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AAV-Mediated Gene Augmentation Therapy Restores Critical Functions in Mutant PRPF31 iPSC-Derived RPE Cells.

作者信息

Brydon Elizabeth M, Bronstein Revital, Buskin Adriana, Lako Majlinda, Pierce Eric A, Fernandez-Godino Rosario

机构信息

Department of Ophthalmology, Ocular Genomics Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.

Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

出版信息

Mol Ther Methods Clin Dev. 2019 Nov 11;15:392-402. doi: 10.1016/j.omtm.2019.10.014. eCollection 2019 Dec 13.


DOI:10.1016/j.omtm.2019.10.014
PMID:31890732
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6909184/
Abstract

Retinitis pigmentosa (RP) is the most common form of inherited vision loss and is characterized by degeneration of retinal photoreceptor cells and the retinal pigment epithelium (RPE). Mutations in pre-mRNA processing factor 31 () cause dominant RP via haploinsufficiency with incomplete penetrance. There is good evidence that the diverse severity of this disease is a result of differing levels of expression of the wild-type allele among patients. Thus, we hypothesize that -related RP will be amenable to treatment by adeno-associated virus (AAV)-mediated gene augmentation therapy. To test this hypothesis, we used induced pluripotent stem cells (iPSCs) with mutations in and differentiated them into RPE cells. The mutant iPSC-RPE cells recapitulate the cellular phenotype associated with the PRPF31 pathology, including defective cell structure, diminished phagocytic function, defects in ciliogenesis, and compromised barrier function. Treatment of the mutant iPSC-RPE cells with AAV- restored normal phagocytosis and cilia formation, and it partially restored structure and barrier function. These results suggest that AAV-based gene therapy targeting RPE cells holds therapeutic promise for patients with -related RP.

摘要
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd1/6909184/4f243911d495/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd1/6909184/24e49214244f/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd1/6909184/c6d9ada5845b/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd1/6909184/feb214790617/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd1/6909184/9f9229fa17f1/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd1/6909184/75d9a8b923d5/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd1/6909184/e8f339299b0b/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd1/6909184/9ba919489429/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd1/6909184/4f243911d495/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd1/6909184/24e49214244f/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd1/6909184/c6d9ada5845b/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd1/6909184/feb214790617/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd1/6909184/9f9229fa17f1/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd1/6909184/75d9a8b923d5/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd1/6909184/e8f339299b0b/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd1/6909184/9ba919489429/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd1/6909184/4f243911d495/gr7.jpg

相似文献

[1]
AAV-Mediated Gene Augmentation Therapy Restores Critical Functions in Mutant PRPF31 iPSC-Derived RPE Cells.

Mol Ther Methods Clin Dev. 2019-11-11

[2]
Modeling PRPF31 retinitis pigmentosa using retinal pigment epithelium and organoids combined with gene augmentation rescue.

NPJ Regen Med. 2022-8-16

[3]
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[4]
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Clin Transl Med. 2022-3

[5]
Gene augmentation prevents retinal degeneration in a CRISPR/Cas9-based mouse model of PRPF31 retinitis pigmentosa.

Nat Commun. 2022-12-13

[6]
Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa.

Nat Commun. 2018-10-12

[7]
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[8]
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[9]
Mutations in pre-mRNA processing factors 3, 8, and 31 cause dysfunction of the retinal pigment epithelium.

Am J Pathol. 2014-10

[10]
Determinants of Disease Penetrance in -Associated Retinopathy.

Genes (Basel). 2021-9-28

引用本文的文献

[1]
Transplantation of human embryonic stem cell-derived retinal pigment epithelial cells via injectable microfluidic-templated microgels for retinal regeneration.

Mater Today Bio. 2025-5-23

[2]
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EBioMedicine. 2025-6

[3]
The RNA content of extracellular vesicles from gene-edited hiPSC-RPE show potential as biomarkers of retinal degeneration.

Mol Ther Methods Clin Dev. 2025-3-18

[4]
The AMD-associated genetic polymorphism CFH Y402H confers vulnerability to Hydroquinone-induced stress in iPSC-RPE cells.

Front Immunol. 2025-2-6

[5]
CFH Haploinsufficiency and Complement Alterations in Early-Onset Macular Degeneration.

Invest Ophthalmol Vis Sci. 2024-4-1

[6]
PRPF31-retinitis pigmentosa: Challenges and opportunities for clinical translation.

Vision Res. 2023-12

[7]
Clinical and Molecular Aspects of C2orf71/PCARE in Retinal Diseases.

Int J Mol Sci. 2023-6-26

[8]
Induced Pluripotent Stem Cells and Genome-Editing Tools in Determining Gene Function and Therapy for Inherited Retinal Disorders.

Int J Mol Sci. 2022-12-3

[9]
Retinal organoids provide unique insights into molecular signatures of inherited retinal disease throughout retinogenesis.

J Anat. 2023-8

[10]
Modeling PRPF31 retinitis pigmentosa using retinal pigment epithelium and organoids combined with gene augmentation rescue.

NPJ Regen Med. 2022-8-16

本文引用的文献

[1]
Pharmaceutical Development of AAV-Based Gene Therapy Products for the Eye.

Pharm Res. 2018-12-27

[2]
Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa.

Nat Commun. 2018-10-12

[3]
Choroideremia Gene Therapy Phase 2 Clinical Trial: 24-Month Results.

Am J Ophthalmol. 2018-9-19

[4]
CRISPR-Cas9 genome editing induces a p53-mediated DNA damage response.

Nat Med. 2018-6-11

[5]
p53 inhibits CRISPR-Cas9 engineering in human pluripotent stem cells.

Nat Med. 2018-6-11

[6]
Synthetic Adeno-Associated Viral Vector Efficiently Targets Mouse and Nonhuman Primate Retina In Vivo.

Hum Gene Ther. 2018-3-20

[7]
Primary Cilium-Mediated Retinal Pigment Epithelium Maturation Is Disrupted in Ciliopathy Patient Cells.

Cell Rep. 2018-1-2

[8]
Rapid, Directed Differentiation of Retinal Pigment Epithelial Cells from Human Embryonic or Induced Pluripotent Stem Cells.

J Vis Exp. 2017-10-30

[9]
Changes in extracellular matrix cause RPE cells to make basal deposits and activate the alternative complement pathway.

Hum Mol Genet. 2018-1-1

[10]
Isolation, culture and characterization of primary mouse RPE cells.

Nat Protoc. 2016-6-9

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