An emerging phenotype of central nervous system involvement in Pompe disease: from bench to bedside and beyond

Korlimarla, Aditi; Lim, Jeong‐A; Kishnani, Priya S.; Sun, Baodong

doi:10.21037/atm.2019.04.49

Cited by 49 publications

(55 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 3 Pompe disease is a multisystem disorder, with skeletal and cardiac muscles being the most prominently affected tissues, but other systems, including the central nervous system (CNS), can also be affected. 1 , 3 , 4 , 5 , 6 , 7 According to severity, age of onset, and disease progression rate, Pompe disease has been categorized into the classic infantile onset (IOPD) and the late onset (LOPD). IOPD starts early in life and primarily manifests as hypotonia, hypertrophic cardiomyopathy, and generalized muscle weakness, leading to death in the first year of life if left untreated.…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have used adeno-associated viruses (AAVs) as a gene therapy delivery system to target via local or systemic administration specific tissues such as skeletal muscles, liver, and CNS. 7 , 15 , 16 AVV-mediated gene therapy can trigger antibody or cell-mediated immune responses to transgene or viral capsid, 16 , 17 , 18 , 19 , 20 as has been observed in clinical trials for hemophilia B 21 using AAV, but liver-directed transgene expression has been shown in pre-clinical studies 22 to potentially overcome this safety concern by induction of immune tolerance. Although AVV-mediated gene therapy remains a promising treatment, the episomal nature of viral persistence results in a dilution effect in replicating cells such as hepatocytes, particularly in younger patients, and thereby increasing safety concerns would arise for multiple dosages in those patients.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Lentiviral Hematopoietic Stem Cell Gene Therapy Rescues Clinical Phenotypes in a Murine Model of Pompe Disease

Piras

Montiel-Equihua

Chan

et al. 2020

Molecular Therapy - Methods & Clinical Development

View full text Add to dashboard Cite

Pompe disease is a lysosomal storage disorder caused by malfunctions of the acid alpha-glucosidase (GAA) enzyme with a consequent toxic accumulation of glycogen in cells. Muscle wasting and hypertrophic cardiomyopathy are the most common clinical signs that can lead to cardiac and respiratory failure within the first year of age in the more severe infantile forms. Currently available treatments have significant limitations and are not curative, highlighting a need for the development of alternative therapies. In this study, we investigated the use of a clinically relevant lentiviral vector to deliver systemically GAA through genetic modification of hematopoietic stem and progenitor cells (HSPCs). The overexpression of GAA in human HSPCs did not exert any toxic effect on this cell population, which conserved its stem cell capacity in xenograft experiments. In a murine model of Pompe disease treated at young age, we observed phenotypic correction of heart and muscle function with a significant reduction of glycogen accumulation in tissues after 6 months of treatment. These findings suggest that lentiviral-mediated HSPC gene therapy can be a safe alternative therapy for Pompe disease.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lentiviral Hematopoietic Stem Cell Gene Therapy Rescues Clinical Phenotypes in a Murine Model of Pompe Disease

Piras

Montiel-Equihua

Chan

et al. 2020

Molecular Therapy - Methods & Clinical Development

View full text Add to dashboard Cite

show abstract

“…Although respiratory dysfunction was traditionally attributed to muscle pathology and weakness, recent evidence in mice and humans indicate pathology in both respiratory muscles and the neurons that control those muscles [44,49,82]. Accumulation of glycogen is seen throughout respiratory muscles and control neurons.…”

Section: Discussionmentioning

confidence: 99%

The Respiratory Phenotype of Pompe Disease Mouse Models

Fusco

McCall

Dhindsa

et al. 2020

IJMS

View full text Add to dashboard Cite

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.

show abstract

“…There are increasing concerns about the long term effects of Pompe disease; including the central nervous system involvement and the resulting impact on developmental outcomes [ 4 ]. To date, studies examining the cognitive functioning, academic skills, speech and language skills and visual-motor abilities of children and adolescents with IPD have shown considerable variability in their skill levels [ [5] , [6] , [7] , [8] , [9] , [10] ]. However, data on the behavioral, social, and emotional profiles of children and adolescents with Pompe disease are very limited.…”

Section: Introductionmentioning

confidence: 99%

Behavioral, social and school functioning in children with Pompe disease

Korlimarla

Spiridigliozzi

Ștefănescu

et al. 2020

Molecular Genetics and Metabolism Reports

Self Cite

View full text Add to dashboard Cite

Purpose To improve our understanding of the behavioral, social, and emotional functioning of children and adolescents with Pompe disease. Method Parents/guardians of 21 children (age 5-18y) with infantile (IPD) or late-onset (LOPD) Pompe disease on long-term enzyme replacement therapy completed three standardized checklists regarding their child's behavior: the Child Behavior Checklist (CBCL), Conners 3 Parent (Conners-3), Behavior Rating Inventory of Executive Function-2 (BRIEF2), and a survey of their child's educational services. Results Descriptive statistics were used to summarize the findings for each behavior checklist. Age standard scores from each checklist were reported for the IPD ( n = 17, 9 females, mean age = 9y, 4 mo; SD = 3y, 8mo) and LOPD ( n = 4, 1 female; mean = 11y, 2mo; SD = 2y, 1mo) groups. The majority of children with Pompe exhibited age-appropriate behavior and emotional functioning on these standardized checklists. However, negative mood symptoms, learning problems, decreased participation in structured social activities, and attentional difficulties were more frequently reported in children with IPD in comparison to same-aged peers. Parents of children with LOPD reported fewer problematic behaviors but endorsed negative mood symptoms and difficulties with peer relations. Most children received accommodations in regular education classrooms at school. Conclusions These standardized behavior checklists are useful screening tools for the early identification and treatment of behavior, emotional, and social concerns in children with Pompe disease.

show abstract

An emerging phenotype of central nervous system involvement in Pompe disease: from bench to bedside and beyond

Cited by 49 publications

References 89 publications

Lentiviral Hematopoietic Stem Cell Gene Therapy Rescues Clinical Phenotypes in a Murine Model of Pompe Disease

Lentiviral Hematopoietic Stem Cell Gene Therapy Rescues Clinical Phenotypes in a Murine Model of Pompe Disease

The Respiratory Phenotype of Pompe Disease Mouse Models

Behavioral, social and school functioning in children with Pompe disease

Contact Info

Product

Resources

About