Using human Pompe disease-induced pluripotent stem cell-derived neural cells to identify compounds with therapeutic potential.
Hum Mol Genet
; 28(23): 3880-3894, 2019 12 01.
Article
em En
| MEDLINE
| ID: mdl-31518394
ABSTRACT
Pompe disease (OMIM # 232300) is a glycogen storage disease caused by autosomal recessive mutations of the gene encoding alpha-1,4-glucosidase (GAA; EC 3.2.1.20). Despite the relatively effective employment of enzyme replacement therapy, some critical medical issues still exist in patients with this disease, including the persistence of abnormalities in the central nervous system (CNS), probably because of the inability of the recombinant GAA to pass through the blood-brain barrier. To address this issue, identification of more therapeutic agents that target the CNS of patients with Pompe disease may be required. In this study, we derived neuronal cells from Pompe disease-induced pluripotent stem cells (Pom-iPSCs) and proved that they are able to recapitulate the hallmark cellular and biochemical phenotypes of Pompe disease. Using the Pom-iPSC-derived neurons as an in vitro drug-testing model, we then identified three compounds, ebselen, wortmannin and PX-866, with therapeutic potential to alleviate Pompe disease-associated pathological phenotypes in the neurons derived from Pom-iPSCs. We confirmed that all three compounds were able to enhance the GAA activity in the Pom-iPSC-derived neurons. Moreover, they were able to enhance the GAA activity in several important internal organs of GAA-deficient mice when co-injected with recombinant human GAA, and we found that intraperitoneal injection of ebselen was able to promote the GAA activity of the GAA-heterozygous mouse brain. Our results prove the usefulness of Pom-iPSC-derived neuronal populations for identifying new compounds with therapeutic potential.
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Base de dados:
MEDLINE
Assunto principal:
Azóis
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Doença de Depósito de Glicogênio Tipo II
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Compostos Organosselênicos
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Alfa-Glucosidases
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Células-Tronco Pluripotentes Induzidas
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Células-Tronco Neurais
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article