Gene therapy into photoreceptors and Müller glial cells restores retinal structure and function in CRB1 retinitis pigmentosa mouse models
Open accessAbstract
Mutations in the Crumbs-homologue-1 (CRB1) gene lead to severe recessive inherited retinal dystrophies. Gene transfer therapy is the most promising cure for retinal dystrophies and has primarily been applied for recessive null conditions via a viral gene expression vector transferring a cDNA encoding an enzyme or channel protein, and targeting expression to one cell type. Therapy for the human CRB1 disease will be more complex, as CRB1 is a structural and signaling transmembrane protein present in three cell classes: Müller glia, cone and rod photoreceptors. In this study, we applied CRB1 and CRB2 gene therapy vectors in Crb1-retinitis pigmentosa mouse models at mid-stage disease. We tested if CRB expression restricted to Müller glial cells or photoreceptors or co-expression in both is required to recover retinal function. We show that targeting both Müller glial cells and photoreceptors with CRB2 ameliorated retinal function and structure in Crb1 mouse models. Surprisingly, targeting a single cell type or all cell types with CRB1 reduced retinal function. We show here the first pre-clinical studies for CRB1-related eye disorders using CRB2 vectors and initial elucidation of the cellular mechanisms underlying CRB1 function.
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Protein expression (GFP, CRB1, or CRB2) was found in photoreceptors after one to three months of rAAV vector administration in wild-type and CRB1-related retinitis pigmentosa mouse models.
“We have found protein expression (GFP, CRB1, or CRB2) in photoreceptors after one to three months of rAAV vector administration in wild-type and CRB1-related retinitis pigmentosa mouse models [24,60].”
From Recombinant Adeno-Associated Viral Vectors (rAAV)-Vector Elements in Ocular Gene Therapy Clinical Trials and Transgene Expression and Bioactivity Assays (2020) · cites this paper as [60]
The Figure 1 legend reports CRB2 expression in photoreceptors of a Crb2 cKO mouse model three weeks after AAV injection, and the ‘Efficient expression of CRB2 proteins upon AAV gene transfer’ section describes its photoreceptor localization. The cited passages do not establish the stated one-to-three-month interval for GFP, CRB1, and CRB2 expression in photoreceptors across both wild-type and CRB1-related retinitis pigmentosa models; the CRB1 photoreceptor result is described as previous work. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe authors achieved efficient expression of CRB1 in retinal cell types by making use of short promoters (<300 bp) and a 50 bp synthetic polyadenylation sequence.
“Nevertheless, we achieved an efficient expression of CRB1 in retinal cell types by making use of short promoters (<300 bp) and a 50 bp synthetic polyadenylation sequence [60].”
From Recombinant Adeno-Associated Viral Vectors (rAAV)-Vector Elements in Ocular Gene Therapy Clinical Trials and Transgene Expression and Bioactivity Assays (2020) · cites this paper as [60]
The Introduction reports that short promoters and a synthetic polyadenylation sequence enabled efficient CRB1 expression in vivo. However, the section on efficient CRB2 expression describes promoters of up to 350 bp, and “Generation and purification of the viral vectors” specifies a 48 bp polyadenylation sequence—not the claimed <300 bp promoters and 50 bp sequence. The paper also presents the earlier CRB1 result as prior work. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe rAAV-CMV-CRB2 rescued the loss of CRB1 function in mouse Müller glial cells.
“The rAAV-CMV-CRB2 rescued the loss of CRB1 function in mouse Müller glial cells [60].”
From Recombinant Adeno-Associated Viral Vectors (rAAV)-Vector Elements in Ocular Gene Therapy Clinical Trials and Transgene Expression and Bioactivity Assays (2020) · cites this paper as [60]
The Results section reports improved retinal function in CRB1-RP mouse models after AAV-CMV-CRB2 treatment targeting both Müller glial cells and photoreceptors. It does not establish rescue of CRB1 function specifically in Müller glial cells; targeting those cells alone did not improve retinal function. Page numbers were unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe rAAV6 variants ShH10 and ShH10-Y445F efficiently infect rat, mouse, and human Müller glial cells.
“An example are the rAAV6 variants ShH10 and ShH10-Y445F that efficiently infect rat, mouse, and human Müller glial cells [60,62,272].”
From Recombinant Adeno-Associated Viral Vectors (rAAV)-Vector Elements in Ocular Gene Therapy Clinical Trials and Transgene Expression and Bioactivity Assays (2020) · cites this paper as [60]
The 'Generation and purification of the viral vectors' section (page not available in our copy) says the AAV6-derived ShH10 variants showed increased transduction of rat and mouse Müller glial cells after intravitreal injection. It does not report transduction of human Müller glial cells, so that species-specific part of the claim is unsupported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredrAAV5 and the rAAV6 variants ShH10 and ShH10-Y445F can efficiently infect both human photoreceptors and Müller glial cells ex vivo.
“We have shown that rAAV5 and the rAAV6 variants ShH10 and ShH10-Y445F can efficiently infect both human photoreceptors and Müller glial cells ex vivo [60,62].”
From Recombinant Adeno-Associated Viral Vectors (rAAV)-Vector Elements in Ocular Gene Therapy Clinical Trials and Transgene Expression and Bioactivity Assays (2020) · cites this paper as [60]
The ‘Generation and purification of the viral vectors’ section reports that ShH10 variants transduce rat and mouse Müller glial cells after intravitreal injection. The ‘Efficient expression of CRB2 proteins upon AAV gene transfer’ section says ShH10Y targets mainly Müller glia, not photoreceptors, by that route. These passages do not establish efficient infection of both cell types in human tissue ex vivo, and they do not report that result for rAAV5. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Intravitreal injection of some rAAVs might result in the transduction of a larger pool of off-target cells, such as the ciliary body and iris epithelium.
“Intravitreal injection of some rAAVs might result in the transduction of a larger pool of off-target cells, such as the ciliary body and iris epithelium [60].”
From Recombinant Adeno-Associated Viral Vectors (rAAV)-Vector Elements in Ocular Gene Therapy Clinical Trials and Transgene Expression and Bioactivity Assays (2020) · cites this paper as [60]
The hRLBP1 promoter (2.6 kb) can restrict expression to Müller glial cells and RPE.
“Moreover, the hRLBP1 promoter (2.6 kb) can restrict expression to Müller glial cells and RPE [60].”
From Recombinant Adeno-Associated Viral Vectors (rAAV)-Vector Elements in Ocular Gene Therapy Clinical Trials and Transgene Expression and Bioactivity Assays (2020) · cites this paper as [60]
The Discussion (page unavailable) mentions large Müller-glial-cell-specific promoters but does not identify hRLBP1 or describe a 2.6-kb promoter that restricts expression to Müller glial cells and RPE. Searches for hRLBP1, 2.6 kb, and RLBP1 with RPE found no passage addressing that specific claim. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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Simple and complex retinal dystrophies are associated with profoundly different disease networks
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AAV Gene Augmentation Therapy for CRB1-Associated Retinitis Pigmentosa
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Self-citationNovel gene variants in Polish patients with Leber congenital amaurosis (LCA)
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CRB2 Loss in Rod Photoreceptors Is Associated with Progressive Loss of Retinal Contrast Sensitivity
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Ng, B., Kaukonen, M. K., McClements, M. E., Shamsnajafabadi, H., MacLaren, R. E., & Cehajic‐Kapetanovic, J. (2024) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2024.101289 · Cited by 13 · see citing works
Cell-cell interaction in the pathogenesis of inherited retinal diseases
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Human CRB1 and CRB2 form homo- and heteromeric protein complexes in the retina
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- Authors
- Pellissier, L. P., Quinn, P. M., Alves, C. H., Vos, R. M., Klooster, J., Flannery, J. G., Heimel, J. A., & Wijnholds, J.
- Affiliations
- Royal Netherlands Academy of Arts and Sciences (NL)
- University of California, Berkeley (US)
- Netherlands Institute for Neuroscience (NL)
- Corresponding author
- Wijnholds, Jan
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-02-20
- Volume
- 24
- Issue
- 11
- Pages
- 3104-3118
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2016182278
- Cited by
- 86
- References
- 30
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 7 · 2023: 11 · 2022: 8 · 2021: 8 · 2020: 8 · 2019: 11 · 2018: 6 · 2017: 10 · 2016: 5 · 2015: 3
- FWCI
- 3.47
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- Human Molecular Genetics (publishedVersion, other-oa)
- PubMed (publishedVersion)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- HAL (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (submittedVersion, other-oa)
- Funders
- Oogfonds
- National Eye Institute (R01EY013533, R01EY022975)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Keywords
- CRB1, retinitis pigmentosa, CrB2, gene therapy, Müller cells, photoreceptors, retinal dystrophy, retinal function recovery
- MeSH terms
- Animals, Carrier Proteins, Disease Models, Animal, Humans, Membrane Proteins, Mice, Inbred C57BL, Nerve Tissue Proteins, Retina, Retinitis Pigmentosa, Genetic Therapy, Retinal Rod Photoreceptor Cells, Retinal Cone Photoreceptor Cells, HEK293 Cells, Intravitreal Injections, Ependymoglial Cells
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