Journal article
Development and biological characterization of a clinical gene transfer vector for the treatment of MAK-associated retinitis pigmentosa
Gene therapy, Vol.29(5), pp.259-288
05/2022
DOI: 10.1038/s41434-021-00291-5
PMCID: PMC9159943
PMID: 34518651
Abstract
AbstractBy combining next generation whole exome sequencing and induced pluripotent stem cell (iPSC) technology we found that an Alu repeat inserted in exon 9 of the MAK gene results in a loss of normal MAK transcript and development of human autosomal recessive retinitis pigmentosa (RP). Although a relatively rare cause of disease in the general population, the MAK variant is enriched in individuals of Jewish ancestry. In this population, 1 in 55 individuals are carriers and one third of all cases of recessive RP is caused by this gene. The purpose of this study was to determine if a viral gene augmentation strategy could be used to safely restore functional MAK protein as a step toward a treatment for early stage MAK-associated RP. Patient iPSC-derived photoreceptor precursor cells were generated and transduced with viral vectors containing the MAK transcript. One week after transduction, transcript and protein could be detected via rt-PCR and western blotting respectively. Using patient-derived fibroblast cells and mak knockdown zebra fish we demonstrate that over-expression of the retinal MAK transgene restored the cells ability to regulate primary cilia length. In addition, the visual defect in mak knockdown zebrafish was mitigated via treatment with the retinal MAK transgene. There was no evidence of local or systemic toxicity at 1-month or 3-months following subretinal delivery of clinical grade vector into wild type rats. The findings reported here will help pave the way for initiation of a phase 1 clinical trial for the treatment of patients with MAK-associated RP.
Details
- Title: Subtitle
- Development and biological characterization of a clinical gene transfer vector for the treatment of MAK-associated retinitis pigmentosa
- Creators
- Budd A Tucker - Roy J. and Lucille A. Carver College of MedicineErin R Burnight - Roy J. and Lucille A. Carver College of MedicineCathryn M Cranston - Roy J. and Lucille A. Carver College of MedicineMallory J Ulferts - Roy J. and Lucille A. Carver College of MedicineMeagan A Luse - Roy J. and Lucille A. Carver College of MedicineTrudi Westfall - University of IowaC. Anthony Scott - University of IowaAutumn Marsden - University of IowaKatherine Gibson-CorleyLuke A Wiley - Roy J. and Lucille A. Carver College of MedicineIan C Han - Roy J. and Lucille A. Carver College of MedicineDiane C Slusarski - University of IowaRobert F Mullins - Roy J. and Lucille A. Carver College of MedicineEdwin M Stone - Roy J. and Lucille A. Carver College of Medicine
- Resource Type
- Journal article
- Publication Details
- Gene therapy, Vol.29(5), pp.259-288
- DOI
- 10.1038/s41434-021-00291-5
- PMID
- 34518651
- PMCID
- PMC9159943
- NLM abbreviation
- Gene Ther
- ISSN
- 0969-7128
- eISSN
- 1476-5462
- Language
- English
- Electronic publication date
- 09/14/2021
- Date published
- 05/2022
- Academic Unit
- The University of Iowa Institute for Vision Research; Iowa Neuroscience Institute; Biology; Fraternal Order of Eagles Diabetes Research Center; Ophthalmology and Visual Sciences
- Record Identifier
- 9984187027902771
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