Using Patient-Specific Induced Pluripotent Stem Cells and Wild-Type Mice to Develop a Gene Augmentation-Based Strategy to Treat CLN3-Associated Retinal Degeneration

Luke A Wiley; Erin R Burnight; Arlene V Drack; Bailey B Banach; Dalyz Ochoa; Cathryn M Cranston; Robert A Madumba; Jade S East; Robert F Mullins; Edwin M Stone; Budd A Tucker

doi:10.1089/hum.2016.049

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Using Patient-Specific Induced Pluripotent Stem Cells and Wild-Type Mice to Develop a Gene Augmentation-Based Strategy to Treat CLN3-Associated Retinal Degeneration

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Using Patient-Specific Induced Pluripotent Stem Cells and Wild-Type Mice to Develop a Gene Augmentation-Based Strategy to Treat CLN3-Associated Retinal Degeneration

Luke A Wiley, Erin R Burnight, Arlene V Drack, Bailey B Banach, Dalyz Ochoa, Cathryn M Cranston, Robert A Madumba, Jade S East, Robert F Mullins, Edwin M Stone, …

Human gene therapy, Vol.27(10), pp.835-846

10/01/2016

DOI: 10.1089/hum.2016.049

PMCID: PMC5035933

PMID: 27400765

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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.

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Title: Subtitle: Using Patient-Specific Induced Pluripotent Stem Cells and Wild-Type Mice to Develop a Gene Augmentation-Based Strategy to Treat CLN3-Associated Retinal Degeneration
Creators: Luke A Wiley
Erin R Burnight
Arlene V Drack
Bailey B Banach
Dalyz Ochoa
Cathryn M Cranston
Robert A Madumba
Jade S East
Robert F Mullins
Edwin M Stone
Budd A Tucker
Resource Type: Journal article
Publication Details: Human gene therapy, Vol.27(10), pp.835-846
DOI: 10.1089/hum.2016.049
PMID: 27400765
PMCID: PMC5035933
NLM abbreviation: Hum Gene Ther
ISSN: 1043-0342
eISSN: 1557-7422
Publisher: Mary Ann Liebert, Inc
Language: English
Date published: 10/01/2016
Academic Unit: Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Ophthalmology and Visual Sciences
Record Identifier: 9983979969402771

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