RARE DISEASE
Blue cone monochromatism
Blue cone monochromatism
Blue cone monochromatism
Synonyms: Atypical X-linked achromatopsia, Blue cone monochromacy, Color blindness, blue monocone monochromatic type, S cone monochromacy, S cone monochromatism, X-linked incomplete achromatopsia
Synonyms: Atypical X-linked achromatopsia, Blue cone monochromacy, Color blindness, blue monocone monochromatic type, S cone monochromacy, S cone monochromatism, X-linked incomplete achromatopsia
Synonyms: Atypical X-linked achromatopsia, Blue cone monochromacy, Color blindness, blue monocone monochromatic type, S cone monochromacy, S cone monochromatism, X-linked incomplete achromatopsia
Drug discovery
1
drug
With orphan designation
Overview
Blue Cone Monochromatism (BCM) is a rare X-linked retinal disorder caused by mutations in the OPN1LW/OPN1MW gene cluster, leading to nonfunctional long (L)- and middle (M)-wavelength cones. Affected individuals exhibit low visual acuity (20/60–20/200), photophobia, nystagmus, myopia, and severe color vision deficits, relying solely on intact short-wavelength (S) cones and rods. Diagnosis combines clinical evaluation, electroretinography, and genetic testing [1][4][7].
Therapies
Symptomatic care: Magenta/brown-tinted lenses reduce photophobia [15], low-vision aids (e.g., magnifiers) [15], and myopia correction.
Emerging therapies: Intravitreal/subretinal gene therapy (AAV vectors) to restore L/M-opsin expression; ADVM-062 (Adverum Biotechnologies) and preclinical trials in animal models show promise [1][3][13][18].
Categories: rare genetic diseases, rare ophthalmic disorders
Research Papers
51 drug discovery papers about Blue cone monochromatism, with 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
51 drug discovery papers about Blue cone monochromatism, with 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
gene therapies
2026-06-11 |
List of metabolites from targeted metabolomics.
Blue cone monochromacy (BCM) is an X-linked cone dystrophy characterized by loss of long- (L) and medium-wavelength (M) cone function. A common cause is the C203R missense mutation, which occurs in both OPN1LW and OPN1MW, or in hybrid OPN1LW/OPN1MW opsin genes. Because BCM primarily affects foveal cones, we generated Opn1mwC198R/Opn1sw-/-/Nrl-/- (C198RAC) mice carrying the murine equivalent of the human C203R mutation on an all-cone retinal background. C198RAC mice exhibited absent photopic ERG responses and significantly shortened cone outer segments, recapitulating foveal cone deficits in BCM. Metabolomic profiling further revealed altered retinal metabolism, including reduced cGMP and elevated oxidative stress–related metabolites. To evaluate therapy, we delivered AAV8-Y733F expressing human L-opsin (OPN1LW) cDNA under the cone-specific PR2.1 promoter at 1 and 5 months of age. Treatment restored cone function, regenerated outer segment structures, and provided rescue for at least 5 months post-injection in both early- and late-treatment groups. These results demonstrate that densely packed cones expressing only the C198R mutant opsin remain viable targets for gene therapy. Together, this study establishes the C198RAC mouse as a cone-rich model mimicking foveal cone conditions in BCM and provides compelling preclinical evidence that AAV-mediated gene augmentation can rescue cone outer segment structure and function, supporting the feasibility of gene therapy for BCM.
2026-06-11 | Gene therapy rescues cone function in an all-cone retina mouse model with the most common cone opsin C203R missense mutation.
Blue cone monochromacy (BCM) is an X-linked cone dystrophy characterized by loss of long- (L) and medium-wavelength (M) cone function. A common cause is the C203R missense mutation, which occurs in both OPN1LW and OPN1MW, or in hybrid OPN1LW/OPN1MW opsin genes. Because BCM primarily affects foveal cones, we generated Opn1mwC198R/Opn1sw-/-/Nrl-/- (C198RAC) mice carrying the murine equivalent of the human C203R mutation on an all-cone retinal background. C198RAC mice exhibited absent photopic ERG responses and significantly shortened cone outer segments, recapitulating foveal cone deficits in BCM. Metabolomic profiling further revealed altered retinal metabolism, including reduced cGMP and elevated oxidative stress-related metabolites. To evaluate therapy, we delivered AAV8-Y733F expressing human L-opsin (OPN1LW) cDNA under the cone-specific PR2.1 promoter at 1 and 5 months of age. Treatment restored cone function, regenerated outer segment structures, and provided rescue for at least 5 months post-injection in both early- and late-treatment groups. These results demonstrate that densely packed cones expressing only the C198R mutant opsin remain viable targets for gene therapy. Together, this study establishes the C198RAC mouse as a cone-rich model mimicking foveal cone conditions in BCM and provides compelling preclinical evidence that AAV-mediated gene augmentation can rescue cone outer segment structure and function, supporting the feasibility of gene therapy for BCM.
2026-05-20 | Gene therapy rescues cone function in opn1mw -/- /opn1sw -/- /Nrl -/- mice, an all-cone model of blue cone monochromacy.
Blue cone monochromacy (BCM) is a congenital vision disorder caused by the loss of L- and M-cone function, leading to severe loss of visual acuity and color perception deficits. To test gene therapy for BCM in a model that mimics the densely packed foveal cones of human retinas, we generated a triple knockout (TKO) mouse model (Opn1mw -/- /Opn1sw -/- /Nrl -/-) with an all-cone retina lacking cone opsins. These mice exhibit abolished cone function, disrupted phototransduction, and altered metabolite profiles resulting from loss of opsin. We then administered AAV-mediated human L-opsin gene supplementation therapy at 1 and 5 months of age to assess cone treatability before and after cone degeneration occurs. Treatment restored cone function, replenished essential cone phototransduction proteins, and partially regenerated some cone outer segment membrane structure. Rescue effects persisted for at least 5 months post-treatment in both younger and older treated groups. These findings demonstrate that opsin-deficient, densely packed cones remain viable targets for gene therapy and support the clinical potential of this approach in BCM patients.
2025-11-25 | Molecular mechanisms limiting the AAV gene therapy treatment window in mouse models of blue cone monochromacy.
Blue cone monochromacy (BCM) is a severe X-linked blinding disorder caused by mutations in the OPN1LW/OPN1MW locus, resulting in impaired cone function and structural degeneration. We conduct a comparative analysis of AAV gene therapy in Opn1mw-/-/Opn1sw-/- (double knockout, DKO) and Opn1mwC198R/Opn1sw-/- (C198R) BCM mouse models to contrast therapeutic outcomes at different stages. We demonstrate the AAV8Y733F capsid achieves superior rescue compared to AAV5. Both DKO and C198R models show comparable therapeutic outcomes, with efficacy consistently decreasing in older mice. Structural analysis reveals both models display rapid degenerative changes in cone outer and inner segments. We observe age-related reductions in transgene expression for both models, potentially resulting from decreased cone transducibility, transgene silencing/downregulation, or disease-related genome expression alterations. Notably, the Pde6c and Cngb3 promoters maintain robust activity in degenerating cones. These findings suggest use of an optimized cone promoter can ultimately extend the therapeutic window and treatment longevity in BCM cones.
2025-09-07 | Gene Therapy Rescues Cone Function in an All-cone Retina Mouse Model for Blue Cone Monochromacy with the Most Common C203R Missense Mutation
Abstract Blue cone monochromacy (BCM) is an X-linked cone dystrophy characterized by loss of long- (L) and medium-wavelength (M) cone function. A common cause is the C203R missense mutation, which occurs in both OPN1LW and OPN1MW , or in hybrid OPN1LW/OPN1MW opsin genes. Because BCM primarily affects foveal cones, we generated Opn1mw C198R /Opn1sw -/- /Nrl -/- ( C198RAC ) mice carrying the murine equivalent of the human C203R mutation on an all-cone retinal background. C198RAC mice exhibited absent photopic ERG responses and significantly shortened cone outer segments, recapitulating foveal cone deficits in BCM. Metabolomic profiling further revealed altered retinal metabolism, including reduced cGMP and elevated oxidative stress–related metabolites. To evaluate therapy, we delivered AAV8-Y733F expressing human L-opsin (OPN1LW) cDNA under the cone-specific PR2.1 promoter at 1 and 5 months of age. Treatment restored cone function, regenerated outer segment structures, and provided rescue for at least 5 months post-injection in both early- and late-treatment groups. These results demonstrate that densely packed cones expressing only the C198R mutant opsin remain viable targets for gene therapy. Together, this study establishes the C198RAC mouse as a cone-rich model of BCM and provides compelling preclinical evidence that AAV-mediated gene augmentation can restore cone structure and function, supporting the feasibility of gene therapy for BCM.
small molecules
2021-12-13 | ATF6 is essential for human cone photoreceptor development.
Endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) signaling promote the pathology of many human diseases. Loss-of-function variants of the UPR regulator Activating Transcription Factor 6 (ATF6) cause severe congenital vision loss diseases such as achromatopsia by unclear pathomechanisms. To investigate this, we generated retinal organoids from achromatopsia patient induced pluripotent stem cells carrying ATF6 disease variants and from gene-edited ATF6 null hESCs. We found that achromatopsia patient and ATF6 null retinal organoids failed to form cone structures concomitant with loss of cone phototransduction gene expression, while rod photoreceptors developed normally. Adaptive optics retinal imaging of achromatopsia patients carrying ATF6 variants also showed absence of cone inner/outer segment structures but preserved rod structures, mirroring the defect in cone formation observed in our retinal organoids. These results establish that ATF6 is essential for human cone development. Interestingly, we find that a selective small molecule ATF6 signaling agonist restores the transcriptional activity of some ATF6 disease-causing variants and stimulates cone growth and gene expression in patient retinal organoids carrying these variants. These findings support that pharmacologic targeting of the ATF6 pathway can promote human cone development and should be further explored for blinding retinal diseases.
2020-12-23 | Non-photopic and photopic visual cycles differentially regulate immediate, early, and late phases of cone photoreceptor-mediated vision.
Cone photoreceptors in the retina enable vision over a wide range of light intensities. However, the processes enabling cone vision in bright light (i.e. photopic vision) are not adequately understood. Chromophore regeneration of cone photopigments may require the retinal pigment epithelium (RPE) and/or retinal Müller glia. In the RPE, isomerization of all-trans-retinyl esters to 11-cis-retinol is mediated by the retinoid isomerohydrolase Rpe65. A putative alternative retinoid isomerase, dihydroceramide desaturase-1 (DES1), is expressed in RPE and Müller cells. The retinol-isomerase activities of Rpe65 and Des1 are inhibited by emixustat and fenretinide, respectively. Here, we tested the effects of these visual cycle inhibitors on immediate, early, and late phases of cone photopic vision. In zebrafish larvae raised under cyclic light conditions, fenretinide impaired late cone photopic vision, while the emixustat-treated zebrafish unexpectedly had normal vision. In contrast, emixustat-treated larvae raised under extensive dark-adaptation displayed significantly attenuated immediate photopic vision concomitant with significantly reduced 11-cis-retinaldehyde (11cRAL). Following 30 min of light, early photopic vision was recovered, despite 11cRAL levels remaining significantly reduced. Defects in immediate cone photopic vision were rescued in emixustat- or fenretinide-treated larvae following exogenous 9-cis-retinaldehyde supplementation. Genetic knockout of Des1 (degs1) or retinaldehyde-binding protein 1b (rlbp1b) did not eliminate photopic vision in zebrafish. Our findings define molecular and temporal requirements of the nonphotopic or photopic visual cycles for mediating vision in bright light.
2017-05-12 | Endoplasmic reticulum (ER) Ca2+-channel activity contributes to ER stress and cone death in cyclic nucleotide-gated channel deficiency
Endoplasmic reticulum (ER) stress and mislocalization of improperly folded proteins have been shown to contribute to photoreceptor death in models of inherited retinal degenerative diseases. In particular, mice with cone cyclic nucleotide-gated (CNG) channel deficiency, a model for achromatopsia, display both early-onset ER stress and opsin mistrafficking. By 2 weeks of age, these mice show elevated signaling from all three arms of the ER-stress pathway, and by 1 month, cone opsin is improperly distributed away from its normal outer segment location to other retinal layers. This work investigated the role of Ca2+-release channels in ER stress, protein mislocalization, and cone death in a mouse model of CNG-channel deficiency. We examined whether preservation of luminal Ca2+ stores through pharmacological and genetic suppression of ER Ca2+ efflux protects cones by attenuating ER stress. We demonstrated that the inhibition of ER Ca2+-efflux channels reduced all three arms of ER-stress signaling while improving opsin trafficking to cone outer segments and decreasing cone death by 20–35%. Cone-specific gene deletion of the inositol-1,4,5-trisphosphate receptor type I (IP3R1) also significantly increased cone density in the CNG-channel-deficient mice, suggesting that IP3R1 signaling contributes to Ca2+ homeostasis and cone survival. Consistent with the important contribution of organellar Ca2+ signaling in this achromatopsia mouse model, significant differences in dynamic intraorganellar Ca2+ levels were detected in CNG-channel-deficient cones. These results thus identify a novel molecular link between Ca2+ homeostasis and cone degeneration, thereby revealing novel therapeutic targets to preserve cones in inherited retinal degenerative diseases. Endoplasmic reticulum (ER) stress and mislocalization of improperly folded proteins have been shown to contribute to photoreceptor death in models of inherited retinal degenerative diseases. In particular, mice with cone cyclic nucleotide-gated (CNG) channel deficiency, a model for achromatopsia, display both early-onset ER stress and opsin mistrafficking. By 2 weeks of age, these mice show elevated signaling from all three arms of the ER-stress pathway, and by 1 month, cone opsin is improperly distributed away from its normal outer segment location to other retinal layers. This work investigated the role of Ca2+-release channels in ER stress, protein mislocalization, and cone death in a mouse model of CNG-channel deficiency. We examined whether preservation of luminal Ca2+ stores through pharmacological and genetic suppression of ER Ca2+ efflux protects cones by attenuating ER stress. We demonstrated that the inhibition of ER Ca2+-efflux channels reduced all three arms of ER-stress signaling while improving opsin trafficking to cone outer segments and decreasing cone death by 20–35%. Cone-specific gene deletion of the inositol-1,4,5-trisphosphate receptor type I (IP3R1) also significantly increased cone density in the CNG-channel-deficient mice, suggesting that IP3R1 signaling contributes to Ca2+ homeostasis and cone survival. Consistent with the important contribution of organellar Ca2+ signaling in this achromatopsia mouse model, significant differences in dynamic intraorganellar Ca2+ levels were detected in CNG-channel-deficient cones. These results thus identify a novel molecular link between Ca2+ homeostasis and cone degeneration, thereby revealing novel therapeutic targets to preserve cones in inherited retinal degenerative diseases.
2016-03-27 | High-ambient-contrast augmented reality with a tunable transmittance liquid crystal film and a functional reflective polarizer
We have proposed a compact, yet high ambient contrast ratio augmented reality (AR) system by incorporating a tunable transmittance liquid crystal (LC) cell and a thin functional reflective polarizer. The broadband polarization-independent guest–host LC cell can change the transmittance from ~73% to ~26% with merely 8 V. Its response time (~50 ms) is at least 10× faster than that of photochromic materials used in commercial transition glasses. Combining the LC cell with a light sensor, the tunable transmittance LC cell can efficiently improve the ambient contrast ratio of the AR system under different lighting conditions. Meanwhile, the functional reflective polarizer works similarly to a polarizing beam splitter, except that it is much more compact and lighter weight. With some modification, we also designed a functional reflective polarizer to help people with color vision deficiency.
gene therapies
2026-06-11 |
List of metabolites from targeted metabolomics.
Blue cone monochromacy (BCM) is an X-linked cone dystrophy characterized by loss of long- (L) and medium-wavelength (M) cone function. A common cause is the C203R missense mutation, which occurs in both OPN1LW and OPN1MW, or in hybrid OPN1LW/OPN1MW opsin genes. Because BCM primarily affects foveal cones, we generated Opn1mwC198R/Opn1sw-/-/Nrl-/- (C198RAC) mice carrying the murine equivalent of the human C203R mutation on an all-cone retinal background. C198RAC mice exhibited absent photopic ERG responses and significantly shortened cone outer segments, recapitulating foveal cone deficits in BCM. Metabolomic profiling further revealed altered retinal metabolism, including reduced cGMP and elevated oxidative stress–related metabolites. To evaluate therapy, we delivered AAV8-Y733F expressing human L-opsin (OPN1LW) cDNA under the cone-specific PR2.1 promoter at 1 and 5 months of age. Treatment restored cone function, regenerated outer segment structures, and provided rescue for at least 5 months post-injection in both early- and late-treatment groups. These results demonstrate that densely packed cones expressing only the C198R mutant opsin remain viable targets for gene therapy. Together, this study establishes the C198RAC mouse as a cone-rich model mimicking foveal cone conditions in BCM and provides compelling preclinical evidence that AAV-mediated gene augmentation can rescue cone outer segment structure and function, supporting the feasibility of gene therapy for BCM.
2026-06-11 | Gene therapy rescues cone function in an all-cone retina mouse model with the most common cone opsin C203R missense mutation.
Blue cone monochromacy (BCM) is an X-linked cone dystrophy characterized by loss of long- (L) and medium-wavelength (M) cone function. A common cause is the C203R missense mutation, which occurs in both OPN1LW and OPN1MW, or in hybrid OPN1LW/OPN1MW opsin genes. Because BCM primarily affects foveal cones, we generated Opn1mwC198R/Opn1sw-/-/Nrl-/- (C198RAC) mice carrying the murine equivalent of the human C203R mutation on an all-cone retinal background. C198RAC mice exhibited absent photopic ERG responses and significantly shortened cone outer segments, recapitulating foveal cone deficits in BCM. Metabolomic profiling further revealed altered retinal metabolism, including reduced cGMP and elevated oxidative stress-related metabolites. To evaluate therapy, we delivered AAV8-Y733F expressing human L-opsin (OPN1LW) cDNA under the cone-specific PR2.1 promoter at 1 and 5 months of age. Treatment restored cone function, regenerated outer segment structures, and provided rescue for at least 5 months post-injection in both early- and late-treatment groups. These results demonstrate that densely packed cones expressing only the C198R mutant opsin remain viable targets for gene therapy. Together, this study establishes the C198RAC mouse as a cone-rich model mimicking foveal cone conditions in BCM and provides compelling preclinical evidence that AAV-mediated gene augmentation can rescue cone outer segment structure and function, supporting the feasibility of gene therapy for BCM.
2026-05-20 | Gene therapy rescues cone function in opn1mw -/- /opn1sw -/- /Nrl -/- mice, an all-cone model of blue cone monochromacy.
Blue cone monochromacy (BCM) is a congenital vision disorder caused by the loss of L- and M-cone function, leading to severe loss of visual acuity and color perception deficits. To test gene therapy for BCM in a model that mimics the densely packed foveal cones of human retinas, we generated a triple knockout (TKO) mouse model (Opn1mw -/- /Opn1sw -/- /Nrl -/-) with an all-cone retina lacking cone opsins. These mice exhibit abolished cone function, disrupted phototransduction, and altered metabolite profiles resulting from loss of opsin. We then administered AAV-mediated human L-opsin gene supplementation therapy at 1 and 5 months of age to assess cone treatability before and after cone degeneration occurs. Treatment restored cone function, replenished essential cone phototransduction proteins, and partially regenerated some cone outer segment membrane structure. Rescue effects persisted for at least 5 months post-treatment in both younger and older treated groups. These findings demonstrate that opsin-deficient, densely packed cones remain viable targets for gene therapy and support the clinical potential of this approach in BCM patients.
2025-11-25 | Molecular mechanisms limiting the AAV gene therapy treatment window in mouse models of blue cone monochromacy.
Blue cone monochromacy (BCM) is a severe X-linked blinding disorder caused by mutations in the OPN1LW/OPN1MW locus, resulting in impaired cone function and structural degeneration. We conduct a comparative analysis of AAV gene therapy in Opn1mw-/-/Opn1sw-/- (double knockout, DKO) and Opn1mwC198R/Opn1sw-/- (C198R) BCM mouse models to contrast therapeutic outcomes at different stages. We demonstrate the AAV8Y733F capsid achieves superior rescue compared to AAV5. Both DKO and C198R models show comparable therapeutic outcomes, with efficacy consistently decreasing in older mice. Structural analysis reveals both models display rapid degenerative changes in cone outer and inner segments. We observe age-related reductions in transgene expression for both models, potentially resulting from decreased cone transducibility, transgene silencing/downregulation, or disease-related genome expression alterations. Notably, the Pde6c and Cngb3 promoters maintain robust activity in degenerating cones. These findings suggest use of an optimized cone promoter can ultimately extend the therapeutic window and treatment longevity in BCM cones.
2025-09-07 | Gene Therapy Rescues Cone Function in an All-cone Retina Mouse Model for Blue Cone Monochromacy with the Most Common C203R Missense Mutation
Abstract Blue cone monochromacy (BCM) is an X-linked cone dystrophy characterized by loss of long- (L) and medium-wavelength (M) cone function. A common cause is the C203R missense mutation, which occurs in both OPN1LW and OPN1MW , or in hybrid OPN1LW/OPN1MW opsin genes. Because BCM primarily affects foveal cones, we generated Opn1mw C198R /Opn1sw -/- /Nrl -/- ( C198RAC ) mice carrying the murine equivalent of the human C203R mutation on an all-cone retinal background. C198RAC mice exhibited absent photopic ERG responses and significantly shortened cone outer segments, recapitulating foveal cone deficits in BCM. Metabolomic profiling further revealed altered retinal metabolism, including reduced cGMP and elevated oxidative stress–related metabolites. To evaluate therapy, we delivered AAV8-Y733F expressing human L-opsin (OPN1LW) cDNA under the cone-specific PR2.1 promoter at 1 and 5 months of age. Treatment restored cone function, regenerated outer segment structures, and provided rescue for at least 5 months post-injection in both early- and late-treatment groups. These results demonstrate that densely packed cones expressing only the C198R mutant opsin remain viable targets for gene therapy. Together, this study establishes the C198RAC mouse as a cone-rich model of BCM and provides compelling preclinical evidence that AAV-mediated gene augmentation can restore cone structure and function, supporting the feasibility of gene therapy for BCM.
small molecules
2021-12-13 | ATF6 is essential for human cone photoreceptor development.
Endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) signaling promote the pathology of many human diseases. Loss-of-function variants of the UPR regulator Activating Transcription Factor 6 (ATF6) cause severe congenital vision loss diseases such as achromatopsia by unclear pathomechanisms. To investigate this, we generated retinal organoids from achromatopsia patient induced pluripotent stem cells carrying ATF6 disease variants and from gene-edited ATF6 null hESCs. We found that achromatopsia patient and ATF6 null retinal organoids failed to form cone structures concomitant with loss of cone phototransduction gene expression, while rod photoreceptors developed normally. Adaptive optics retinal imaging of achromatopsia patients carrying ATF6 variants also showed absence of cone inner/outer segment structures but preserved rod structures, mirroring the defect in cone formation observed in our retinal organoids. These results establish that ATF6 is essential for human cone development. Interestingly, we find that a selective small molecule ATF6 signaling agonist restores the transcriptional activity of some ATF6 disease-causing variants and stimulates cone growth and gene expression in patient retinal organoids carrying these variants. These findings support that pharmacologic targeting of the ATF6 pathway can promote human cone development and should be further explored for blinding retinal diseases.
2020-12-23 | Non-photopic and photopic visual cycles differentially regulate immediate, early, and late phases of cone photoreceptor-mediated vision.
Cone photoreceptors in the retina enable vision over a wide range of light intensities. However, the processes enabling cone vision in bright light (i.e. photopic vision) are not adequately understood. Chromophore regeneration of cone photopigments may require the retinal pigment epithelium (RPE) and/or retinal Müller glia. In the RPE, isomerization of all-trans-retinyl esters to 11-cis-retinol is mediated by the retinoid isomerohydrolase Rpe65. A putative alternative retinoid isomerase, dihydroceramide desaturase-1 (DES1), is expressed in RPE and Müller cells. The retinol-isomerase activities of Rpe65 and Des1 are inhibited by emixustat and fenretinide, respectively. Here, we tested the effects of these visual cycle inhibitors on immediate, early, and late phases of cone photopic vision. In zebrafish larvae raised under cyclic light conditions, fenretinide impaired late cone photopic vision, while the emixustat-treated zebrafish unexpectedly had normal vision. In contrast, emixustat-treated larvae raised under extensive dark-adaptation displayed significantly attenuated immediate photopic vision concomitant with significantly reduced 11-cis-retinaldehyde (11cRAL). Following 30 min of light, early photopic vision was recovered, despite 11cRAL levels remaining significantly reduced. Defects in immediate cone photopic vision were rescued in emixustat- or fenretinide-treated larvae following exogenous 9-cis-retinaldehyde supplementation. Genetic knockout of Des1 (degs1) or retinaldehyde-binding protein 1b (rlbp1b) did not eliminate photopic vision in zebrafish. Our findings define molecular and temporal requirements of the nonphotopic or photopic visual cycles for mediating vision in bright light.
2017-05-12 | Endoplasmic reticulum (ER) Ca2+-channel activity contributes to ER stress and cone death in cyclic nucleotide-gated channel deficiency
Endoplasmic reticulum (ER) stress and mislocalization of improperly folded proteins have been shown to contribute to photoreceptor death in models of inherited retinal degenerative diseases. In particular, mice with cone cyclic nucleotide-gated (CNG) channel deficiency, a model for achromatopsia, display both early-onset ER stress and opsin mistrafficking. By 2 weeks of age, these mice show elevated signaling from all three arms of the ER-stress pathway, and by 1 month, cone opsin is improperly distributed away from its normal outer segment location to other retinal layers. This work investigated the role of Ca2+-release channels in ER stress, protein mislocalization, and cone death in a mouse model of CNG-channel deficiency. We examined whether preservation of luminal Ca2+ stores through pharmacological and genetic suppression of ER Ca2+ efflux protects cones by attenuating ER stress. We demonstrated that the inhibition of ER Ca2+-efflux channels reduced all three arms of ER-stress signaling while improving opsin trafficking to cone outer segments and decreasing cone death by 20–35%. Cone-specific gene deletion of the inositol-1,4,5-trisphosphate receptor type I (IP3R1) also significantly increased cone density in the CNG-channel-deficient mice, suggesting that IP3R1 signaling contributes to Ca2+ homeostasis and cone survival. Consistent with the important contribution of organellar Ca2+ signaling in this achromatopsia mouse model, significant differences in dynamic intraorganellar Ca2+ levels were detected in CNG-channel-deficient cones. These results thus identify a novel molecular link between Ca2+ homeostasis and cone degeneration, thereby revealing novel therapeutic targets to preserve cones in inherited retinal degenerative diseases. Endoplasmic reticulum (ER) stress and mislocalization of improperly folded proteins have been shown to contribute to photoreceptor death in models of inherited retinal degenerative diseases. In particular, mice with cone cyclic nucleotide-gated (CNG) channel deficiency, a model for achromatopsia, display both early-onset ER stress and opsin mistrafficking. By 2 weeks of age, these mice show elevated signaling from all three arms of the ER-stress pathway, and by 1 month, cone opsin is improperly distributed away from its normal outer segment location to other retinal layers. This work investigated the role of Ca2+-release channels in ER stress, protein mislocalization, and cone death in a mouse model of CNG-channel deficiency. We examined whether preservation of luminal Ca2+ stores through pharmacological and genetic suppression of ER Ca2+ efflux protects cones by attenuating ER stress. We demonstrated that the inhibition of ER Ca2+-efflux channels reduced all three arms of ER-stress signaling while improving opsin trafficking to cone outer segments and decreasing cone death by 20–35%. Cone-specific gene deletion of the inositol-1,4,5-trisphosphate receptor type I (IP3R1) also significantly increased cone density in the CNG-channel-deficient mice, suggesting that IP3R1 signaling contributes to Ca2+ homeostasis and cone survival. Consistent with the important contribution of organellar Ca2+ signaling in this achromatopsia mouse model, significant differences in dynamic intraorganellar Ca2+ levels were detected in CNG-channel-deficient cones. These results thus identify a novel molecular link between Ca2+ homeostasis and cone degeneration, thereby revealing novel therapeutic targets to preserve cones in inherited retinal degenerative diseases.
2016-03-27 | High-ambient-contrast augmented reality with a tunable transmittance liquid crystal film and a functional reflective polarizer
We have proposed a compact, yet high ambient contrast ratio augmented reality (AR) system by incorporating a tunable transmittance liquid crystal (LC) cell and a thin functional reflective polarizer. The broadband polarization-independent guest–host LC cell can change the transmittance from ~73% to ~26% with merely 8 V. Its response time (~50 ms) is at least 10× faster than that of photochromic materials used in commercial transition glasses. Combining the LC cell with a light sensor, the tunable transmittance LC cell can efficiently improve the ambient contrast ratio of the AR system under different lighting conditions. Meanwhile, the functional reflective polarizer works similarly to a polarizing beam splitter, except that it is much more compact and lighter weight. With some modification, we also designed a functional reflective polarizer to help people with color vision deficiency.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
1 orphan drug designation for Blue cone monochromatism.
1 orphan drug designation for Blue cone monochromatism.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
adeno-associated virus vector carrying complementary deoxyribonucleic acid encoding the human long-wave-sensitive opsin 1 (AAV.7m8-L-opsin) | gene therapies | FDA | — | Blue Gen Therapeutics Foundation |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.