Full-length Dysferlin Transfer by the Hyperactive Sleeping Beauty Transposase Restores Dysferlin-deficient Muscle

Molecular Therapy. Nucleic Acids
Helena EscobarZ Izsvák

Abstract

Dysferlin-deficient muscular dystrophy is a progressive disease characterized by muscle weakness and wasting for which there is no treatment. It is caused by mutations in DYSF, a large, multiexonic gene that forms a coding sequence of 6.2 kb. Sleeping Beauty (SB) transposon is a nonviral gene transfer vector, already used in clinical trials. The hyperactive SB system consists of a transposon DNA sequence and a transposase protein, SB100X, that can integrate DNA over 10 kb into the target genome. We constructed an SB transposon-based vector to deliver full-length human DYSF cDNA into dysferlin-deficient H2K A/J myoblasts. We demonstrate proper dysferlin expression as well as highly efficient engraftment (>1,100 donor-derived fibers) of the engineered myoblasts in the skeletal muscle of dysferlin- and immunodeficient B6.Cg-Dysf(prmd) Prkdc(scid)/J (Scid/BLA/J) mice. Nonviral gene delivery of full-length human dysferlin into muscle cells, along with a successful and efficient transplantation into skeletal muscle are important advances towards successful gene therapy of dysferlin-deficient muscular dystrophy.

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Citations

Oct 5, 2016·Critical Reviews in Biochemistry and Molecular Biology·Suneel A NarayanavariZsuzsanna Izsvák
Apr 13, 2017·Critical Reviews in Biochemistry and Molecular Biology·Michael HudecekZoltán Ivics
Jun 22, 2018·Current Treatment Options in Neurology·Ava Y Lin, Leo H Wang
Nov 2, 2017·Bioscience Reports·Jaitip TipaneeMarinee K Chuah
Jan 21, 2017·Journal of Cell Science·Julia HofhuisSven Thoms
Sep 19, 2017·Human Gene Therapy·Jaitip TipaneeMarinee K Chuah
Jul 19, 2018·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Mary Lynn Chu, Ellen Moran
Feb 19, 2020·Current Gene Therapy·Forough TaheriSeyed M G Hayat
Aug 25, 2019·Cells·Olivier PeulenVincent Castronovo
Aug 17, 2019·Biomaterials·Jason WangNenad Bursac

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Datasets Mentioned

BETA
DQ267935

Methods Mentioned

BETA
FACS
transfection
antisense oligonucleotides
PCR
flow cytometry
electrophoresis
Protein Assay
confocal microscopy

Software Mentioned

Adobe Illustrator
FlowJo
ImageJ
Adobe Photoshop

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