AIMTo identify the genetic defects in a Chinese family with achromatopsia.METHODSA 2.5-year-old boy, who displayed nystagmus, photophobia, and hyperopia since early infancy, was clinically evaluated. To further confir...AIMTo identify the genetic defects in a Chinese family with achromatopsia.METHODSA 2.5-year-old boy, who displayed nystagmus, photophobia, and hyperopia since early infancy, was clinically evaluated. To further confirm and localize the causative mutations in this family, targeted region capture and next-generation sequencing of candidate genes, such as CNGA3, CNGB3, GNAT2, PDE6C, and PDE6H were performed using a custom-made capture array.RESULTSSlit-lamp examination showed no specific findings in the anterior segments. The optic discs and maculae were normal on fundoscopy. The unaffected family members reported no ocular complaints. Clinical signs and symptoms were consistent with a clinical impression of autosomal recessive achromatopsia. The results of sequence analysis revealed two novel missense mutations in CNGA3, c.633T>A (p.D211E) and c.1006G>T (p.V336F), with an autosomal recessive mode of inheritance.CONCLUSIONGenetic analysis of a Chinese family confirmed the clinical diagnosis of achromatopsia. Two novel mutations were identified in CNGA3, which extended the mutation spectrum of this disorder.展开更多
Complete congenital achromatopsia is a devastating hereditary visual disorder. Mutations in the CNGB3 gene account for more than 50% of all known cases of achromatopsia. This work investigated the efficiency of subret...Complete congenital achromatopsia is a devastating hereditary visual disorder. Mutations in the CNGB3 gene account for more than 50% of all known cases of achromatopsia. This work investigated the efficiency of subretinal(SR) delivered AAV8(Y447, 733 F) vector containing a human PR2.1 promoter and a human CNGB3 c DNA in Cngb3-/-/Nrl-/-mice. The Cngb3-/-/Nrl-/- mouse was a cone-dominant model with Cngb3 channel deficiency, which partially mimicked the all-cone foveal structure of human achromatopsia with CNGB3 mutations. Following SR delivery of the vector, AAV-mediated CNGB3 expression restored cone function which was assessed by the restoration of the cone-mediated electroretinogram(ERG) and immunohistochemistry. This therapeutic rescue resulted in long-term improvement of retinal function with the restoration of cone ERG amplitude. This study demonstrated an AAV-mediated gene therapy in a cone-dominant mouse model using a human gene construct and provided the potential to be utilized in clinical trials.展开更多
Inherited retinal degeneration is a major cause of incurable blindness characterized by loss of retinal photoreceptor cells.Inherited retinal degeneration is characterized by high genetic and phenotypic heterogeneity ...Inherited retinal degeneration is a major cause of incurable blindness characterized by loss of retinal photoreceptor cells.Inherited retinal degeneration is characterized by high genetic and phenotypic heterogeneity with several genes mutated in patients affected by these genetic diseases.The high genetic heterogeneity of these diseases hampers the development of effective therapeutic interventions for the cure of a large cohort of patients.Common cell demise mechanisms can be envisioned as targets to treat patients regardless the specific mutation.One of these targets is the increase of intracellular calcium ions,that has been detected in several murine models of inherited retinal degeneration.Recently,neurotrophic factors that favor the efflux of calcium ions to concentrations below toxic levels have been identified as promising molecules that should be evaluated as new treatments for retinal degeneration.Here,we discuss therapeutic options for inherited retinal degeneration and we will focus on neuroprotective approaches,such as the neuroprotective activity of the Pigment epithelium-derived factor.The characterization of specific targets for neuroprotection opens new perspectives together with many questions that require deep analyses to take advantage of this knowledge and develop new therapeutic approaches.We believe that minimizing cell demise by neuroprotection may represent a promising treatment strategy for retinal degeneration.展开更多
Leber＇s congenital amaurosis（LCA）and recent gene therapy advancement for treating inherited retinopathies were extensive literature reviewed using MEDLINE,Pub Med and EMBASE. Adeno-associated viral vectors were the...Leber＇s congenital amaurosis（LCA）and recent gene therapy advancement for treating inherited retinopathies were extensive literature reviewed using MEDLINE,Pub Med and EMBASE. Adeno-associated viral vectors were the most utilised vectors for ocular gene therapy. Cone photoreceptor cells might use an alternate pathway which was not reliant of the retinal pigment epithelium（RPE）derived retinoid isomerohydrolase（RPE65）to access the 11-cis retinal dehydechromophore. Research efforts dedicated on the progression of a gene-based therapy for the treatment of LCA2. Such gene therapy approaches were extremely successful in canine,porcine and rodent LCA2 models. The recombinant AAV2.h RPE65v2 adenoassociated vector contained the RPE65 cDNA and was replication deficient. Its in vitro injection in target cells induced RPE65 protein production. The gene therapy trials that were so far conducted for inherited retinopathies have generated promising results. Phase I clinical trials to cure LCA and choroideremia demonstrated that adeno-associated viral vectors containing RPE genes and photoreceptors respectively,could be successfully administered to inherited retinopathy patients. A phase III trial is presently ongoing and if successful,it will lead the way to additional gene therapy attempts to cure monogenic,inherited retinopathies.展开更多
基金Supported by the National Natural Science Foundation of China(No.81371005No.31100991)
文摘AIMTo identify the genetic defects in a Chinese family with achromatopsia.METHODSA 2.5-year-old boy, who displayed nystagmus, photophobia, and hyperopia since early infancy, was clinically evaluated. To further confirm and localize the causative mutations in this family, targeted region capture and next-generation sequencing of candidate genes, such as CNGA3, CNGB3, GNAT2, PDE6C, and PDE6H were performed using a custom-made capture array.RESULTSSlit-lamp examination showed no specific findings in the anterior segments. The optic discs and maculae were normal on fundoscopy. The unaffected family members reported no ocular complaints. Clinical signs and symptoms were consistent with a clinical impression of autosomal recessive achromatopsia. The results of sequence analysis revealed two novel missense mutations in CNGA3, c.633T>A (p.D211E) and c.1006G>T (p.V336F), with an autosomal recessive mode of inheritance.CONCLUSIONGenetic analysis of a Chinese family confirmed the clinical diagnosis of achromatopsia. Two novel mutations were identified in CNGA3, which extended the mutation spectrum of this disorder.
基金supported by NIH(Grant No.EY023543 to J.P.)Jiangsu Province Foundation for Innovative Research Team(to C.Z.).
文摘Complete congenital achromatopsia is a devastating hereditary visual disorder. Mutations in the CNGB3 gene account for more than 50% of all known cases of achromatopsia. This work investigated the efficiency of subretinal(SR) delivered AAV8(Y447, 733 F) vector containing a human PR2.1 promoter and a human CNGB3 c DNA in Cngb3-/-/Nrl-/-mice. The Cngb3-/-/Nrl-/- mouse was a cone-dominant model with Cngb3 channel deficiency, which partially mimicked the all-cone foveal structure of human achromatopsia with CNGB3 mutations. Following SR delivery of the vector, AAV-mediated CNGB3 expression restored cone function which was assessed by the restoration of the cone-mediated electroretinogram(ERG) and immunohistochemistry. This therapeutic rescue resulted in long-term improvement of retinal function with the restoration of cone ERG amplitude. This study demonstrated an AAV-mediated gene therapy in a cone-dominant mouse model using a human gene construct and provided the potential to be utilized in clinical trials.
基金supported by grants from the Telethon Foundation(GGP14180,GGP19113)the European Union(LSHGCT-2005-512036 and transMed,MSCA-ITN-2017-765441)(all to VM)
文摘Inherited retinal degeneration is a major cause of incurable blindness characterized by loss of retinal photoreceptor cells.Inherited retinal degeneration is characterized by high genetic and phenotypic heterogeneity with several genes mutated in patients affected by these genetic diseases.The high genetic heterogeneity of these diseases hampers the development of effective therapeutic interventions for the cure of a large cohort of patients.Common cell demise mechanisms can be envisioned as targets to treat patients regardless the specific mutation.One of these targets is the increase of intracellular calcium ions,that has been detected in several murine models of inherited retinal degeneration.Recently,neurotrophic factors that favor the efflux of calcium ions to concentrations below toxic levels have been identified as promising molecules that should be evaluated as new treatments for retinal degeneration.Here,we discuss therapeutic options for inherited retinal degeneration and we will focus on neuroprotective approaches,such as the neuroprotective activity of the Pigment epithelium-derived factor.The characterization of specific targets for neuroprotection opens new perspectives together with many questions that require deep analyses to take advantage of this knowledge and develop new therapeutic approaches.We believe that minimizing cell demise by neuroprotection may represent a promising treatment strategy for retinal degeneration.
文摘Leber＇s congenital amaurosis（LCA）and recent gene therapy advancement for treating inherited retinopathies were extensive literature reviewed using MEDLINE,Pub Med and EMBASE. Adeno-associated viral vectors were the most utilised vectors for ocular gene therapy. Cone photoreceptor cells might use an alternate pathway which was not reliant of the retinal pigment epithelium（RPE）derived retinoid isomerohydrolase（RPE65）to access the 11-cis retinal dehydechromophore. Research efforts dedicated on the progression of a gene-based therapy for the treatment of LCA2. Such gene therapy approaches were extremely successful in canine,porcine and rodent LCA2 models. The recombinant AAV2.h RPE65v2 adenoassociated vector contained the RPE65 cDNA and was replication deficient. Its in vitro injection in target cells induced RPE65 protein production. The gene therapy trials that were so far conducted for inherited retinopathies have generated promising results. Phase I clinical trials to cure LCA and choroideremia demonstrated that adeno-associated viral vectors containing RPE genes and photoreceptors respectively,could be successfully administered to inherited retinopathy patients. A phase III trial is presently ongoing and if successful,it will lead the way to additional gene therapy attempts to cure monogenic,inherited retinopathies.
