smooth muscle. 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.

scholarly journals Newborn Screening for Pompe Disease

2020 ◽  
Vol 6 (2) ◽  
pp. 31
Author(s):  
Takaaki Sawada ◽  
Jun Kido ◽  
Kimitoshi Nakamura
Keyword(s):  
Enzyme Activity ◽  
Newborn Screening ◽  
Pompe Disease ◽  
Autosomal Recessive Disorder ◽  
Glycogen Storage Disease Type ◽  
Dried Blood Spots ◽  
Glycogen Storage ◽  
Glycogen Accumulation ◽  
Enzyme Replacement ◽  
Asian Populations

Glycogen storage disease type II (also known as Pompe disease (PD)) is an autosomal recessive disorder caused by defects in α-glucosidase (AαGlu), resulting in lysosomal glycogen accumulation in skeletal and heart muscles. Accumulation and tissue damage rates depend on residual enzyme activity. Enzyme replacement therapy (ERT) should be started before symptoms are apparent in order to achieve optimal outcomes. Early initiation of ERT in infantile-onset PD improves survival, reduces the need for ventilation, results in earlier independent walking, and enhances patient quality of life. Newborn screening (NBS) is the optimal approach for early diagnosis and treatment of PD. In NBS for PD, measurement of AαGlu enzyme activity in dried blood spots (DBSs) is conducted using fluorometry, tandem mass spectrometry, or digital microfluidic fluorometry. The presence of pseudodeficiency alleles, which are frequent in Asian populations, interferes with NBS for PD, and current NBS systems cannot discriminate between pseudodeficiency and cases with PD or potential PD. The combination of GAA gene analysis with NBS is essential for definitive diagnoses of PD. In this review, we introduce our experiences and discuss NBS programs for PD implemented in various countries.

Providing the conduit for treatment: The impact of vascular access and vein preservation in a 5-year-old child with prenatally diagnosed CRIM-negative Infantile Pompe disease

2021 ◽  
pp. 112972982199948
Author(s):  
Matthew Ostroff ◽  
Punita Gupta ◽  
Daniel Garcia
Keyword(s):  
Vascular Access ◽  
Pompe Disease ◽  
Disease Patient ◽  
Tolerance Induction ◽  
Glycogen Storage ◽  
Glycogen Accumulation ◽  
Enzyme Replacement ◽  
Infantile Pompe Disease ◽  
Glycogen Storage Disorder ◽  
The Impact

Pompe disease is an autosomal recessive glycogen storage disorder resulting in progressive glycogen accumulation expressed in infancy with cardiomyopathy and skeletal myopathy. Without treatment by enzyme replacement therapy (ERT), life expectancy is less than 2 years. The cross-reactive immunologic material (CRIM) positive or negative status is the basis for the response to ERT. CRIM-negative patients mount an immune response to ERT, making this the most dangerous presentation. The following case study describes the 5-year course of the first successful treatment of an in utero CRIM-negative Pompe disease patient with prophylactic immune tolerance induction (ITI) and administration of ERT given within the first 2 days of life followed by ultrasound guided vascular access that facilitated by bi-weekly infusions and extensive phlebotomy.

scholarly journals Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase

2017 ◽  
Vol 9 (418) ◽  
pp. eaam6375 ◽  
Author(s):  
Francesco Puzzo ◽  
Pasqualina Colella ◽  
Maria G. Biferi ◽  
Deeksha Bali ◽  
Nicole K. Paulk ◽  
...  
Keyword(s):  
Pompe Disease ◽  
Therapeutic Potential ◽  
Scale Up ◽  
Glycogen Storage Disease Type ◽  
Neuromuscular Disorder ◽  
The Body ◽  
Respiratory Dysfunction ◽  
Glycogen Accumulation ◽  
Enzyme Replacement ◽  
Hepatic Expression

Glycogen storage disease type II or Pompe disease is a severe neuromuscular disorder caused by mutations in the lysosomal enzyme, acid α-glucosidase (GAA), which result in pathological accumulation of glycogen throughout the body. Enzyme replacement therapy is available for Pompe disease; however, it has limited efficacy, has high immunogenicity, and fails to correct pathological glycogen accumulation in nervous tissue and skeletal muscle. Using bioinformatics analysis and protein engineering, we developed transgenes encoding GAA that could be expressed and secreted by hepatocytes. Then, we used adeno-associated virus (AAV) vectors optimized for hepatic expression to deliver the GAA transgenes to Gaa knockout (Gaa−/−) mice, a model of Pompe disease. Therapeutic gene transfer to the liver rescued glycogen accumulation in muscle and the central nervous system, and ameliorated cardiac hypertrophy as well as muscle and respiratory dysfunction in the Gaa−/− mice; mouse survival was also increased. Secretable GAA showed improved therapeutic efficacy and lower immunogenicity compared to nonengineered GAA. Scale-up to nonhuman primates, and modeling of GAA expression in primary human hepatocytes using hepatotropic AAV vectors, demonstrated the therapeutic potential of AAV vector–mediated liver expression of secretable GAA for treating pathological glycogen accumulation in multiple tissues in Pompe disease.

scholarly journals Modeling CNS Involvement in Pompe Disease Using Neural Stem Cells Generated from Patient-Derived Induced Pluripotent Stem Cells

Cells ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 8
Author(s):  
Yu-Shan Cheng ◽  
Shu Yang ◽  
Junjie Hong ◽  
Rong Li ◽  
Jeanette Beers ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Pompe Disease ◽  
Drug Efficacy ◽  
Cns Involvement ◽  
Glycogen Accumulation ◽  
Induced Pluripotent ◽  
Alpha Glucosidase

Pompe disease is a lysosomal storage disorder caused by autosomal recessive mutations in the acid alpha-glucosidase (GAA) gene. Acid alpha-glucosidase deficiency leads to abnormal glycogen accumulation in patient cells. Given the increasing evidence of central nervous system (CNS) involvement in classic infantile Pompe disease, we used neural stem cells, differentiated from patient induced pluripotent stem cells, to model the neuronal phenotype of Pompe disease. These Pompe neural stem cells exhibited disease-related phenotypes including glycogen accumulation, increased lysosomal staining, and secondary lipid buildup. These morphological phenotypes in patient neural stem cells provided a tool for drug efficacy evaluation. Two potential therapeutic agents, hydroxypropyl-β-cyclodextrin and δ-tocopherol, were tested along with recombinant human acid alpha-glucosidase (rhGAA) in this cell-based Pompe model. Treatment with rhGAA reduced LysoTracker staining in Pompe neural stem cells, indicating reduced lysosome size. Additionally, treatment of diseased neural stem cells with the combination of hydroxypropyl-β-cyclodextrin and δ-tocopherol significantly reduced the disease phenotypes. These results demonstrated patient-derived Pompe neural stem cells could be used as a model to study disease pathogenesis, to evaluate drug efficacy, and to screen compounds for drug discovery in the context of correcting CNS defects.

scholarly journals Ventilation and neurochemical changes during µ-opioid receptor activation or blockade of excitatory receptors in the hypoglossal motor nucleus of goats

2017 ◽  
Vol 123 (6) ◽  
pp. 1532-1544 ◽  
Author(s):  
Thomas M. Langer ◽  
Suzanne E. Neumueller ◽  
Emma Crumley ◽  
Nicholas J. Burgraff ◽  
Sawan Talwar ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Pulmonary Ventilation ◽  
Respiratory Control ◽  
Nrem Sleep ◽  
Receptor Activation ◽  
Motor Nucleus ◽  
Physiological Conditions ◽  
Neurochemical Changes ◽  
Underlying Mechanisms ◽  
The Brain

Neuromodulator interdependence posits that changes in one or more neuromodulators are compensated by changes in other modulators to maintain stability in the respiratory control network. Herein, we studied compensatory neuromodulation in the hypoglossal motor nucleus (HMN) after chronic implantation of microtubules unilaterally ( n = 5) or bilaterally ( n = 5) into the HMN. After recovery, receptor agonists or antagonists in mock cerebrospinal fluid (mCSF) were dialyzed during the awake and non-rapid eye movement (NREM) sleep states. During day studies, dialysis of the µ-opioid inhibitory receptor agonist [d-Ala2, N-MePhe4, Gly-ol]enkephalin (DAMGO; 100 µM) decreased pulmonary ventilation (V̇i), breathing frequency ( f), and genioglossus (GG) muscle activity but did not alter neuromodulators measured in the effluent mCSF. However, neither unilateral dialysis of a broad spectrum muscarinic receptor antagonist (atropine; 50 mM) nor unilateral or bilateral dialysis of a mixture of excitatory receptor antagonists altered V̇i or GG activity, but all of these did increase HMN serotonin (5-HT) levels. Finally, during night studies, DAMGO and excitatory receptor antagonist decreased ventilatory variables during NREM sleep but not during wakefulness. These findings contrast with previous dialysis studies in the ventral respiratory column (VRC) where unilateral DAMGO or atropine dialysis had no effects on breathing and bilateral DAMGO or unilateral atropine increased V̇i and f and decreased GABA or increased 5-HT, respectively. Thus we conclude that the mechanisms of compensatory neuromodulation are less robust in the HMN than in the VRC under physiological conditions in adult goats, possibly because of site differences in the underlying mechanisms governing neuromodulator release and consequently neuronal activity, and/or responsiveness of receptors to compensatory neuromodulators. NEW & NOTEWORTHY Activation of inhibitory µ-opioid receptors in the hypoglossal motor nucleus decreased ventilation under physiological conditions and did not affect neurochemicals in effluent dialyzed mock cerebral spinal fluid. These findings contrast with studies in the ventral respiratory column where unilateral [d-Ala2, N-MePhe4, Gly-ol]enkephalin (DAMGO) had no effects on ventilation and bilateral DAMGO or unilateral atropine increased ventilation and decreased GABA or increased serotonin, respectively. Our data support the hypothesis that mechanisms that govern local compensatory neuromodulation within the brain stem are site specific under physiological conditions.

scholarly journals Postnatal developmental expressions of neurotransmitters and receptors in various brain stem nuclei of rats

2005 ◽  
Vol 98 (4) ◽  
pp. 1442-1457 ◽  
Author(s):  
Qiuli Liu ◽  
Margaret T. T. Wong-Riley
Keyword(s):  
Brain Stem ◽  
Respiratory Control ◽  
Nucleus Ambiguus ◽  
Hypoglossal Nucleus ◽  
Motor Nucleus ◽  
Developmental Trend ◽  
Receptor Subunit ◽  
Cuneate Nucleus ◽  
Glycine Receptors ◽  
Dorsal Motor Nucleus

Previously, we reported that the expression of cytochrome oxidase in a number of brain stem nuclei exhibited a plateau or reduction at postnatal day (P) 3–4 and a dramatic decrease at P12, against a general increase with age. The present study examined the expression of glutamate, N-methyl-d-aspartate receptor subunit 1 (NMDAR1), GABA, GABAB receptors, glycine receptors, and glutamate receptor subunit 2 (GluR2) in the ventrolateral subnucleus of the solitary tract nucleus, nucleus ambiguus, hypoglossal nucleus, medial accessory olivary nucleus, dorsal motor nucleus of the vagus, and cuneate nucleus, from P2 to P21 in rats. Results showed that 1) the expression of glutamate increased with age in a majority of the nuclei, whereas that of NMDAR1 showed heterogeneity among the nuclei; 2) GABA and GABAB expressions decreased with age, whereas that of glycine receptors increased with age; 3) GluR2 showed two peaks, at P3–4 and P12; and 4) glutamate and NMDAR1 showed a significant reduction, whereas GABA, GABAB receptors, glycine receptors, and GluR2 exhibited a concomitant increase at P12. These features were present but less pronounced in hypoglossal nucleus and dorsal motor nucleus of the vagus and were absent in the cuneate nucleus. These data suggest that brain stem nuclei, directly or indirectly related to respiratory control, share a common developmental trend with the pre-Bötzinger complex in having a transient period of imbalance between inhibitory and excitatory drives at P12. During this critical period, the respiratory system may be more vulnerable to excessive exogenous stressors.

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