In vivo base editing rescues cone photoreceptors in a mouse model of early-onset inherited retinal degeneration

Choi, Elliot H.; Suh, Suk-Hwan; Foik, Andrzej T.; Leinonen, Henri; Newby, Gregory A.; Gao, Xin D.; Banskota, Samagya; Hoang, Thanh; Du, Samuel W.; Dong, Zhiqian; Raguram, Aditya; Blackshaw, Seth; Lyon, David C.; Liu, David R.; Palczewski, Krzysztof

doi:10.1038/s41467-022-29490-3

Cited by 49 publications

(36 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We believe that the bystander effect problem will be solved in the future. In this study, as in the previously reported a Rpe65-rd12 base editing study( 18 ), the positive effects of high levels of editing at the target site were much higher than the possible negative effects of the bystander despite the bystander editing.…”

Section: Discussionsupporting

confidence: 76%

“…The adenine base editors (ABEs), which is composed of dCas9 and adenine deaminase, can convert A•T to G•C or C•G to T•A. In recent years, studies have reported that lentiviral vector-delivered ABE could correct Rpe65 mutation in the retinal pigment epithelium of rd12 mice, a mouse model of Leber congenital amaurosis (LCA)( 17, 18 ). To explore whether base editing can effectively rescue the dysfunction of photoreceptors and provide a potential therapeutic strategy for RP, we aimed to correct the Pde6b mutation in the rd10 mouse model, which recapitulates the human condition and is analogous to the mutations that cause human RP( 19, 20 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

In vivo base editing rescues photoreceptors in a mouse model of retinitis pigmentosa

Yang

She

et al. 2022

Preprint

View full text Add to dashboard Cite

Retinitis pigmentosa (RP) is a group of retinal diseases that cause the progressive death of retinal photoreceptor cells and eventually blindness. Mutations in the β-domain of the phosphodiesterase 6 (Pde6b) gene are among the most identified causes of autosomal recessive RP. Here, we report a base editing approach in which adeno-associated virus (AAV)-mediated adenine base editor (ABE) delivery to postmitotic photoreceptors is used to correct the Pde6b mutation in a retinal degeneration 10 (rd10) mouse model of RP. Subretinal delivery of AAV8-ABE corrects Pde6b mutation with up to 37.41% efficiency at the DNA level and up to 91.95% efficiency at the cDNA level, restores PDE6B expression, preserves photoreceptors and rescues visual function. RNA-seq reveals upregulation of genes associated with phototransduction and photoreceptor survival. Our data demonstrate that base editing is a potential gene therapy that could provide durable protection against RP.

show abstract

Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

In vivo base editing rescues photoreceptors in a mouse model of retinitis pigmentosa

Yang

She

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…This was followed by testing contrast. Single units were recorded along the whole depth of the primary visual cortex (V1) as presented in previous studies ( Foik et al, 2018 ; Suh et al, 2020 ; Frankowski et al, 2021 ; Choi et al, 2022 ; Lewandowski et al, 2022 ).…”

Section: Methodsmentioning

confidence: 99%

Visual System Hyperexcitability and Compromised V1 Receptive Field Properties in Early-Stage Retinitis Pigmentosa in Mice

Leinonen

Lyon²,

Palczewski³

et al. 2022

eNeuro

Self Cite

View full text Add to dashboard Cite

Inherited retinal degenerative diseases are a prominent cause of blindness. Although mutations causing death of photoreceptors are mostly known, the pathophysiology downstream in the inner retina and along the visual pathway is incompletely characterized in the earliest disease stages. Here, we investigated retinal, midbrain and cortical visual function using electroretinography (ERG), the optomotor response (OMR), visual evoked potentials (VEPs), respectively, and single unit electrophysiology at the primary visual cortex (V1) in light-adapted juvenile (approximately one-month-old) and young adult (three-month-old) Rho P23H/WT mice, representative of early-stage retinitis pigmentosa (RP). Photopic ERG revealed up to ∼30% hypersensitivity to light in Rho P23H/WT mice, as measured by the light intensity required to generate half-maximal b-wave (I 50 parameter). Rho P23H/WT mice also showed increased OMRs toward low spatial frequency (SF) drifting gratings, indicative of visual overexcitation at the midbrain level. At the V1 level, VEPs and single-cell recordings revealed prominent hyperexcitability in the juvenile Rho P23H/WT mice. Mean VEP amplitudes for light ON stimuli were nearly doubled in one-month-old Rho P23H/WT mice compared with controls, and more than doubled for light OFF. Single-cell recordings showed a significantly increased spontaneous V1 neuron firing in the Rho P23H/WT mice, and persistent contrast and temporal sensitivities. In contrast, direction selectivity was severely compromised. Our data suggest that during early RP, the visual pathway becomes hyperexcited. This could have both compensatory and deleterious consequences for visual behavior. Further studies on the mechanisms of hyperexcitability are warranted as this could lead to therapeutic interventions for RP.

show abstract

“…The adenine and cytosine base editors were delivered and transduced efficiently into the retinal cells. However, small insertion and deletions were observed in the mice [ 89 ]. The prime editing has successfully edited the Dnmt1 gene in mouse retina with fewer off-target effects.…”

Section: Base and Prime Editing: Advanced Gene Editing Tools To Cure ...mentioning

confidence: 99%

CRISPR/Cas9—A Promising Therapeutic Tool to Cure Blindness: Current Scenario and Future Prospects

Ahmad

2022

IJMS

View full text Add to dashboard Cite

CRISPR-based targeted genome editing is bringing revolutionary changes in the research arena of biological sciences. CRISPR/Cas9 has been explored as an efficient therapeutic tool for the treatment of genetic diseases. It has been widely used in ophthalmology research by using mouse models to correct pathogenic mutations in the eye stem cells. In recent studies, CRISPR/Cas9 has been used to correct a large number of mutations related to inherited retinal disorders. In vivo therapeutic advantages for retinal diseases have been successfully achieved in some rodents. Current advances in the CRISPR-based gene-editing domain, such as modified Cas variants and delivery approaches have optimized its application to treat blindness. In this review, recent progress and challenges of the CRISPR-Cas system have been discussed to cure blindness and its prospects.

show abstract

In vivo base editing rescues cone photoreceptors in a mouse model of early-onset inherited retinal degeneration

Cited by 49 publications

References 43 publications

In vivo base editing rescues photoreceptors in a mouse model of retinitis pigmentosa

In vivo base editing rescues photoreceptors in a mouse model of retinitis pigmentosa

Visual System Hyperexcitability and Compromised V1 Receptive Field Properties in Early-Stage Retinitis Pigmentosa in Mice

CRISPR/Cas9—A Promising Therapeutic Tool to Cure Blindness: Current Scenario and Future Prospects

Contact Info

Product

Resources

About