First-in-Human Gene Therapy Trial of AAV8-hCARp.hCNGB3 in Adults and Children with CNGB3-associated Achromatopsia
Achromatopsia (ACHM) is a rare, autosomal, recessive, predominantly stationary cone dysfunction syndrome affecting an estimated 1 in 30,000 births worldwide.1-3 This disabling congenital disorder is characterized by absent or markedly impaired color discrimination, reduced visual acuity (VA; usually 20/200), central scotoma, eccentric fixation, disabling sensitivity to light (ie, photoaversion [PA]), and pendular nystagmus.2-4 It is primarily caused by sequence variants in genes that are critical to phototransduction in cone photoreceptors; most cases are associated with changes in either CNGA3 or CNGB3, which encode the Î...
Source: American Journal of Ophthalmology - May 10, 2023 Category: Opthalmology Authors: Michel Michaelides, Nashila Hirji, Sui Chien Wong, Cagri G. Besirli, Serena Zaman, Neruban Kumaran, Anastasios Georgiadis, Alexander J. Smith, Caterina Ripamonti, Irene Gottlob, Anthony G. Robson, Alberta Thiadens, Robert H. Henderson, Penny Fleck, Eddy A Tags: Original Articles Source Type: research
Genes, Vol. 14, Pages 690: Genetic and Clinical Characterization of Danish Achromatopsia Patients
Kessel
Achromatopsia is a rare congenital condition with cone photoreceptor dysfunction causing color blindness, reduced vision, nystagmus and photophobia. New treatments are being developed, but the current evidence is still conflicting regarding possible progression over time, and there is no clear genotype-phenotype correlation. This natural history study aimed to further explore the course of disease and potential clinical differences between various genotypes. The retrospective design allowed for the study of a large cohort with a long follow-up. Patients were identified from the Danish national registries. If no...
Source: Genes - March 10, 2023 Category: Genetics & Stem Cells Authors: Mette Kj øbæk Gundestrup Andersen Mette Bertelsen Karen Gr ønskov Susanne Kohl Line Kessel Tags: Article Source Type: research
Genes, Vol. 14, Pages 519: Clinical and Genetic Features of Korean Patients with Achromatopsia
Se Joon Woo
This multicenter study aimed to characterize Korean patients with achromatopsia. The patients’ genotypes and phenotypes were retrospectively evaluated. Twenty-one patients (with a mean age at the baseline of 10.9 years) were enrolled and followed up for a mean of 7.3 years. A targeted gene panel or exome sequencing was performed. The pathogenic variants of the four genes and their frequencies were identified. CNGA3 and PDE6C were equally the most prevalent genes: CNGA3 (N = 8, 38.1%), PDE6C (N = 8, 38.1%), CNGB3 (N = 3, 14.3%), and GNAT2 (N = 2, 9.5%). The degree of functional and structural d...
Source: Genes - February 18, 2023 Category: Genetics & Stem Cells Authors: Yong Je Choi Kwangsic Joo Hyun Taek Lim Sung Soo Kim Jinu Han Se Joon Woo Tags: Article Source Type: research
Mitochondria and Endoplasmic Reticulum Stress in Retinal Organoids from Vision Loss Patients
Am J Pathol. 2022 Dec 16:S0002-9440(22)00397-2. doi: 10.1016/j.ajpath.2022.12.002. Online ahead of print.ABSTRACTActivating transcription factor 6 (ATF6), a key regulator of the unfolded protein response (UPR), is required for endoplasmic reticulum (ER) function and protein homeostasis. Variants of ATF6 that abrogate transcriptional activity cause morphologic and molecular defects in cones manifesting clinically as the human vision loss disease achromatopsia (ACHM). ATF6 is expressed in all retinal cells. However, the effect of disease-associated ATF6 variants on other retinal cell types remains unclear. To investigate thi...
Source: Am J Pathol - December 19, 2022 Category: Pathology Authors: Eun-Jin Lee Monica Sophia Diaz-Aguilar Hyejung Min Jihee Choi Diego Adrian Valdez Duran Julia M Grandjean R Luke Wiseman Heike Kroeger Jonathan H Lin Source Type: research
Mitochondria and Endoplasmic Reticulum Stress in Retinal Organoids from Vision Loss Patients
Am J Pathol. 2022 Dec 16:S0002-9440(22)00397-2. doi: 10.1016/j.ajpath.2022.12.002. Online ahead of print.ABSTRACTActivating transcription factor 6 (ATF6), a key regulator of the unfolded protein response (UPR), is required for endoplasmic reticulum (ER) function and protein homeostasis. Variants of ATF6 that abrogate transcriptional activity cause morphologic and molecular defects in cones manifesting clinically as the human vision loss disease achromatopsia (ACHM). ATF6 is expressed in all retinal cells. However, the effect of disease-associated ATF6 variants on other retinal cell types remains unclear. To investigate thi...
Source: The American Journal of Pathology - December 19, 2022 Category: Pathology Authors: Eun-Jin Lee Monica Sophia Diaz-Aguilar Hyejung Min Jihee Choi Diego Adrian Valdez Duran Julia M Grandjean R Luke Wiseman Heike Kroeger Jonathan H Lin Source Type: research
Mitochondria and Endoplasmic Reticulum Stress in Retinal Organoids from Vision Loss Patients
Am J Pathol. 2022 Dec 16:S0002-9440(22)00397-2. doi: 10.1016/j.ajpath.2022.12.002. Online ahead of print.ABSTRACTActivating transcription factor 6 (ATF6), a key regulator of the unfolded protein response (UPR), is required for endoplasmic reticulum (ER) function and protein homeostasis. Variants of ATF6 that abrogate transcriptional activity cause morphologic and molecular defects in cones manifesting clinically as the human vision loss disease achromatopsia (ACHM). ATF6 is expressed in all retinal cells. However, the effect of disease-associated ATF6 variants on other retinal cell types remains unclear. To investigate thi...
Source: Am J Pathol - December 19, 2022 Category: Pathology Authors: Eun-Jin Lee Monica Sophia Diaz-Aguilar Hyejung Min Jihee Choi Diego Adrian Valdez Duran Julia M Grandjean R Luke Wiseman Heike Kroeger Jonathan H Lin Source Type: research
Mitochondria and Endoplasmic Reticulum Stress in Retinal Organoids from Vision Loss Patients
Am J Pathol. 2022 Dec 16:S0002-9440(22)00397-2. doi: 10.1016/j.ajpath.2022.12.002. Online ahead of print.ABSTRACTActivating transcription factor 6 (ATF6), a key regulator of the unfolded protein response (UPR), is required for endoplasmic reticulum (ER) function and protein homeostasis. Variants of ATF6 that abrogate transcriptional activity cause morphologic and molecular defects in cones manifesting clinically as the human vision loss disease achromatopsia (ACHM). ATF6 is expressed in all retinal cells. However, the effect of disease-associated ATF6 variants on other retinal cell types remains unclear. To investigate thi...
Source: The American Journal of Pathology - December 19, 2022 Category: Pathology Authors: Eun-Jin Lee Monica Sophia Diaz-Aguilar Hyejung Min Jihee Choi Diego Adrian Valdez Duran Julia M Grandjean R Luke Wiseman Heike Kroeger Jonathan H Lin Source Type: research
Mitochondria and Endoplasmic Reticulum Stress in Retinal Organoids from Patients with Vision Loss
Activating transcription factor 6 (ATF6), a key regulator of the unfolded protein response, is required for endoplasmic reticulum function and protein homeostasis. Variants of ATF6 that abrogate transcriptional activity cause morphologic and molecular defects in cones, manifesting clinically as the human vision loss disease achromatopsia (ACHM). ATF6 is expressed in all retinal cells. However, the effect of disease-associated ATF6 variants on other retinal cell types remains unclear. To investigate this question, we analyzed bulk RNA-sequencing transcriptomes from retinal organoids generated from patients with ACHM, carryi...
Source: American Journal of Pathology - December 16, 2022 Category: Pathology Authors: Eun-Jin Lee, Monica S. Diaz-Aguilar, Hyejung Min, Jihee Choi, Diego A. Valdez Duran, Julia M. Grandjean, R. Luke Wiseman, Heike Kroeger, Jonathan H. Lin Tags: Regular article Source Type: research
Mitochondria and Endoplasmic Reticulum Stress in Retinal Organoids from Vision Loss Patients
Activating transcription factor 6 (ATF6), a key regulator of the unfolded protein response (UPR), is required for endoplasmic reticulum (ER) function and protein homeostasis. Variants of ATF6 that abrogate transcriptional activity cause morphologic and molecular defects in cones manifesting clinically as the human vision loss disease achromatopsia (ACHM). ATF6 is expressed in all retinal cells. However, the effect of disease-associated ATF6 variants on other retinal cell types remains unclear. To investigate this question, we analyzed bulk-RNA-seq transcriptomes from retinal-organoids generated from ACHM patients carrying ...
Source: American Journal of Pathology - December 16, 2022 Category: Pathology Authors: Eun-Jin Lee, Monica Sophia Diaz-Aguilar, Hyejung Min, Jihee Choi, Diego Adrian Valdez Duran, Julia M. Grandjean, R. Luke Wiseman, Heike Kroeger, Jonathan H. Lin Tags: Regular Article Source Type: research
Frequency-dependent retinal responsiveness to sinusoidal electrical stimulation in achromatopsia
Exp Eye Res. 2022 Dec 11:109349. doi: 10.1016/j.exer.2022.109349. Online ahead of print.NO ABSTRACTPMID:36516904 | DOI:10.1016/j.exer.2022.109349 (Source: Experimental Eye Research)
Source: Experimental Eye Research - December 14, 2022 Category: Opthalmology Authors: Ronja Jung Melanie Kempf Lisa Pohl Friederike Kort üm Milda Reith Carina Kelbsch Susanne Kohl Helmut Wilhelm Barbara Wilhelm Katarina Stingl Krunoslav Stingl Source Type: research
Frequency-dependent retinal responsiveness to sinusoidal electrical stimulation in achromatopsia
Exp Eye Res. 2022 Dec 11:109349. doi: 10.1016/j.exer.2022.109349. Online ahead of print.NO ABSTRACTPMID:36516904 | DOI:10.1016/j.exer.2022.109349 (Source: Experimental Eye Research)
Source: Experimental Eye Research - December 14, 2022 Category: Opthalmology Authors: Ronja Jung Melanie Kempf Lisa Pohl Friederike Kort üm Milda Reith Carina Kelbsch Susanne Kohl Helmut Wilhelm Barbara Wilhelm Katarina Stingl Krunoslav Stingl Source Type: research
REPRODUCTIVE OPHTHALMOLOGY: The Intersection of Inherited Eye Diseases and Reproductive Technologies
Conclusion:
A close collaboration between patients, families, ophthalmologists, reproductive genetic counselors, and reproductive endocrinology and infertility specialists is the ideal model for taking care of patients interested in preimplantation genetic testing for preventing the transmission of inherited eye diseases. (Source: RETINA)
Source: RETINA - October 25, 2022 Category: Opthalmology Tags: Review Source Type: research
Three-year results of phase I retinal gene therapy trial for CNGA3-mutated achromatopsia: results of a non randomised controlled trial
Conclusion
The results demonstrate a very good safety profile of the therapy even at the highest dose administered. The small sample size limits the statistical power of efficacy analyses. However, trial results inform on the most promising design and endpoints for future clinical trials. Such trials have to determine whether treatment of younger patients results in greater functional gains by avoiding amblyopia as a potential limiting factor. (Source: British Journal of Ophthalmology)
Source: British Journal of Ophthalmology - October 20, 2022 Category: Opthalmology Authors: Reichel, F. F., Michalakis, S., Wilhelm, B., Zobor, D., Muehlfriedel, R., Kohl, S., Weisschuh, N., Sothilingam, V., Kuehlewein, L., Kahle, N., Seitz, I., Paquet-Durand, F., Tsang, S. H., Martus, P., Peters, T., Seeliger, M., Bartz-Schmidt, K. U., Ueffing, Tags: Original articles - Clinical science Source Type: research
GSE195895 Increased H3K27 trimethylation contributes to cone survival in a mouse model of cone dystrophy
This study uses the Pde6ccpfl1 mouse model of achromatopsia, a cone-specific vision loss IRD, to investigate the potential gene-independent therapeutic benefits of a histone demethylase inhibitor GSK-J4 on cone cell survival. We investigated the effects of GSK-J4 treatment on cone cell survival in vivo and ex vivo and changes in cone-specific gene expression via single-cell RNA sequencing. A single intravitreal GSK-J4 injection led to transcriptional changes in pathways involved in mitochondrial dysfunction, endoplasmic reticulum stress, among other key epigenetic pathways, highlighting the complex interplay between methyl...
Source: GEO: Gene Expression Omnibus - July 20, 2022 Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Mus musculus Source Type: research
Increased H3K27 trimethylation contributes to cone survival in a mouse model of cone dystrophy
This study uses the Pde6ccpfl1 mouse model of achromatopsia, a cone-specific vision loss IRD (Inherited retinal disease), to investigate the potential gene-independent therapeutic benefits of a histone demethylase inhibitor GSK-J4 on cone cell survival. We investigated the effects of GSK-J4 treatment on cone cell survival in vivo and ex vivo and changes in cone-specific gene expression via single-cell RNA sequencing. A single intravitreal GSK-J4 injection led to transcriptional changes in pathways involved in mitochondrial dysfunction, endoplasmic reticulum stress, among other key epigenetic pathways, highlighting the comp...
Source: Cellular and Molecular Life Sciences : CMLS - July 10, 2022 Category: Cytology Authors: Annie L Miller Paula I Fuller-Carter Klaudija Masarini Marijana Samardzija Kim W Carter Rabab Rashwan Xin Ru Lim Alicia A Brunet Abha Chopra Ramesh Ram Christian Grimm Marius Ueffing Livia S Carvalho Dragana Trifunovi ć Source Type: research
