title: Using Patient-Specific Induced Pluripotent Stem Cells and Wild-Type Mice to Develop a Gene Augmentation-Based Strategy to Treat CLN3-Associated Retinal Degeneration.
abstract: Juvenile neuronal ceroid lipofuscinosis (JNCL) is a childhood neurodegenerative disease with early-onset, severe central vision loss. Affected children develop seizures and CNS degeneration accompanied by severe motor and cognitive deficits. There is no cure for JNCL, and patients usually die during the second or third decade of life. In this study, independent lines of induced pluripotent stem cells (iPSCs) were generated from two patients with molecularly confirmed mutations in CLN3, the gene mutated in JNCL. Clinical-grade adeno-associated adenovirus serotype 2 (AAV2) carrying the full-length coding sequence of human CLN3 was generated in a U.S. Food and Drug Administration-registered cGMP facility. AAV2-CLN3 was efficacious in restoring full-length CLN3 transcript and protein in patient-specific fibroblasts and iPSC-derived retinal neurons. When injected into the subretinal space of wild-type mice, purified AAV2-CLN3 did not show any evidence of retinal toxicity. This study provides proof-of-principle for initiation of a clinical trial using AAV-mediated gene augmentation for the treatment of children with CLN3-associated retinal degeneration.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Stephen A. Wynn Institute for Vision Research, Carver College of Medicine, University of Iowa , Iowa City, Iowa.
authors.forename: Luke A
authors.initials: LA
authors.lastname: Wiley
authors.affiliation: Department of Ophthalmology and Visual Sciences, Stephen A. Wynn Institute for Vision Research, Carver College of Medicine, University of Iowa , Iowa City, Iowa.
authors.forename: Erin R
authors.initials: ER
authors.lastname: Burnight
authors.affiliation: Department of Ophthalmology and Visual Sciences, Stephen A. Wynn Institute for Vision Research, Carver College of Medicine, University of Iowa , Iowa City, Iowa.
authors.forename: Arlene V
authors.initials: AV
authors.lastname: Drack
authors.affiliation: Department of Ophthalmology and Visual Sciences, Stephen A. Wynn Institute for Vision Research, Carver College of Medicine, University of Iowa , Iowa City, Iowa.
authors.forename: Bailey B
authors.initials: BB
authors.lastname: Banach
authors.affiliation: Department of Ophthalmology and Visual Sciences, Stephen A. Wynn Institute for Vision Research, Carver College of Medicine, University of Iowa , Iowa City, Iowa.
authors.forename: Dalyz
authors.initials: D
authors.lastname: Ochoa
authors.affiliation: Department of Ophthalmology and Visual Sciences, Stephen A. Wynn Institute for Vision Research, Carver College of Medicine, University of Iowa , Iowa City, Iowa.
authors.forename: Cathryn M
authors.initials: CM
authors.lastname: Cranston
authors.affiliation: Department of Ophthalmology and Visual Sciences, Stephen A. Wynn Institute for Vision Research, Carver College of Medicine, University of Iowa , Iowa City, Iowa.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Madumba
authors.affiliation: Department of Ophthalmology and Visual Sciences, Stephen A. Wynn Institute for Vision Research, Carver College of Medicine, University of Iowa , Iowa City, Iowa.
authors.forename: Jade S
authors.initials: JS
authors.lastname: East
authors.affiliation: Department of Ophthalmology and Visual Sciences, Stephen A. Wynn Institute for Vision Research, Carver College of Medicine, University of Iowa , Iowa City, Iowa.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Mullins
authors.affiliation: Department of Ophthalmology and Visual Sciences, Stephen A. Wynn Institute for Vision Research, Carver College of Medicine, University of Iowa , Iowa City, Iowa.
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Stone
authors.affiliation: Department of Ophthalmology and Visual Sciences, Stephen A. Wynn Institute for Vision Research, Carver College of Medicine, University of Iowa , Iowa City, Iowa.
authors.forename: Budd A
authors.initials: BA
authors.lastname: Tucker
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000637:transplantation*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000627:therapeutic use; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics* / Q000627:therapeutic use; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D009474:Neurons / Q000378:metabolism; D012160:Retina / Q000378:metabolism / Q000473:pathology; D012162:Retinal Degeneration / Q000235:genetics / Q000473:pathology / Q000628:therapy*
chemical_list: C105199:CLN3 protein, human; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones