Article
Multidisciplinary Sciences
Samuel G. Jacobson, Artur Cideciyan, Allen C. Ho, Igor Peshenko, Alexandra Garafalo, Alejandro J. Roman, Alexander Sumaroka, Vivian Wu, Arun K. Krishnan, Rebecca Sheplock, Sanford L. Boye, Alexander M. Dizhoor, Shannon E. Boye
Summary: The ongoing first-in-human clinical trial of gene therapy for Leber congenital amaurosis due to mutations in the GUCY2D gene has shown promising early results, demonstrating safety and efficacy in both rod and cone photoreceptor function.
Article
Ophthalmology
Xufeng Dai, Xumin Jin, Qian Ye, Haixiao Huang, Lan Duo, Chunjie Lu, Jinhua Bao, Hao Chen
Summary: High expression of the RPE-specific RPE65 enzyme is crucial for generating 11-cis-retinal, a key component for vision. Deficiency in RPE65 can lead to severe retinal dysfunction, but early treatment with 11-cis-retinal in a mouse model shows promise in delaying cone degeneration and preserving retinal function.
EXPERIMENTAL EYE RESEARCH
(2021)
Article
Cell Biology
Matthew J. Annear, Freya M. Mowat, Laurence M. Occelli, Alexander J. Smith, Paul G. Curran, James W. Bainbridge, Robin R. Ali, Simon M. Petersen-Jones
Summary: The Rpe65-deficient dog model has been crucial for studying LCA2 translational therapies. This study provided a comprehensive report on the natural history of retinal changes in this model, showing age-related decline in retinal sensitivity and thickness. The findings suggest that photoreceptor loss leads to vision impairment, but some desensitized photoreceptors may still exist in older dogs.
Article
Biotechnology & Applied Microbiology
Albert M. Maguire, Jean Bennett, Elena M. Aleman, Bart P. Leroy, Tomas S. Aleman
Summary: Luxturna, the first FDA-approved gene therapy product for a genetic disease, has reversed blindness in individuals with retinal degenerative disease. It has not only transformed the lives of many previously destined to live a life of blindness, but also sparked interest in developing gene therapy treatments for other inherited retinal diseases.
Article
Biochemistry & Molecular Biology
Carey Y. L. Huh, Henri Leinonen, Taylor Nakayama, Julia R. Tomasello, Jianye Zhang, Jack Zeitoun, John P. Peach, Maximilian Halabi, Jianying Z. Kiser, Krzysztof Palczewski, Philip D. Kiser, Sunil P. Gandhi
Summary: This study found that adult mice can recover visual responsiveness in the primary visual cortex following the correction of retinal defects through retinoid treatment. The treatment increases the number and amplitude of visually responsive neurons and restores the balance of eye-specific responses in the cortex. Additionally, it rescues the modulation of cortical responses by arousal.
Article
Biotechnology & Applied Microbiology
Gustavo D. Aguirre, Artur Cideciyan, Valerie L. Dufour, Ana Ripolles-Garcia, Raghavi Sudharsan, Malgorzata Swider, Roman Nikonov, Simone Iwabe, Sanford L. Boye, William W. Hauswirth, Samuel G. Jacobson, William A. Beltran
Summary: Gene therapy using AAV-mediated NPHP5 gene augmentation successfully restores photoreceptor structure, function, and vision in a canine model of Leber congenital amaurosis, offering a potential path for translation to human treatment.
Article
Genetics & Heredity
Isabelle Perrault, Sylvain Hanein, Xavier Gerard, Nelson Mounguengue, Ryme Bouyakoub, Mohammed Zarhrate, Cecile Fourrage, Fabienne Jabot-Hanin, Beatrice Bocquet, Isabelle Meunier, Xavier Zanlonghi, Josseline Kaplan, Jean-Michel Rozet
Summary: This study investigates the non-coding regions of a non-syndromic LCA gene, identifying the most frequent disease allele.
Review
Genetics & Heredity
Chu-Hsuan Huang, Chung-May Yang, Chang-Hao Yang, Yu-Chih Hou, Ta-Ching Chen
Summary: Leber's congenital amaurosis (LCA) is a severe genetic retinal disease responsible for 20% of childhood blindness, with its genetic background widely understood and disease-causing variants identified in 38 genes. Different pathogenetic mechanisms result in dysfunction or absence of encoded proteins in the visual cycle, leading to extensive heterogeneity in clinical phenotypes. Gene therapy shows promise in managing LCA, with ongoing clinical trials focusing on common disease-causing genes such as RPE65.
Article
Genetics & Heredity
Amani Albakri, Phattrawan Pisuchpen, Jenina E. Capasso, Adele Schneider, Sarina Kopinsky, Tom Glaser, John P. -W. Chiang, Anamaria Akapito Yomai, Donna McNear, Alex V. Levin
Summary: The purpose of this article is to determine the cause of Leber congenital amaurosis (LCA) in Chuuk state, Federated States of Micronesia (FSM). Five patients with early-onset vision loss were examined in Chuuk state, FSM, and were initially misdiagnosed with microphthalmia. However, a complete ophthalmological exam established a clinical diagnosis of LCA. DNA sequencing revealed a homozygous CRB1 NM_201253.3:c.3134del pathogenic variant in affected individuals. This discovery of a founder pathogenic variant in CRB1 will lead to appropriate recurrence risk counseling.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
(2023)
Article
Genetics & Heredity
Elisa Sorrentino, Elena Albion, Chiara Modena, Muharrem Daja, Stefano Cecchin, Stefano Paolacci, Jan Miertus, Matteo Bertelli, Paolo Enrico Maltese, Pietro Chiurazzi, Liborio Stuppia, Leonardo Colombo, Giuseppe Marceddu
Summary: PacMAGI is an automated pipeline for analyzing PacBio data and detecting second hits on the RPE65 gene. In our study, we used this pipeline to detect second hits in LCA or RP patients with only a single heterozygous variant, and we identified a previously undetected pathogenic variant.
Article
Genetics & Heredity
Elisa Sorrentino, Elena Albion, Chiara Modena, Muharrem Daja, Stefano Cecchin, Stefano Paolacci, Jan Miertus, Matteo Bertelli, Paolo Enrico Maltese, Pietro Chiurazzi, Liborio Stuppia, Leonardo Colombo, Giuseppe Marceddu
Summary: Third generation sequencing methods like PacBio provide detailed information on structural variants and promoters. Our automated pipeline, PacMAGI, assists in the analysis of PacBio data. Bi-allelic mutations in the RPE65 gene are associated with inherited retinal diseases, with NGS analysis focusing on coding regions and intron/exon junctions.
Article
Engineering, Biomedical
Susie Suh, Elliot H. Choi, Henri Leinonen, Andrzej T. Foik, Gregory A. Newby, Wei-Hsi Yeh, Zhiqian Dong, Philip D. Kiser, David C. Lyon, David R. Liu, Krzysztof Palczewski
Summary: Subretinal viral delivery of an adenine base editor and a single-guide RNA targeting a nonsense mutation in the Rpe65 gene restores near-normal levels of retinal and visual functions in mice.
NATURE BIOMEDICAL ENGINEERING
(2021)
Article
Ophthalmology
Francesco Testa, Vittoria Murro, Sabrina Signorini, Leonardo Colombo, Giancarlo Iarossi, Francesco Parmeggiani, Benedetto Falsini, Anna Paola Salvetti, Raffaella Brunetti-Pierri, Giorgia Aprile, Chiara Bertone, Agnese Suppiej, Francesco Romano, Marianthi Karali, Simone Donati, Paolo Melillo, Andrea Sodi, Luciano Quaranta, Luca Rossetti, Luca Buzzonetti, Marzio Chizzolini, Stanislao Rizzo, Giovanni Staurenghi, Sandro Banfi, Claudio Azzolini, Francesca Simonelli
Summary: This study investigated the development of inherited retinal degenerations (IRD) due to mutations in the RPE65 gene in an Italian population. By collecting data on visual acuity, visual field, and imaging, the study found a correlation between genotype and phenotype, which can contribute to better management of RPE65-associated IRD patients.
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
(2022)
Review
Genetics & Heredity
Wenhua Duan, Taicheng Zhou, Huawei Jiang, Minhui Zhang, Min Hu, Liwei Zhang
Summary: This study identified a novel variant in the CRB1 gene in a Chinese family with LCA, expanding the spectrum of CRB1 variants causing LCA.
BMC MEDICAL GENOMICS
(2022)
Review
Ophthalmology
Bart P. Leroy, David G. Birch, Jacque L. Duncan, Byron L. Lam, Robert K. Koenekoop, Fernanda B. O. Porto, Stephen R. Russell, Aniz Girach
Summary: LCA10, caused by CEP290 mutations, is a genetic retinal disease leading to severe visual impairment in early childhood. There are currently no approved treatments, but investigational strategies include RNA editing using antisense oligonucleotides or CRISPR-based approaches. The antisense oligonucleotide therapy QR-110 has shown promising results in early trials, with ongoing phase 3 clinical trials.
RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES
(2021)
Article
Veterinary Sciences
Shin Ae Park, Dodd Sledge, Colleen F. Monahan, Leandro Teixeira, Ryan Boyd, Katie Freeman, Kristin Koehl, Christine Harman, Kirk Munoz, Laurence M. Occelli, Chris G. Pirie, Harriet Davidson, Simon Petersen-Jones, Andras M. Komaromy
Summary: This is a case series describing atypical chorioretinal lesions in dogs with primary angle-closure glaucoma (PACG), suggesting a possible association between the two.
BMC VETERINARY RESEARCH
(2022)
Article
Ophthalmology
Nate Pasmanter, Laurence M. Occelli, Andras M. Komaromy, Simon M. Petersen-Jones
Summary: This study assessed different extended electroretinographic protocols to evaluate the contribution of retinal cells and characterize dogs with inherited retinal disease. The results showed that different stimuli could separate rod and cone responses, and the amplitudes varied with increasing background luminance. Extended flicker protocols were well fit with mathematical models in normal dogs. These protocols provide additional information on the health and function of retinal cells and allow quantifiable comparison between normal dogs and those with retinal disease.
DOCUMENTA OPHTHALMOLOGICA
(2022)
Article
Veterinary Sciences
Simon M. Petersen-Jones, Nate Pasmanter, Laurence M. Occelli, Kristen J. Gervais, Freya M. Mowat, Janice Querubin, Paige A. Winkler
Summary: The study describes an inherited abnormal negative response electroretinogram (NRE) in Papillon dogs that affects both dark- and light-adapted ERG responses.
VETERINARY OPHTHALMOLOGY
(2022)
Article
Ophthalmology
Simon M. Petersen-Jones, Nathaniel Pasmanter, Laurence M. Occelli, Janice R. Querubin, Paige A. Winkler
Summary: This study reports the persistence of small, desensitized rod ERG responses in CNGB1 mutant dogs, which may be due to low levels of CNGA1 in outer segments.
DOCUMENTA OPHTHALMOLOGICA
(2022)
Article
Mathematical & Computational Biology
Zhen Zhang, Yong Lin, Jingyi Liu
Summary: This study introduces a method called BAMBOO to address the challenge of multiple primary endpoints in phase 2 oncology clinical trials. The method models the phase 2 log hazard ratios for each primary endpoint as a bivariate normal random variable, allowing for estimation of the unknown correlation parameter. The method can also be extended to include additional surrogate endpoints. Simulation results show that the proposed method can better handle the issue of prior-data conflict compared to existing approaches.
STATISTICS IN BIOPHARMACEUTICAL RESEARCH
(2023)
Article
Veterinary Sciences
Nate Pasmanter, Simon M. M. Petersen-Jones
Summary: This study investigates the changes in rod pathways under different lighting conditions in dogs using a long flash protocol with varying background luminance and stimulus strength. The results show that the b-wave of rod response is significantly reduced in mesopic conditions, resulting in a predominantly negative waveform. Rod bipolar cells saturate with dimmer backgrounds than rod photoreceptors, contributing to a large underlying negativity in mesopic backgrounds. These findings highlight the changes in signaling pathway of rod-driven responses that extend the range of lighting conditions over which the retina functions.
BMC VETERINARY RESEARCH
(2022)
Article
Veterinary Sciences
Andrea L. Minella, Kristina Narfstrom Wiechel, Simon M. Petersen-Jones
Summary: Mutations in the CEP290 gene in rdAc cats lead to a truncation of the protein by 157 amino acids, resulting in a milder phenotype compared to human patients with CEP290 mutations. The retention of some full-length CEP290 protein in mutant cats may contribute to the less severe phenotype.
VETERINARY OPHTHALMOLOGY
(2023)
Article
Pathology
Enrico Cristante, Sidath E. Liyanage, Alexander J. Smith, Robin R. Ali, James W. B. Bainbridge
Summary: The study reveals that HIF1a promotes RPE degeneration and choroidal neovascularization in CreTrp1 mice, while HIF2a has a protective effect.
AMERICAN JOURNAL OF PATHOLOGY
(2023)
Article
Medicine, General & Internal
Roger S. McIntyre, Pedro Such, Murat Yildirim, Jessica Madera-McDonough, Zhen Zhang, Frank Larsen, Matthew Harlin
Summary: This study aimed to evaluate the safety and efficacy of Ari 2MRTU 960 in patients with bipolar I disorder. The results showed that Ari 2MRTU 960 was well tolerated and had similar efficacy compared to AOM 400.
CURRENT MEDICAL RESEARCH AND OPINION
(2023)
Article
Ophthalmology
Michele M. Salzman, Natascha Merten, Wojciech K. Panek, Gilad Fefer, Alejandra Mondino, Hans D. Westermeyer, Margaret E. Gruen, Natasha J. Olby, Freya M. Mowat
Summary: This study aimed to determine the association between age and retinal full-field electroretinographic (ERG) measures in companion dogs, and to serve as an important translational model species for human neurologic aging. The results showed that age had significant effects on ERG peak times and amplitudes, indicating slower and reduced responses in aged dogs. The findings are important for understanding the process of neurologic aging in canine species.
DOCUMENTA OPHTHALMOLOGICA
(2023)
Article
Veterinary Sciences
Alex M. M. Lynch, Laura K. K. Ruterbories, James B. B. Robertson, Katharine F. F. Lunn, Freya M. M. Mowat
Summary: This study investigated the hemostatic profiles of dogs with sudden acquired retinal degeneration syndrome (SARDS) and found that dogs with SARDS exhibited a hypercoagulable state. However, the role of hypercoagulability in the pathogenesis of SARDS remains to be determined.
JOURNAL OF VETERINARY INTERNAL MEDICINE
(2023)
Article
Veterinary Sciences
Mariza Bortolini, Paige A. Winkler, Juan Carlos Duque Moreno, Mario Teruo Sato, Bianca Luiza Valduga Guareschi, Simon M. Petersen-Jones, Fabiano Montiani-Ferreira
Summary: In this study, we identified a newly identified form of progressive retinal atrophy (PRA) in German Spitzes associated with a mutation in the GUCY2D gene. The initial clinical features included pale papilla and mild vascular attenuation, and the affected dogs showed impaired vision under both scotopic and photopic conditions. Fundus photography and optical coherence tomography revealed multiple small retinal bullae and retinal thinning. Pedigree analysis supported an autosomal recessive inheritance. A mutation was identified in the GUCY2D gene, which was found to be associated with the disease.
VETERINARY OPHTHALMOLOGY
(2023)
Article
Veterinary Sciences
Callie M. Rogers, Michele M. Salzman, Zhanhai Li, Natascha Merten, Leah J. Russell, Hannah K. Lillesand, Freya M. Mowat
Summary: A newly designed questionnaire was used to assess visual behaviors in older dogs in different lighting conditions, and the results showed that visual behavior in older dogs varied with age and lighting conditions. Objective measurements of retinal function supported the subjective assessments of visual function in dogs.
FRONTIERS IN VETERINARY SCIENCE
(2023)
Article
Veterinary Sciences
Jenelle M. Francis, Freya M. Mowat, Allison Ludwig, Jacqueline M. Hicks, Stephanie A. Pumphrey
Summary: Nuclear sclerosis may be associated with visual deficits in companion dogs, but its association with myopia is weak.
VETERINARY OPHTHALMOLOGY
(2023)
Review
Medicine, General & Internal
Mahiul M. K. Muqit, Manjit Mehat, Catey Bunce, James W. Bainbridge
Summary: This study aimed to assess the potential role of combined pars plana vitrectomy and intravitreal antibiotics in the acute management of exogenous endophthalmitis. A randomized controlled trial was conducted, and the results showed no significant difference in visual acuity between the two treatment groups at three and six months of follow-up. There was also no clear evidence of a difference in the need for additional surgical procedures.
COCHRANE DATABASE OF SYSTEMATIC REVIEWS
(2022)