title: TFEB overexpression promotes glycogen clearance of Pompe disease iPSC-derived skeletal muscle.
abstract: Pompe disease (PD) is a lysosomal disorder caused by acid α-glucosidase (GAA) deficiency. Progressive muscular weakness is the major symptom of PD, and enzyme replacement therapy can improve the clinical outcome. However, to achieve a better clinical outcome, alternative therapeutic strategies are being investigated, including gene therapy and pharmacological chaperones. We previously used lentiviral vector-mediated GAA gene transfer in PD patient-specific induced pluripotent stem cells. Some therapeutic efficacy was observed, although glycogen accumulation was not normalized. Transcription factor EB is a master regulator of lysosomal biogenesis and autophagy that has recently been associated with muscular pathology, and is now a potential therapeutic target in PD model mice. Here, we differentiated skeletal muscle from PD patient-specific induced pluripotent stem cells by forced MyoD expression. Lentiviral vector-mediated GAA and transcription factor EB gene transfer independently improved GAA enzyme activity and reduced glycogen content in skeletal muscle derived from PD-induced pluripotent stem cells. Interestingly, GAA and transcription factor EB cooperatively improved skeletal muscle pathology, both biochemically and morphologically. Thus, our findings show that abnormal lysosomal biogenesis is associated with the muscular pathology of PD, and transcription factor EB gene transfer is effective as an add-on strategy to GAA gene transfer.
authors.affiliation: Division of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan; Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Division of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan; Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Division of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine , Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Higuchi
authors.affiliation: Division of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine , Tokyo, Japan.
authors.forename: Yohta
authors.initials: Y
authors.lastname: Shimada
authors.affiliation: Division of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan; Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ida
authors.affiliation: Division of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan; Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Toya
authors.initials: T
authors.lastname: Ohashi