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Allele-specific gene editing to rescue dominant CRX-associated LCA7 phenotypes in a retinal organoid model
- Source :
- Stem cell reports, vol 16, iss 11, Stem Cell Reports
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- Summary Cases of Leber congenital amaurosis caused by mutations in CRX (LCA7) exhibit an early form of the disease and show signs of significant photoreceptor dysfunction and eventual loss. To establish a translational in vitro model system to study gene-editing-based therapies, we generated LCA7 retinal organoids harboring a dominant disease-causing mutation in CRX. Our LCA7 retinal organoids develop signs of immature and dysfunctional photoreceptor cells, providing us with a reliable in vitro model to recapitulate LCA7. Furthermore, we performed a proof-of-concept study in which we utilize allele-specific CRISPR/Cas9-based gene editing to knock out mutant CRX and saw moderate rescue of photoreceptor phenotypes in our organoids. This work provides early evidence for an effective approach to treat LCA7, which can be applied more broadly to other dominant genetic diseases.<br />Graphical abstract<br />Highlights • A retinal organoid model of CRX-associated Leber congenital amaurosis was generated • LCA7 retinal organoids show impaired photoreceptor maturation and gene expression • scRNA-seq profiling revealed both rod and cone photoreceptor dysfunction • Allele-specific editing of mutant CRX promotes disease rescue in retinal organoids<br />LCA7 currently has no effective treatments; therefore, Dr. Lamba and colleagues generated LCA7 retinal organoids from patient-derived stem cells. The retinal organoids recapitulated LCA7 disease phenotypes, allowing for testing of an allele-specific gene editing approach. Early signs of disease rescue were achieved, providing evidence for a promising new strategy to treat LCA7 and other dominant retinal diseases.
- Subjects :
- Leber Congenital Amaurosis
Mutant
Neurodegenerative
Eye
medicine.disease_cause
Biochemistry
chemistry.chemical_compound
Genome editing
Models
CRISPR
RNA-Seq
Genes, Dominant
Gene Editing
Pediatric
Microscopy
Mutation
LCA7
gene editing
Single Nucleotide
Phenotype
Cell biology
Organoids
CRX
Induced Pluripotent Stem Cells
Clinical Sciences
Biology
Electron
Models, Biological
Polymorphism, Single Nucleotide
Leber congenital amaurosis
Article
Retina
Cell Line
Microscopy, Electron, Transmission
allelic knockdown
scRNA-seq
Genetics
medicine
Organoid
Transmission
Humans
Dominant
Genetic Predisposition to Disease
Polymorphism
CRISPR/Cas9
Eye Disease and Disorders of Vision
Alleles
Homeodomain Proteins
Base Sequence
retinal organoid
Cas9
Gene Expression Profiling
Neurosciences
Retinal
Cell Biology
Biological
Good Health and Well Being
Genes
chemistry
Trans-Activators
Biochemistry and Cell Biology
photoreceptors cells
Developmental Biology
Subjects
Details
- ISSN :
- 22136711
- Volume :
- 16
- Database :
- OpenAIRE
- Journal :
- Stem Cell Reports
- Accession number :
- edsair.doi.dedup.....d88204b16224676ac14706abf8a4b5d3