Intermediate filament protein accumulation in motor neurons derived from giant axonal neuropathy iPSCs rescued by restoration of gigaxonin.
Giant axonal neuropathy (GAN) is a progressive neurodegenerative disease caused by autosomal recessive mutations in the GAN gene resulting in a loss of a ubiquitously expressed protein, gigaxonin. Gene replacement therapy is a promising strategy for treatment of the disease; however, the effectiveness and safety of gigaxonin reintroduction have not been tested in human GAN nerve cells. Here we report the derivation of induced pluripotent stem cells (iPSCs) from three GAN patients with different GAN mutations. Motor neurons differentiated from GAN iPSCs exhibit accumulation of neurofilament (NF-L) and peripherin (PRPH) protein and formation of PRPH aggregates, the key pathological phenotypes observed in patients. Introduction of gigaxonin either using a lentiviral vector or as a stable transgene resulted in normalization of NEFL and PRPH levels in GAN neurons and disappearance of PRPH aggregates. Importantly, overexpression of gigaxonin had no adverse effect on survival of GAN neurons, supporting the feasibility of gene replacement therapy. Our findings demonstrate that GAN iPSCs provide a novel model for studying human GAN neuropathologies and for the development and testing of new therapies in relevant cell types.
Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, NY 10032, USA, Center for Motor Neuron Biology and Disease, Departments of Pathology and Cell Biology, Neurology, and Neuroscience, Columbia Stem Cell Initiative.
Bethany L
BL
Johnson-Kerner
New York Stem Cell Foundation, New York, NY 10032, USA.
Faizzan S
FS
Ahmad
Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, NY 10032, USA.
Alejandro Garcia
AG
Diaz
Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, NY 10032, USA.
John Palmer
JP
Greene
Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Steven J
SJ
Gray
Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Richard Jude
RJ
Samulski
Department of Pediatrics and Medicine, Columbia University Medical Center, New York, NY 10032, USA.
Wendy K
WK
Chung
Department of Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium.
Rudy
R
Van Coster
Departments of Pediatric Neurology, University of South Alabama, Mobile, AL, USA.
Paul
P
Maertens
New York Stem Cell Foundation, New York, NY 10032, USA.
Scott A
SA
Noggle
Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, NY 10032, USA, Center for Motor Neuron Biology and Disease, Departments of Pathology and Cell Biology, Neurology, and Neuroscience, Columbia Stem Cell Initiative, Department of Rehabilitation and Regenerative Medicine.
Christopher E
CE
Henderson
Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, NY 10032, USA, Center for Motor Neuron Biology and Disease, Departments of Pathology and Cell Biology, Neurology, and Neuroscience, Columbia Stem Cell Initiative, hw350@columbia.edu.
Hynek
H
Wichterle
D001369:Axons; D002454:Cell Differentiation; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D056768:Giant Axonal Neuropathy / Q000235:genetics* / Q000628:therapy; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D007381:Intermediate Filament Proteins / Q000235:genetics*; D007382:Intermediate Filaments / Q000235:genetics / Q000378:metabolism; D007621:Karyotyping; D016086:Lentivirus / Q000235:genetics; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism*; D009154:Mutation; D010641:Phenotype
D003598:Cytoskeletal Proteins; C416508:GAN protein, human; D007381:Intermediate Filament Proteins