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Haruhiro Yamashita - One of the best experts on this subject based on the ideXlab platform.
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reduced disc shedding and phagocytosis of photoreceptor outer segment contributes to kava kava extract induced Retinal Degeneration in f344 n rats
Toxicologic Pathology, 2018Co-Authors: Haruhiro Yamashita, Shyamal D Peddada, Kevin Gerrish, Mark J Hoenerhoff, Keith R. Shockley, Deloris Sutton, Connie A. CummingsAbstract:There was a significant increase in the incidence of Retinal Degeneration in F344/N rats chronically exposed to Kava kava extract (KKE) in National Toxicology Program (NTP) bioassay. A retrospective evaluation of these rat retinas indicated a similar spatial and morphological alteration as seen in light-induced Retinal Degeneration in albino rats. Therefore, it was hypothesized that KKE has a potential to exacerbate the light-induced Retinal Degeneration. To investigate the early mechanism of Retinal Degeneration, we conducted a 90-day F344/N rat KKE gavage study at doses of 0 and 1.0 g/kg (dose which induced Retinal Degeneration in the 2-year NTP rat KKE bioassay). The morphological evaluation indicated reduced number of phagosomes in the Retinal pigment epithelium (RPE) of the superior retina. Transcriptomic alterations related to Retinal epithelial homeostasis and melatoninergic signaling were observed in microarray analysis. Phagocytosis of photoreceptor outer segment by the underlying RPE is essentia...
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reduced disc shedding and phagocytosis of photoreceptor outer segment contributes to kava kava extract induced Retinal Degeneration in f344 n rats
Toxicologic Pathology, 2018Co-Authors: Haruhiro Yamashita, Shyamal D Peddada, Kevin Gerrish, Connie A. Cummings, Mark J Hoenerhoff, Keith R. Shockley, Deloris Sutton, Yu WangAbstract:There was a significant increase in the incidence of Retinal Degeneration in F344/N rats chronically exposed to Kava kava extract (KKE) in National Toxicology Program (NTP) bioassay. A retrospective evaluation of these rat retinas indicated a similar spatial and morphological alteration as seen in light-induced Retinal Degeneration in albino rats. Therefore, it was hypothesized that KKE has a potential to exacerbate the light-induced Retinal Degeneration. To investigate the early mechanism of Retinal Degeneration, we conducted a 90-day F344/N rat KKE gavage study at doses of 0 and 1.0 g/kg (dose which induced Retinal Degeneration in the 2-year NTP rat KKE bioassay). The morphological evaluation indicated reduced number of phagosomes in the Retinal pigment epithelium (RPE) of the superior retina. Transcriptomic alterations related to Retinal epithelial homeostasis and melatoninergic signaling were observed in microarray analysis. Phagocytosis of photoreceptor outer segment by the underlying RPE is essential to maintain the homeostasis of the photoreceptor layer and is regulated by melatonin signaling. Therefore, reduced photoreceptor outer segment disc shedding and subsequent lower number of phagosomes in the RPE and alterations in the melatonin pathway may have contributed to the increased incidences of Retinal Degeneration observed in F344/N rats in the 2-year KKE bioassay.
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chemical exacerbation of light induced Retinal Degeneration in f344 n rats in national toxicology program rodent bioassays
Toxicologic Pathology, 2016Co-Authors: Haruhiro Yamashita, Shyamal D Peddada, Mark J Hoenerhoff, Robert C Sills, Arun R PandiriAbstract:Retinal Degeneration due to chronic ambient light exposure is a common spontaneous age-related finding in albino rats, but it can also be related to exposures associated with environmental chemicals and drugs. Typically, light-induced Retinal Degeneration has a central/hemispherical localization whereas chemical-induced Retinal Degeneration has a diffuse localization. This study was conducted to identify and characterize treatment-related Retinal Degeneration in National Toxicology Program rodent bioassays. A total of 3 chronic bioassays in F344/N rats (but not in B6C3F1/N mice) were identified that had treatment-related increases in Retinal Degeneration (kava kava extract, acrylamide, and leucomalachite green). A retrospective light microscopic evaluation of the retinas from rats in these 3 studies showed a dose-related increase in the frequencies of Retinal Degeneration, beginning with the loss of photoreceptor cells, followed by the inner nuclear layer cells. These dose-related increased frequencies of...
Mark J Hoenerhoff - One of the best experts on this subject based on the ideXlab platform.
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reduced disc shedding and phagocytosis of photoreceptor outer segment contributes to kava kava extract induced Retinal Degeneration in f344 n rats
Toxicologic Pathology, 2018Co-Authors: Haruhiro Yamashita, Shyamal D Peddada, Kevin Gerrish, Mark J Hoenerhoff, Keith R. Shockley, Deloris Sutton, Connie A. CummingsAbstract:There was a significant increase in the incidence of Retinal Degeneration in F344/N rats chronically exposed to Kava kava extract (KKE) in National Toxicology Program (NTP) bioassay. A retrospective evaluation of these rat retinas indicated a similar spatial and morphological alteration as seen in light-induced Retinal Degeneration in albino rats. Therefore, it was hypothesized that KKE has a potential to exacerbate the light-induced Retinal Degeneration. To investigate the early mechanism of Retinal Degeneration, we conducted a 90-day F344/N rat KKE gavage study at doses of 0 and 1.0 g/kg (dose which induced Retinal Degeneration in the 2-year NTP rat KKE bioassay). The morphological evaluation indicated reduced number of phagosomes in the Retinal pigment epithelium (RPE) of the superior retina. Transcriptomic alterations related to Retinal epithelial homeostasis and melatoninergic signaling were observed in microarray analysis. Phagocytosis of photoreceptor outer segment by the underlying RPE is essentia...
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reduced disc shedding and phagocytosis of photoreceptor outer segment contributes to kava kava extract induced Retinal Degeneration in f344 n rats
Toxicologic Pathology, 2018Co-Authors: Haruhiro Yamashita, Shyamal D Peddada, Kevin Gerrish, Connie A. Cummings, Mark J Hoenerhoff, Keith R. Shockley, Deloris Sutton, Yu WangAbstract:There was a significant increase in the incidence of Retinal Degeneration in F344/N rats chronically exposed to Kava kava extract (KKE) in National Toxicology Program (NTP) bioassay. A retrospective evaluation of these rat retinas indicated a similar spatial and morphological alteration as seen in light-induced Retinal Degeneration in albino rats. Therefore, it was hypothesized that KKE has a potential to exacerbate the light-induced Retinal Degeneration. To investigate the early mechanism of Retinal Degeneration, we conducted a 90-day F344/N rat KKE gavage study at doses of 0 and 1.0 g/kg (dose which induced Retinal Degeneration in the 2-year NTP rat KKE bioassay). The morphological evaluation indicated reduced number of phagosomes in the Retinal pigment epithelium (RPE) of the superior retina. Transcriptomic alterations related to Retinal epithelial homeostasis and melatoninergic signaling were observed in microarray analysis. Phagocytosis of photoreceptor outer segment by the underlying RPE is essential to maintain the homeostasis of the photoreceptor layer and is regulated by melatonin signaling. Therefore, reduced photoreceptor outer segment disc shedding and subsequent lower number of phagosomes in the RPE and alterations in the melatonin pathway may have contributed to the increased incidences of Retinal Degeneration observed in F344/N rats in the 2-year KKE bioassay.
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chemical exacerbation of light induced Retinal Degeneration in f344 n rats in national toxicology program rodent bioassays
Toxicologic Pathology, 2016Co-Authors: Haruhiro Yamashita, Shyamal D Peddada, Mark J Hoenerhoff, Robert C Sills, Arun R PandiriAbstract:Retinal Degeneration due to chronic ambient light exposure is a common spontaneous age-related finding in albino rats, but it can also be related to exposures associated with environmental chemicals and drugs. Typically, light-induced Retinal Degeneration has a central/hemispherical localization whereas chemical-induced Retinal Degeneration has a diffuse localization. This study was conducted to identify and characterize treatment-related Retinal Degeneration in National Toxicology Program rodent bioassays. A total of 3 chronic bioassays in F344/N rats (but not in B6C3F1/N mice) were identified that had treatment-related increases in Retinal Degeneration (kava kava extract, acrylamide, and leucomalachite green). A retrospective light microscopic evaluation of the retinas from rats in these 3 studies showed a dose-related increase in the frequencies of Retinal Degeneration, beginning with the loss of photoreceptor cells, followed by the inner nuclear layer cells. These dose-related increased frequencies of...
Val C Sheffield - One of the best experts on this subject based on the ideXlab platform.
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tudca slows Retinal Degeneration in two different mouse models of retinitis pigmentosa and prevents obesity in bardet biedl syndrome type 1 mice
Investigative Ophthalmology & Visual Science, 2012Co-Authors: Arlene V Drack, Val C Sheffield, Edwin M Stone, Alina V Dumitrescu, Sajag Bhattarai, Daniel Gratie, Robert F MullinsAbstract:Gene replacement therapy is currently the best hope for patients with progressive Retinal Degenerations due to genetic defects; however, at present only one subtype, RPE65-related Leber congenital amaurosis (LCA), has clinical gene therapy results reported.1–3 For patients who may benefit from gene therapy in the future or who exhibit only the earliest signs of Retinal Degeneration, there is a real need for treatments to slow or stop the progress of disease. In the absence of specific genetic information for a given patient, this could also be a temporizing measure until a genetic diagnosis can be found and a specific therapy devised and administered. An ideal treatment would ameliorate Retinal Degeneration from several different genetic causes. One group of agents that may have this property is antiapoptotic molecules. Apoptosis is the final pathway in programmed cell death. If this pathway can be aborted or delayed, photoreceptor cells may live and function longer. Tauroursodeoxycholic acid (TUDCA) is the active component in bear bile, which has been used in traditional Chinese medicine for thousands of years. In 2006, Boatright et al.4 showed that systemic TUDCA decreased apoptosis and Retinal Degeneration in mice with either light-induced Retinal damage or genetic Retinal Degeneration (RP due to a mutation in the Pde6beta gene in the rd10 mouse) at P18 and P30.5,6 TUDCA has also been found to disrupt apoptosis in animal models of neurodegenerative diseases, such as Alzheimer7,8 and Huntington Disease,9,10 and recently was reported to slow Retinal Degeneration in the Pro23His rat, a model of human autosomal dominant RP.11 We hypothesized that the antiapoptotic effect of TUDCA is also beneficial in treating ciliopathies, a different class of Retinal degenerative disorder. Ciliopathies are characterized by having a primary dysfunction of the cilia, usually in several organ systems, including the connecting cilium of the photoreceptor cell. Disease may result from abnormal formation of the cilium, or abnormal transport within it. To test our hypothesis, we treated a mouse model of Bardet-Biedl syndrome (BBS) type 1, an autosomal recessive ciliopathy that causes severe Retinal Degeneration in humans. This Retinal Degeneration, which is caused by the most common BBS1 mutation in humans.12 is replicated in homozygous Bbs1M390R/M390R mice. BBS was first described in the 1920s by George Bardet, reporting two French girls with the triad of obesity, polydactyly, and RP.13 In 1922, Arthur Biedl reported similar cases.14 Because the syndrome was reminiscent of earlier cases described in 1866 by Laurence and Moon, in 1925 Solis-Cohen and Weiss coined the term Laurence-Moon-Bardet-Biedl syndrome. Later, Laurence and Moon were removed from the name, as their patients eventually developed paraplegia. To date at least 15 BBS genes have been identified. The protein products of seven of these genes associate in vivo to create the BBSome, a protein complex important to intracellular transport and intraflagellar trafficking.15,16 Three other known BBS proteins associate to form the BBS chaperone complex.17,18 Inactivation of any one of these BBS genes may adversely affect the BBSome and/or chaperone complex and therefore affect transport within the cell, explaining how mutations of many different genes can cause the same unusual findings as those in BBS—postaxial polydactyly, obesity, RP, renal and gonadal anomalies, and, in some cases, developmental delay. How this mistrafficking induces dysfunction and apoptosis of photoreceptor cells in the retina is not known. Since the Retinal Degeneration in rd10 mice has been reported to be ameliorated by TUDCA,4,5 we replicated the published protocol in this model as a positive control for our intervention, and in addition we observed the rd10 mice longer than previously reported. We also tested the same treatment protocol on rd1 and rd16 mice, which are models of very rapid Retinal Degeneration analogous to that in autosomal recessive (ar)RP and CEP290-related LCA, respectively, in humans. The purpose of this study was to evaluate the effects of systemic TUDCA on the course of Retinal Degeneration in Bbs1M390R/M390R, rd10, rd1, and rd16 models by electroretinography (ERG), optical coherence tomography (OCT), and histology. We found that, compared to untreated controls and vehicle injected controls, the severity of Retinal Degeneration is lessened in two of the models tested. Treatment with TUDCA also attenuated the severity of obesity in Bbs1M390R/M390R mice.
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a peripherin Retinal Degeneration slow mutation pro 210 arg associated with macular and peripheral Retinal Degeneration
Ophthalmology, 1995Co-Authors: Michael B Gorin, Kelly Jackson, Robert E Ferrell, Val C Sheffield, Samuel G Jacobson, Donald J M Gass, Elysey Mitchell, Edwin M StoneAbstract:Background: Mutations in the peripherin/Retinal Degeneration slow (RDS gene have been identified in patients with retinitis pigmentosa and pattern macular dystrophy. The authors initially examined a large family affected with both peripheral and macular Degeneration, inherited as an autosomal dominant trait. Screening for peripherin/RDS mutations identified a previously unreported nucleotide alteration in all of the affected individuals. Two additional families later were found to have this same mutation. Methods: DNA samples from the members of three unrelated families were screened for peripherin/RDS mutations by denaturing gradient gel electrophoresis of the polymerase chain reaction-amplified peripherin/RDS coding sequences. The sequence change that was detected was further characterized by DNA sequencing. Family members were examined and evaluated with psychophysical and electrophysiologic methods. Results: A proline to arginine mutation in codon 210 of peripherin/RDS was found in all clinically affected individuals. Macular changes included extensive geographic atrophy, pigment epithelial changes, and/or drusen. The proline to arginine mutation was not found among 100 healthy individuals, making it unlikely to be a nondisease-causing polymorphism. Conclusions: The authors identified a novel peripherin/RDS gene mutation associated with autosomal dominant Retinal Degeneration in patients from three different families. The largest family showed a broad variability in the expressivity of the mutation. The overlap of clinical features with those of age-related maculopathy highlights the need to consider photoreceptor-specific genes as potential factors in the etiology of the latter condition.
Austin Roorda - One of the best experts on this subject based on the ideXlab platform.
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longitudinal study of cone photoreceptors during Retinal Degeneration and in response to ciliary neurotrophic factor treatment
Investigative Ophthalmology & Visual Science, 2011Co-Authors: Katherine E. Talcott, Kavitha Ratnam, Austin Roorda, S Sundquist, Anna S Lucero, Brandon J Lujan, Weng Tao, Travis C Porco, Jacque L. DuncanAbstract:Inherited Retinal Degenerations represent a genetically heterogeneous group of diseases that include retinitis pigmentosa (RP) and Usher syndrome type 2. Retinal Degenerations are characterized by slowly progressive death of rod and cone photoreceptors and relentless vision loss.1 One of the challenges that has hampered the development of treatments that may slow vision loss in Retinal Degeneration is the lack of sensitive outcome measures of disease progression.2 Objective, sensitive measures of photoreceptor survival may reduce the time required to identify a treatment effect of an experimental therapy. Neurotrophic factors such as ciliary neurotrophic factor (CNTF) have shown promise in slowing the progression of Retinal Degeneration.3,4 Recent studies suggest CNTF can prevent and reverse secondary cone Degeneration caused by a mutation in rhodopsin, a rod-specific gene.5 A phase 1 study6 of CNTF delivered by intravitreal implantation of a device containing encapsulated cells transfected with the human CNTF gene showed promising results in 10 patients with inherited Retinal Degeneration. Two phase 2 studies were initiated in patients with earlier (CNTF4; ClinicalTrials.gov number, NCT00447980) and later stage (CNTF3; ClinicalTrials.gov number, NCT00447993) inherited Retinal Degeneration. The objective of the CNTF4 study was to investigate whether CNTF treatment slows the loss of visual field sensitivity relative to the contralateral control eye over 24 months. However, natural history studies of Retinal Degeneration predict that significant changes in visual function may be measured reliably only after more than 7 years,7–9 suggesting that significant photoreceptor loss is necessary before changes in visual acuity function can be measured reliably. Outcome measures with greater sensitivity than standard measures of visual function can provide are urgently needed to assess photoreceptors during disease progression and in response to experimental treatments such as CNTF in eyes with Retinal Degeneration. Standard clinical imaging techniques cannot visualize individual photoreceptors because of optical imperfections in living eyes. However, adaptive optics (AO) ophthalmoscopy, including adaptive optics scanning laser ophthalmoscopy (AOSLO), can produce images of individual cone photoreceptors noninvasively in living eyes.10–12 Direct visualization of cones allows comparison of cone spacing and density and, in ideal situations, tracking of individual cones longitudinally. Cone spacing and density have been used to characterize both normal eyes and eyes with Retinal Degeneration.11,13–20 However, they have not been used to track disease progression or response to treatment, including CNTF, in eyes with Retinal Degeneration. We present the first images of individual cone photoreceptors observed longitudinally in normal eyes and in patients with inherited Retinal Degenerations during disease progression. We also report changes in cone photoreceptor structure in response to CNTF therapy in three patients with inherited Retinal Degenerations participating in the CNTF4 phase 2 clinical trial.
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cone structure in Retinal Degeneration associated with mutations in the peripherin rds gene
Investigative Ophthalmology & Visual Science, 2011Co-Authors: Jacque L. Duncan, Anya S Lucero, Kavitha Ratnam, Suvi Sundquist, Katherine E. Talcott, Yuhua Zhang, Austin RoordaAbstract:Peripherin/RDS is an integral membrane glycoprotein involved in photoreceptor outer segment formation.1 peripherin/RDS mutations on chromosome 6p were first reported to cause autosomal dominant retinitis pigmentosa (RP)2,3 but have since been shown to cause a wide variety of Retinal phenotypes including pattern dystrophy,4,5 cone-rod dystrophy,6 adult vitelliform macular dystrophy,7 central areolar choroidal dystrophy,8,9 and autosomal dominant macular dystrophy.10 Peripherin/RDS forms a complex with ROM1, which also plays a role in photoreceptor outer segment disc formation, and heterozygous mutations in peripherin/RDS and ROM1 may produce a digenic form of RP.11 The highly conserved second intradiscal loop is thought to be integral for peripherin/RDS protein function and, thus, for outer segment disc generation and stabilization.6,12 More than 90 different mutations in the peripherin/RDS gene have been associated with Retinal Degeneration, and mutations at the same amino acid position have been associated with diverse clinical phenotypes (http://www.retina-international.org/sci-news/rdsmut.htm). Mutations affecting the intradiscal D2 domain of peripherin/RDS manifest a variety of different Retinal Degeneration phenotypes, supporting the importance of this region for normal photoreceptor outer segment structure and survival. Altering the DNA from cysteine to thymidine at position 514 of the peripherin/RDS cDNA causes an arginine to tryptophan substitution at position 172 (R172W), which has been associated with macular dystrophy, central areolar choroidal dystrophy, cone dystrophy, and cone rod dystrophy.6,10,13–23 Changing guanine to adenosine at position 623 alters the amino acid at position 208 from glycine to aspartic acid (G208D) and is thought to alter the secondary structure of the protein.24 The G208D mutation has been associated with atypical autosomal dominant RP,25 pattern macular dystrophy,10 and central areolar dystrophy.13 Substituting guanine for cysteine at position 629 changes the amino acid at position 210 from proline to arginine (P210R)23,26 and produces adult foveomacular dystrophy26 and both macular and peripheral Retinal Degeneration, including cone-rod Degeneration and RP.23,27 Finally, substituting guanine for adenosine at position 637 changes the amino acid at position 213 from cysteine to tyrosine and causes pattern dystrophy.4 This cysteine is thought to play an important role in intrachain or interchain disulfide bond formation, and mutations at this location may disrupt photoreceptor disc membrane integrity, resulting in photoreceptor Degeneration and lipofuscin accumulation in RPE cells.4 Given the dramatic phenotypic variation observed within and between families with the same mutation, the effect of peripherin/RDS mutations on cone structure in living eyes is not clearly understood. Adaptive optics scanning laser ophthalmoscopy (AOSLO) uses adaptive optics to overcome optical imperfections in living eyes and can be used to obtain Retinal images with lateral resolution of approximately 2 μm, allowing direct visualization of photoreceptors.28–31 Direct visualization of the cone mosaic in patients with Retinal Degeneration allows comparison of cone spacing, density, and regularity with healthy subjects.32–35 In combination with other imaging and diagnostic modalities, measures of cone structure provide insight into the effect different types of Retinal Degeneration have on macular cones.32,33,36–38 Here we present high-resolution Retinal images for four patients with mutations in the peripherin/RDS gene, allowing direct in vivo genotype-phenotype correlation of cone photoreceptor structure and function at the cellular level.
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cone structure in Retinal Degeneration associated with mutations in the peripherin rds gene
Investigative Ophthalmology & Visual Science, 2011Co-Authors: Jacque L. Duncan, Anya S Lucero, Kavitha Ratnam, Katherine E. Talcott, Yuhua Zhang, S Sundquist, Austin RoordaAbstract:Peripherin/RDS is an integral membrane glycoprotein involved in photoreceptor outer segment formation.1 peripherin/RDS mutations on chromosome 6p were first reported to cause autosomal dominant retinitis pigmentosa (RP)2,3 but have since been shown to cause a wide variety of Retinal phenotypes including pattern dystrophy,4,5 cone-rod dystrophy,6 adult vitelliform macular dystrophy,7 central areolar choroidal dystrophy,8,9 and autosomal dominant macular dystrophy.10 Peripherin/RDS forms a complex with ROM1, which also plays a role in photoreceptor outer segment disc formation, and heterozygous mutations in peripherin/RDS and ROM1 may produce a digenic form of RP.11 The highly conserved second intradiscal loop is thought to be integral for peripherin/RDS protein function and, thus, for outer segment disc generation and stabilization.6,12 More than 90 different mutations in the peripherin/RDS gene have been associated with Retinal Degeneration, and mutations at the same amino acid position have been associated with diverse clinical phenotypes (http://www.retina-international.org/sci-news/rdsmut.htm). Mutations affecting the intradiscal D2 domain of peripherin/RDS manifest a variety of different Retinal Degeneration phenotypes, supporting the importance of this region for normal photoreceptor outer segment structure and survival. Altering the DNA from cysteine to thymidine at position 514 of the peripherin/RDS cDNA causes an arginine to tryptophan substitution at position 172 (R172W), which has been associated with macular dystrophy, central areolar choroidal dystrophy, cone dystrophy, and cone rod dystrophy.6,10,13–23 Changing guanine to adenosine at position 623 alters the amino acid at position 208 from glycine to aspartic acid (G208D) and is thought to alter the secondary structure of the protein.24 The G208D mutation has been associated with atypical autosomal dominant RP,25 pattern macular dystrophy,10 and central areolar dystrophy.13 Substituting guanine for cysteine at position 629 changes the amino acid at position 210 from proline to arginine (P210R)23,26 and produces adult foveomacular dystrophy26 and both macular and peripheral Retinal Degeneration, including cone-rod Degeneration and RP.23,27 Finally, substituting guanine for adenosine at position 637 changes the amino acid at position 213 from cysteine to tyrosine and causes pattern dystrophy.4 This cysteine is thought to play an important role in intrachain or interchain disulfide bond formation, and mutations at this location may disrupt photoreceptor disc membrane integrity, resulting in photoreceptor Degeneration and lipofuscin accumulation in RPE cells.4 Given the dramatic phenotypic variation observed within and between families with the same mutation, the effect of peripherin/RDS mutations on cone structure in living eyes is not clearly understood. Adaptive optics scanning laser ophthalmoscopy (AOSLO) uses adaptive optics to overcome optical imperfections in living eyes and can be used to obtain Retinal images with lateral resolution of approximately 2 μm, allowing direct visualization of photoreceptors.28–31 Direct visualization of the cone mosaic in patients with Retinal Degeneration allows comparison of cone spacing, density, and regularity with healthy subjects.32–35 In combination with other imaging and diagnostic modalities, measures of cone structure provide insight into the effect different types of Retinal Degeneration have on macular cones.32,33,36–38 Here we present high-resolution Retinal images for four patients with mutations in the peripherin/RDS gene, allowing direct in vivo genotype-phenotype correlation of cone photoreceptor structure and function at the cellular level.
Edwin M Stone - One of the best experts on this subject based on the ideXlab platform.
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tudca slows Retinal Degeneration in two different mouse models of retinitis pigmentosa and prevents obesity in bardet biedl syndrome type 1 mice
Investigative Ophthalmology & Visual Science, 2012Co-Authors: Arlene V Drack, Val C Sheffield, Edwin M Stone, Alina V Dumitrescu, Sajag Bhattarai, Daniel Gratie, Robert F MullinsAbstract:Gene replacement therapy is currently the best hope for patients with progressive Retinal Degenerations due to genetic defects; however, at present only one subtype, RPE65-related Leber congenital amaurosis (LCA), has clinical gene therapy results reported.1–3 For patients who may benefit from gene therapy in the future or who exhibit only the earliest signs of Retinal Degeneration, there is a real need for treatments to slow or stop the progress of disease. In the absence of specific genetic information for a given patient, this could also be a temporizing measure until a genetic diagnosis can be found and a specific therapy devised and administered. An ideal treatment would ameliorate Retinal Degeneration from several different genetic causes. One group of agents that may have this property is antiapoptotic molecules. Apoptosis is the final pathway in programmed cell death. If this pathway can be aborted or delayed, photoreceptor cells may live and function longer. Tauroursodeoxycholic acid (TUDCA) is the active component in bear bile, which has been used in traditional Chinese medicine for thousands of years. In 2006, Boatright et al.4 showed that systemic TUDCA decreased apoptosis and Retinal Degeneration in mice with either light-induced Retinal damage or genetic Retinal Degeneration (RP due to a mutation in the Pde6beta gene in the rd10 mouse) at P18 and P30.5,6 TUDCA has also been found to disrupt apoptosis in animal models of neurodegenerative diseases, such as Alzheimer7,8 and Huntington Disease,9,10 and recently was reported to slow Retinal Degeneration in the Pro23His rat, a model of human autosomal dominant RP.11 We hypothesized that the antiapoptotic effect of TUDCA is also beneficial in treating ciliopathies, a different class of Retinal degenerative disorder. Ciliopathies are characterized by having a primary dysfunction of the cilia, usually in several organ systems, including the connecting cilium of the photoreceptor cell. Disease may result from abnormal formation of the cilium, or abnormal transport within it. To test our hypothesis, we treated a mouse model of Bardet-Biedl syndrome (BBS) type 1, an autosomal recessive ciliopathy that causes severe Retinal Degeneration in humans. This Retinal Degeneration, which is caused by the most common BBS1 mutation in humans.12 is replicated in homozygous Bbs1M390R/M390R mice. BBS was first described in the 1920s by George Bardet, reporting two French girls with the triad of obesity, polydactyly, and RP.13 In 1922, Arthur Biedl reported similar cases.14 Because the syndrome was reminiscent of earlier cases described in 1866 by Laurence and Moon, in 1925 Solis-Cohen and Weiss coined the term Laurence-Moon-Bardet-Biedl syndrome. Later, Laurence and Moon were removed from the name, as their patients eventually developed paraplegia. To date at least 15 BBS genes have been identified. The protein products of seven of these genes associate in vivo to create the BBSome, a protein complex important to intracellular transport and intraflagellar trafficking.15,16 Three other known BBS proteins associate to form the BBS chaperone complex.17,18 Inactivation of any one of these BBS genes may adversely affect the BBSome and/or chaperone complex and therefore affect transport within the cell, explaining how mutations of many different genes can cause the same unusual findings as those in BBS—postaxial polydactyly, obesity, RP, renal and gonadal anomalies, and, in some cases, developmental delay. How this mistrafficking induces dysfunction and apoptosis of photoreceptor cells in the retina is not known. Since the Retinal Degeneration in rd10 mice has been reported to be ameliorated by TUDCA,4,5 we replicated the published protocol in this model as a positive control for our intervention, and in addition we observed the rd10 mice longer than previously reported. We also tested the same treatment protocol on rd1 and rd16 mice, which are models of very rapid Retinal Degeneration analogous to that in autosomal recessive (ar)RP and CEP290-related LCA, respectively, in humans. The purpose of this study was to evaluate the effects of systemic TUDCA on the course of Retinal Degeneration in Bbs1M390R/M390R, rd10, rd1, and rd16 models by electroretinography (ERG), optical coherence tomography (OCT), and histology. We found that, compared to untreated controls and vehicle injected controls, the severity of Retinal Degeneration is lessened in two of the models tested. Treatment with TUDCA also attenuated the severity of obesity in Bbs1M390R/M390R mice.
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a peripherin Retinal Degeneration slow mutation pro 210 arg associated with macular and peripheral Retinal Degeneration
Ophthalmology, 1995Co-Authors: Michael B Gorin, Kelly Jackson, Robert E Ferrell, Val C Sheffield, Samuel G Jacobson, Donald J M Gass, Elysey Mitchell, Edwin M StoneAbstract:Background: Mutations in the peripherin/Retinal Degeneration slow (RDS gene have been identified in patients with retinitis pigmentosa and pattern macular dystrophy. The authors initially examined a large family affected with both peripheral and macular Degeneration, inherited as an autosomal dominant trait. Screening for peripherin/RDS mutations identified a previously unreported nucleotide alteration in all of the affected individuals. Two additional families later were found to have this same mutation. Methods: DNA samples from the members of three unrelated families were screened for peripherin/RDS mutations by denaturing gradient gel electrophoresis of the polymerase chain reaction-amplified peripherin/RDS coding sequences. The sequence change that was detected was further characterized by DNA sequencing. Family members were examined and evaluated with psychophysical and electrophysiologic methods. Results: A proline to arginine mutation in codon 210 of peripherin/RDS was found in all clinically affected individuals. Macular changes included extensive geographic atrophy, pigment epithelial changes, and/or drusen. The proline to arginine mutation was not found among 100 healthy individuals, making it unlikely to be a nondisease-causing polymorphism. Conclusions: The authors identified a novel peripherin/RDS gene mutation associated with autosomal dominant Retinal Degeneration in patients from three different families. The largest family showed a broad variability in the expressivity of the mutation. The overlap of clinical features with those of age-related maculopathy highlights the need to consider photoreceptor-specific genes as potential factors in the etiology of the latter condition.