Mutation-Dependent Pathomechanisms Determine the Phenotype in the Bestrophinopathies DOI Open Access

Anna-Lena Nachtigal,

Andrea Milenkovic,

Caroline Brandl

et al.

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(5), P. 1597 - 1597

Published: Feb. 26, 2020

Best vitelliform macular dystrophy (BD), autosomal dominant vitreoretinochoroidopathy (ADVIRC), and the recessive bestrophinopathy (ARB), together known as bestrophinopathies, are caused by mutations in bestrophin-1 (BEST1) gene affecting anion transport through plasma membrane of retinal pigment epithelium (RPE). To date, while no treatment exists a better understanding BEST1-related pathogenesis may help to define therapeutic targets. Here, we systematically characterize functional consequences mutant BEST1 thirteen RPE patient cell lines differentiated from human induced pluripotent stem cells (hiPSCs). Both BD ARB hiPSC-RPEs display strong reduction BEST1-mediated function compared control, ADVIRC trigger an increased permeability suggesting stabilized open state condition channel gating. Furthermore, differ degree protein turnover site subcellular quality control with adverse effects on lysosomal pH only BD-related lines. The latter finding is consistent altered processing catalytic enzymes lysosomes. present study provides deeper insight into distinct molecular mechanisms three bestrophinopathies facilitating categorization more than 300 that result phenotypes.

Language: Английский

Microglial Function Is Distinct in Different Anatomical Locations during Retinal Homeostasis and Degeneration DOI Creative Commons

Emily G. O’Koren,

Yu Chen, Mikael Klingeborn

et al.

Immunity, Journal Year: 2019, Volume and Issue: 50(3), P. 723 - 737.e7

Published: March 1, 2019

Language: Английский

Citations

330
Inherited retinal diseases: Therapeutics, clinical trials and end points—A review DOI Creative Commons
Michalis Georgiou, Kaoru Fujinami, Michel Michaelides

et al.

Clinical and Experimental Ophthalmology, Journal Year: 2021, Volume and Issue: 49(3), P. 270 - 288

Published: March 9, 2021

Abstract Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of disorders characterised by photoreceptor degeneration or dysfunction. These typically present with severe vision loss that can be progressive, disease onset ranging from congenital to late adulthood. The advances in genetics, imaging molecular biology, have conspired create the ideal environment for establishing treatments IRDs, first approved gene therapy commencement multiple clinical trials. scope this review is familiarise clinicians scientists current management prospects novel therapies for: (1) macular dystrophies, (2) cone cone‐rod (3) dysfunction syndromes, (4) Leber amaurosis, (5) rod‐cone (6) rod syndromes (7) chorioretinal dystrophies. We also briefly summarise investigated end points ongoing

Language: Английский

Citations

123
Phenotyping and genotyping inherited retinal diseases: Molecular genetics, clinical and imaging features, and therapeutics of macular dystrophies, cone and cone-rod dystrophies, rod-cone dystrophies, Leber congenital amaurosis, and cone dysfunction syndromes DOI
Michalis Georgiou, Anthony G. Robson, Kaoru Fujinami

et al.

Progress in Retinal and Eye Research, Journal Year: 2024, Volume and Issue: 100, P. 101244 - 101244

Published: Jan. 25, 2024

Language: Английский

Citations

53
Mutation-independent rhodopsin gene therapy by knockdown and replacement with a single AAV vector DOI Open Access
Artur V. Cideciyan, Raghavi Sudharsan, Valérie Dufour

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2018, Volume and Issue: 115(36)

Published: Aug. 20, 2018

Inherited retinal degenerations are caused by mutations in >250 genes that affect photoreceptor cells or the pigment epithelium and result vision loss. For autosomal recessive X-linked degenerations, significant progress has been achieved field of gene therapy as evidenced growing number clinical trials recent commercialization first for a form congenital blindness. However, despite efforts to develop treatment most common dominant retinitis pigmentosa (adRP) >150 rhodopsin (RHO) gene, translation clinic stalled. Here, we identified highly efficient shRNA targets human (and canine) RHO mutation-independent manner. In single adeno-associated viral (AAV) vector combined this with replacement cDNA made resistant RNA interference tested construct naturally occurring canine model RHO-adRP. Subretinal injections led nearly complete suppression endogenous RNA, while resulted up 30% normal protein levels. Noninvasive imaging showed photoreceptors treated areas were completely protected from degeneration. Histopathology confirmed retention structure expression rod outer segments. Long-term (>8 mo) follow-up electroretinography indicated stable structural functional preservation. The efficacy clinically relevant large-animal paves way treating patients

Language: Английский

Citations

131
Interpretation of OCT and OCTA images from a histological approach: Clinical and experimental implications DOI
Nicolás Cuenca, Isabel Ortuño‐Lizarán, Xavier Sánchez‐Sáez

et al.

Progress in Retinal and Eye Research, Journal Year: 2020, Volume and Issue: 77, P. 100828 - 100828

Published: Jan. 6, 2020

Language: Английский

Citations

102
Advancing Clinical Trials for Inherited Retinal Diseases: Recommendations from the Second Monaciano Symposium DOI Creative Commons
Debra A. Thompson, Alessandro Iannaccone, Robin R. Ali

et al.

Translational Vision Science & Technology, Journal Year: 2020, Volume and Issue: 9(7), P. 2 - 2

Published: June 3, 2020

Major advances in the study of inherited retinal diseases (IRDs) have placed efforts to develop treatments for these blinding conditions at forefront emerging field precision medicine. As a result, growth clinical trials IRDs has increased rapidly over past decade and is expected further accelerate as more therapeutic possibilities emerge qualified participants are identified. Although guided by established principles, specialized trials, requiring analysis novel outcome measures endpoints small patient populations, present multiple challenges relative design ethical considerations. This position paper reviews recent accomplishments existing presents set recommendations aimed advancing future progress. The goal stimulate discussions among researchers, funding agencies, industry, policy makers that will design, conduct, needed approval effective IRDs, while promoting advocacy ensuring safety.

Language: Английский

Citations

76
Vitelliform maculopathy: Diverse etiologies originating from one common pathway DOI
Claudio Iovino, Prithvi Ramtohul, Adrian Au

et al.

Survey of Ophthalmology, Journal Year: 2023, Volume and Issue: 68(3), P. 361 - 379

Published: Jan. 30, 2023

Language: Английский

Citations

25
Large Animal Models of Inherited Retinal Degenerations: A Review DOI Creative Commons
Paige A. Winkler, Laurence M. Occelli, Simon M. Petersen‐Jones

et al.

Cells, Journal Year: 2020, Volume and Issue: 9(4), P. 882 - 882

Published: April 3, 2020

Studies utilizing large animal models of inherited retinal degeneration (IRD) have proven important in not only the development translational therapeutic approaches, but also improving our understanding disease mechanisms. The dog is predominant species utilized because spontaneous IRD common canine pet population. Cats are a source IRDs. Other with IRDs include sheep, horses and non-human primates (NHP). pig has valuable due to ease which transgenic animals can be generated work ongoing produce engineered other including NHP. These offer advantages over widely used laboratory rodent models. globe size dimensions more closely parallel those humans and, most importantly, they region high cone density denser photoreceptor packing for acuity vision. Laboratory rodents lack such as macular critical cause vision loss humans, having comparable model particularly important. This review will discuss several been study mechanisms relevant equivalent human IRD.

Language: Английский

Citations

68
Leber Congenital Amaurosis (LCA): Potential for Improvement of Vision DOI Creative Commons
Artur V. Cideciyan, Samuel G. Jacobson

Investigative Ophthalmology & Visual Science, Journal Year: 2019, Volume and Issue: 60(5), P. 1680 - 1680

Published: April 22, 2019

Language: Английский

Citations

66
Long-Term Structural Outcomes of Late-Stage RPE65 Gene Therapy DOI Creative Commons

Kristin L. Gardiner,

Artur V. Cideciyan,

Małgorzata Świder

et al.

Molecular Therapy, Journal Year: 2019, Volume and Issue: 28(1), P. 266 - 278

Published: Sept. 3, 2019

The form of hereditary childhood blindness Leber congenital amaurosis (LCA) caused by biallelic RPE65 mutations is considered treatable with a gene therapy product approved in the US and Europe. resulting vision improvement well accepted, but long-term outcomes on natural history retinal degeneration are controversial. We treated four RPE65-mutant dogs mid-life (age = 5–6 years) followed them (4–5 years). At time intervention at mid-life, there were intra-ocular inter-animal differences local photoreceptor layer health ranging from near normal to complete degeneration. Treated locations having more than 63% photoreceptors showed robust treatment-related retention long term. regions less retained progressive similar untreated matched initial stage disease. Unexpectedly, both study eyes tended show compared control eyes. These results support hypothesis that successful arrest progression may only occur relatively intervention, be heretofore unknown mechanisms causing long-distance partial treatment effects beyond region subretinal injection.

Language: Английский

Citations

66