Cones and cone pathways remain functional in advanced retinal degeneration

Ellis, Erika; Paniagua, Antonio E.; Scalabrino, Miranda L.; Thapa, Mishek; Rathinavelu, Jay; Jiao, Yuekan; Williams, David S.; Field, Greg D.; Fain, Gordon; Sampath, Alapakkam P.

doi:10.1016/j.cub.2023.03.007

Cited by 8 publications

(9 citation statements)

References 54 publications

(82 reference statements)

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“…The preceding histological assessments suggest that retinal function might be compromised with late treatment relative to the early and mid treatment timepoints. However, previous studies have also indicated that retinal function can remain relatively robust despite marked changes in photoreceptor morphology and density in the Cngb1 neo/neo and rd10 models of RP 4,5 . To determine the impact of treatment timepoint on retinal function, we measured visual responses among RGCs, the output neurons of the retina, using a large-scale multielectrode array (MEA) [23][24][25] .…”

Section: Gliosis Present In Late Treated Retinasmentioning

confidence: 95%

“…These results indicate that spatial and temporal receptive field structure between 4-7M post-treatment do not depend strongly on the treatment time point. This is not particularly surprising because cone-mediated receptive field structure is relatively robust even to severe rod loss and changes in cone morphology 4,5 .…”

Section: Gliosis Present In Late Treated Retinasmentioning

confidence: 99%

“…To examine this issue, we used a mouse model of gene therapy for retinitis pigmentosa (RP) in which complete genetic rescue across the retina can be achieved without the use of viral vectors. This mouse does not express the beta subunit of the rod-photoreceptor cGMP-gated (CNG) channel because a neomycin cassette flanked by loxP sites was inserted into intron 19 of the Cngb1 locus (Cngb1 neo/neo ) [3][4][5] . This prevents CNGB1 expression and reduces the formation of CNG channels, ultimately leading to rod degeneration and death similar to humans with RP 6 .…”

Section: Introductionmentioning

confidence: 99%

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Late gene therapy limits the restoration of retinal function in a mouse model of retinitis pigmentosa

Scalabrino

Thapa

Sampath

et al. 2023

Preprint

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Retinitis pigmentosa is an inherited photoreceptor degeneration that begins with rod loss followed by cone loss and eventual blindness. Gene therapies are being developed, but it is unknown how retinal function depends on the time of intervention. To uncover this dependence, we utilized a mouse model of retinitis pigmentosa capable of artificial genetic rescue. This model enables a benchmark of best-case gene therapy by removing the variables that complicate the ability to answer this vital question. Complete genetic rescue was performed at 25%, 50%, and 70% rod loss (early, mid and late, respectively). Early and mid treatment restored retinal function to near wild-type levels, specifically the sensitivity and signal fidelity of retinal ganglion cells (RGCs), the 'output' neurons of the retina. However, some anatomical defects persisted. Late treatment retinas exhibited continued, albeit slowed, loss of sensitivity and signal fidelity among RGCs, as well as persistent gliosis. We conclude that gene replacement therapies delivered after 50% rod loss are unlikely to restore visual function to normal. This is critical information for administering gene therapies to rescue vision.

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Section: Gliosis Present In Late Treated Retinasmentioning

confidence: 95%

Section: Gliosis Present In Late Treated Retinasmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Late gene therapy limits the restoration of retinal function in a mouse model of retinitis pigmentosa

Scalabrino

Thapa

Sampath

et al. 2023

Preprint

Self Cite

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“…Critically, retinal ganglion cells (RGCs), the output neurons of the retina, remain connected to the brain 1,2 . This enables responses initiated by surviving photoreceptors to remain detectable late into disease progression 3 . The maintained connectivity of RGCs also provides a lifeline for restoring vision in profound blindness, either through regeneration of lost photoreceptors from stem cells, or introduction of light sensitivity in surviving retinal neurons with optoelectronic 4 , optogenetic 5,6 , or opto-pharmacological tools 7,8 .…”

Section: Introductionmentioning

confidence: 99%

Retinoic acid-dependent loss of synaptic output from bipolar cells impairs visual information processing in inherited retinal degeneration

Ganzen,

Yadav,

Wei

et al. 2023

Preprint

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In retinitis pigmentosa (RP), rod and cone photoreceptors degenerate, depriving downstream neurons of light-sensitive input, leading to vision impairment or blindness. Although downstream neurons survive, some undergo morphological and physiological remodeling. Bipolar cells (BCs) link photoreceptors, which sense light, to retinal ganglion cells (RGCs), which send information to the brain. While photoreceptor loss disrupts input synapses to BCs, whether BC output synapses remodel is unknown. Here we report that synaptic output from BCs plummets in mouse models of RP owing to loss of voltage-gated Ca2+channels. Remodeling reduces the dynamic range and the reliability of the BC output synapse to repeated optogenetic stimuli, eliminating RGC firing at high stimulus frequencies. However, the consequences of functional BC remodeling can be reversed by inhibiting the retinoic acid receptor (RAR). RAR inhibitors targeted to BCs present a new therapeutic opportunity for mitigating detrimental effects of remodeling on signals initiated by surviving photoreceptors or vision-restoring tools.

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“…Most studies utilizing gene therapy to prolong cone survival have not directly assayed cone physiology ( 10 , 18 ). Similarly, studies of untreated RP mouse strains have not characterized cone physiology over time until recently with one RP strain ( 19 ), and several studies that did carry out such assessments have left some open questions that we wished to address. For example, following gene therapy aimed at improving cone survival and function in RP mice, electrophysiology measurements were made at a stage before all of the rods were gone ( 3 ).…”

mentioning

confidence: 99%

Chromophore supply modulates cone function and survival in retinitis pigmentosa mouse models

Xue

Sun²,

Wang

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Retinitis pigmentosa (RP) is an ocular disease characterized by the loss of night vision, followed by the loss of daylight vision. Daylight vision is initiated in the retina by cone photoreceptors, which are gradually lost in RP, often as bystanders in a disease process that initiates in their neighboring rod photoreceptors. Using physiological assays, we investigated the timing of cone electroretinogram (ERG) decline in RP mouse models. A correlation between the time of loss of the cone ERG and the loss of rods was found. To investigate a potential role of the visual chromophore supply in this loss, mouse mutants with alterations in the regeneration of the retinal chromophore, 11- cis retinal, were examined. Reducing chromophore supply via mutations in Rlbp1 or Rpe65 resulted in greater cone function and survival in a RP mouse model. Conversely, overexpression of Rpe65 and Lrat , genes that can drive the regeneration of the chromophore, led to greater cone degeneration. These data suggest that abnormally high chromophore supply to cones upon the loss of rods is toxic to cones, and that a potential therapy in at least some forms of RP is to slow the turnover and/or reduce the level of visual chromophore in the retina.

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Cones and cone pathways remain functional in advanced retinal degeneration

Cited by 8 publications

References 54 publications

Late gene therapy limits the restoration of retinal function in a mouse model of retinitis pigmentosa

Late gene therapy limits the restoration of retinal function in a mouse model of retinitis pigmentosa

Retinoic acid-dependent loss of synaptic output from bipolar cells impairs visual information processing in inherited retinal degeneration

Chromophore supply modulates cone function and survival in retinitis pigmentosa mouse models

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