Article
Medicine, Research & Experimental
Melita Kaltak, Rocio Blanco-Garavito, Laurie L. Molday, Claire-Marie Dhaenens, Eric E. Souied, Gerard Platenburg, Jim Swildens, Robert S. Molday, Frans P. M. Cremers
Summary: This study investigated the exon skipping phenomenon of exon 17 in the ABCA4 gene associated with Stargardt disease (STGD1) and designed corresponding oligonucleotides to induce exon 17 skipping. The results showed that the deletion of exon 17 in ABCA4 does not result in the absence of protein activity and does not cause a severe STGD1 phenotype when in trans with a null allele. Therefore, the impact of severe variants in exon 17 can potentially be ameliorated by exon skipping using antisense oligonucleotides (AONs), generating partial ABCA4 activity in STGD1 patients.
JOURNAL OF TRANSLATIONAL MEDICINE
(2023)
Review
Medicine, General & Internal
Liang Wang, Serena M. Shah, Simran Mangwani-Mordani, Ninel Z. Gregori
Summary: This article reviews the recent updates in clinical trials targeting the management of STGD1, including gene therapy, small molecule therapy, and stem cell therapy. While some treatment options have shown promise in attenuating disease progression, further research is still needed.
JOURNAL OF CLINICAL MEDICINE
(2023)
Review
Genetics & Heredity
Saoud Al-Khuzaei, Suzanne Broadgate, Charlotte R. Foster, Mital Shah, Jing Yu, Susan M. Downes, Stephanie Halford
Summary: Stargardt disease and ABCA4 retinopathies are caused by pathogenic variants in the ABCA4 gene, leading to toxic build-up of vitamin A derivatives. Accurate genetic testing is crucial in determining therapeutic approaches, as well as the importance of functional studies to assess protein function.
Article
Medicine, General & Internal
Alexandra Miere, Olivia Zambrowski, Arthur Kessler, Carl-Joe Mehanna, Carlotta Pallone, Daniel Seknazi, Paul Denys, Francesca Amoroso, Eric Petit, Eric H. Souied
Summary: The study shows that a pretrained deep learning classifier performs well in distinguishing between STGD1 and PSPD, with an accuracy of 0.882. Compared to retina specialists, the CNN had a better performance.
JOURNAL OF CLINICAL MEDICINE
(2021)
Article
Medicine, Research & Experimental
Pietro De Angeli, Peggy Reuter, Stefan Hauser, Ludger Schoels, Katarina Stingl, Bernd Wissinger, Susanne Kohl
Summary: This study reports the design and evaluation of three CRISPR-Cas9 approaches for correcting abnormal splicing caused by deep-intronic pathogenic variants in Stargardt disease, demonstrating the potential of CRISPR-Cas9 in splicing correction.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2022)
Article
Ophthalmology
Maximilian Pfau, Laryssa A. Huryn, Marisa P. Boyle, Catherine A. Cukras, Wadih M. Zein, Amy Turriff, Ehsan Ullah, Robert B. Hufnagel, Brett G. Jeffrey, Brian P. Brooks
Summary: The study aimed to assess the ability to detect change and retest reliability for a panel of visual function assessments in ABCA4 retinopathy. Longitudinal, multifaceted functional testing was conducted on patients with ABCA4 retinopathy, revealing that microperimetry, macular function, and electroretinography were the most sensitive assessments to detect disease progression, but were only accessible to a subset of participants.
AMERICAN JOURNAL OF OPHTHALMOLOGY
(2023)
Article
Genetics & Heredity
Maria Rodriguez-Hidalgo, Suzanne E. de Bruijn, Zelia Corradi, Kim Rodenburg, Araceli Lara-Lopez, Alicia Valverde-Megias, Almudena Avila-Fernandez, Lidia Fernandez-Caballero, Marta Del Pozo-Valero, Jordi Corominas, Christian Gilissen, Cristina Irigoyen, Frans P. M. Cremers, Carmen Ayuso, Javier Ruiz-Ederra, Susanne Roosing
Summary: In this study, the pathogenicity of the c.6480-35A>G variant on splicing in Stargardt disease was investigated. The deep-learning tool SpliceAI and a midigene splice assay in HEK293T cells were used for in silico and in vitro analysis respectively. The results confirmed the splice-altering effect of the variant, which led to a premature stop codon. The presence of this variant in a second unrelated individual affected with STGD provides sufficient evidence to classify it as a likely pathogenic variant. This research emphasizes the importance of studying non-coding regions and performing functional assays for a conclusive molecular diagnosis.
FRONTIERS IN GENETICS
(2023)
Article
Biotechnology & Applied Microbiology
Ruiting Li, Qiuping Jing, Kaiqin She, Qingnan Wang, Xiu Jin, Qinyu Zhao, Jing Su, Li Song, Jiamei Fu, Xiaoyi Wu, Qiuxia Xu, Fang Lu, Yuquan Wei, Yang Yang
Summary: In this study, various dual split intein ABCA4 vectors were designed and the most efficient vectors were identified through in vitro screening. A novel dual AAV8-ABCA4 vector was constructed and proven to express full-length ABCA4 protein at a high level, reducing bisretinoid formation and correcting the visual function of ABCA4-knockout mice. The therapeutic effects and safety of different dosages were evaluated in a mouse model, with 1.00 x 10(9) GC/eye treatment showing guaranteed efficacy and safety. These results support the future clinical translation of the optimized dual AAV8-ABCA4 approach for the treatment of Stargardt disease.
HUMAN GENE THERAPY
(2023)
Article
Ophthalmology
Zelia Corradi, Manar Salameh, Mubeen Khan, Elise Heon, Ketan Mishra, Rebekkah J. Hitti-Malin, Yahya AlSwaiti, Alice Aslanian, Eyal Banin, Brian P. Brooks, Wadih M. Zein, Robert B. Hufnagel, Susanne Roosing, Claire-Marie Dhaenens, Dror Sharon, Frans P. M. Cremers, Alaa AlTalbishi
Summary: This study characterized an intron 7 variant in the ABCA4 gene found in Palestinian individuals with Stargardt disease or cone-rod dystrophy. The variant was found to disrupt a predicted branchpoint, leading to protein truncation and early-onset Stargardt disease. The variant was also found to be one of the most common disease-causing variants in inherited retinal dystrophy in West-Bank Palestine.
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
(2022)
Article
Ophthalmology
Winston Lee, Jana Zernant, Takayuki Nagasaki, Rando Allikmets
Summary: This study did not support the association between sex and certain mild ABCA4 alleles in a larger cohort of individuals with Stargardt disease. While sex is an important variable in medicine, its putative association with clinical outcomes should be rigorously scrutinized.
JAMA OPHTHALMOLOGY
(2021)
Review
Ophthalmology
Robert S. Molday, Fabian A. Garces, Jessica Fernandes Scortecci, Laurie L. Molday
Summary: ABCA4 is a transporter protein that plays a crucial role in preventing the accumulation of toxic retinoid compounds in photoreceptor cells. Its loss-of-function mutations are associated with Stargardt disease and other retinopathies characterized by impaired central vision. Cryo-electron microscopy studies have provided insights into the molecular architecture and mechanisms of ABCA4. Additionally, the functional characterization of disease-causing mutations has allowed for the development of a classification system and potential therapeutic treatments for ABCA4-associated diseases.
PROGRESS IN RETINAL AND EYE RESEARCH
(2022)
Article
Chemistry, Multidisciplinary
Da Sun, Wenyu Sun, Song-Qi Gao, Cheng Wei, Amirreza Naderi, Andrew L. Schilb, Josef Scheidt, Sangjoon Lee, Timothy S. Kern, Krzysztof Palczewski, Zheng-Rong Lu
Summary: Developing gene replacement therapy for large gene mutations in retinal disorders, such as Stargardt disease, remains a challenge. A non-viral gene therapy using ECO/pDNA nanoparticles has shown promise, with modified ABCA4 plasmids with SV40 enhancer demonstrating increased gene expression. The addition of sucrose stabilized the nanoparticles, leading to improved transfection efficiency, while sorbitol showed fluctuating results.
JOURNAL OF CONTROLLED RELEASE
(2021)
Article
Multidisciplinary Sciences
Jessica Fernandes Scortecci, Laurie L. Molday, Susan B. Curtis, Fabian A. Garces, Pankaj Panwar, Filip Van Petegem, Robert S. Molday
Summary: ABCA4 is a crucial transporter protein that flips N-retinylidene-phosphatidylethanolamine (N-Ret-PE) in photoreceptor membranes. Mutations in ABCA4 are associated with vision loss. The structural analysis provides insight into the substrate binding and transport mechanism of ABCA4.
NATURE COMMUNICATIONS
(2021)
Article
Medicine, Research & Experimental
Da Sun, Wenyu Sun, Song-Qi Gao, Jonathan Lehrer, Amirreza Naderi, Cheng Wei, Sangjoon Lee, Andrew L. Schilb, Josef Scheidt, Ryan C. Hall, Elias I. Traboulsi, Krzysztof Palczewski, Zheng-Rong Lu
Summary: Stargardt disease, caused by mutations in ABCA4 gene, is a common form of inherited retinal genetic disorders. Gene therapy using self-assembly nanoparticles shows promising results in treating this disease by producing specific and prolonged expression of ABCA4, reducing the accumulation of toxic substances in the eye.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2022)
Article
Biochemistry & Molecular Biology
Melita Kaltak, Zelia Corradi, Rob W. J. Collin, Jim Swildens, Frans P. M. Cremers
Summary: This study investigated the impact of synonymous and missense variants in ABCA4 on pre-mRNA splicing. It identified 16 out of 18 analyzed variants that caused splice aberrations. These findings highlight the causal role of coding ABCA4 variants in splicing abnormalities, improving the severity assessment of missense and synonymous ABCA4 variants, and guiding new treatment strategies for STGD1.
HUMAN MOLECULAR GENETICS
(2023)
Editorial Material
Transplantation
Johannes Birtel, Peter Charbel Issa, Philipp Herrmann, Bernd Hoppe, Anja Katrin Buscher
NEPHROLOGY DIALYSIS TRANSPLANTATION
(2022)
Article
Ophthalmology
Kristina Hess, Kristin Raming, Peter Charbel Issa, Philipp Herrmann, Frank G. Holz, Maximilian Pfau
Summary: This study revealed a significant association between aging and ONHD with GCL thinning in patients with PXE, but not with the number of anti-VEGF injections.
BRITISH JOURNAL OF OPHTHALMOLOGY
(2023)
Article
Ophthalmology
Ariel Yuhan Ong, Axelle Rigaudy, Shafak Toufeeq, Julian Robins, Zaid Shalchi, Mandeep Singh Bindra, Peter Charbel Issa
Summary: This study evaluated the characteristics, treatment patterns, and outcomes of acute postoperative endophthalmitis. It found that intravitreal injections were the leading cause of endophthalmitis, and the primary procedure had no effect on the presentation, management, or visual outcomes of endophthalmitis.
Article
Ophthalmology
Beatrice Emmanouil, Martin Wasik, Peter Charbel Issa, Dorothy Halliday, Allyson Parry, Srilakshmi M. Sharma
Summary: This case-control study used spectral domain optical coherence tomography (SD-OCT) to systematically analyze central retinal findings in patients with neurofibromatosis type 2 (NF2). Retinal tufts were the most common abnormality, found in 43% of NF2 patients, and had a high specificity and positive predictive value for NF2. SD-OCT imaging was effective in detecting retinal abnormalities and the prevalence of these abnormalities increased with the severity of NF2 genetic mutations.
OPHTHALMIC RESEARCH
(2022)
Article
Ophthalmology
Kristina Hess, Kristin Raming, Martin Gliem, Peter Charbel Issa, Philipp Herrmann, Frank G. Holz, Maximilian Pfau
Summary: The study aimed to quantify choriocapillaris (CC) flow alterations in early Sorsby fundus dystrophy (SFD) and investigate the relationship with choroidal and outer retinal microstructure. The results showed that SFD patients had significantly higher CC flow deficits compared to controls, and that this was associated with choroidal thickness and altered microstructure of photoreceptors.
Review
Ophthalmology
Imran H. Yusuf, Andrew M. Garrett, Robert E. MacLaren, Peter Charbel Issa
Summary: Cadherins are a superfamily of intercellular adhesion molecules that play important roles in tissue morphogenesis, neural circuit formation, and maintenance of the retina. Mutations in genes encoding cadherins have been identified as causes of inherited retinal degeneration. This review summarizes the classification and function of cadherins in the inner and outer retina, and provides an overview of the molecular genetics and clinical phenotypes of monogenic retinal cadherinopathies.
PROGRESS IN RETINAL AND EYE RESEARCH
(2022)
Article
Genetics & Heredity
Federica E. Poli, Imran H. Yusuf, Penny Clouston, Morag Shanks, Jennifer Whitfield, Peter Charbel Issa, Robert E. MacLaren
Summary: This study reports three missense variants in the MERTK gene and analyzes the associated phenotypic data. These variants are associated with non-syndromic retinitis pigmentosa. MERTK is a promising candidate for viral-mediated gene replacement therapy.
OPHTHALMIC GENETICS
(2023)
Article
Pediatrics
Johannes Birtel, Roselie M. Diederen, Philipp Herrmann, Sophie Kaspar, Bodo B. Beck, Sander F. Garrelfs, Bernd Hoppe, Peter Charbel Issa
Summary: Primary hyperoxalurias (PH1-3) are rare inherited disorders characterized by overproduction of oxalate, leading to organ damage. The study investigated retinal disease manifestation in patients with PH2 and PH3 and found rare occurrences and mild changes, especially in PH2-associated kidney failure.
PEDIATRIC NEPHROLOGY
(2023)
Article
Ophthalmology
Birgit Lorenz, Joana Tavares, L. Ingeborgh van den Born, Joao Pedro Marques, Elisabetta Pilotto, Katarina Stingl, Peter Charbel Issa, Dorothee Leroux, Helene Dollfus, Hendrik P. N. Scholl
Summary: A survey conducted among European countries revealed differences in the management of IRDs, but consistent diagnostic work-up and increased use of genetic testing. The participation in natural history and gene therapy trials has significantly increased, reflecting the advancements in gene therapy development. The survey provides crucial data for researchers, clinicians, patient advocate groups, pharmaceutical companies, and investors.
OPHTHALMIC RESEARCH
(2023)
Article
Ophthalmology
Ariel Yuhan Ong, Johannes Birtel, Eleftherios Agorogiannis, Srilakshmi M. Sharma, Peter Charbel Issa
Summary: The study explores the different topographic distributions of multiple-evanescent white dot syndrome (MEWDS) and its association with secondary MEWDS disease. Clinical evaluation and multimodal retinal imaging were conducted on 27 subjects with MEWDS, revealing that MEWDS lesions are mainly located around the optic disc (59%) and macula (24%). Secondary MEWDS occurs in the presence of concurrent chorioretinal pathology, often resulting in coexisting lesions. The majority of patients showed symptom resolution and retinal changes within 3 months.
GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY
(2023)
Article
Ophthalmology
Tomasz Szeligowski, Dun J. J. Fu, Noa Fernandez-Ledo, Johannes Birtel, Sher A. Aslam, Chetan K. Patel, Kanmin Xue, Peter Charbel Issa
Summary: This study aimed to describe photoreceptor damage in patients with Terson syndrome as a potential cause for inconsistent clinical outcomes. Clinical evaluation and retinal imaging were conducted in six patients. Results showed consistent outer retinal changes indicating photoreceptor damage. The observed retinal abnormalities demonstrated incomplete recovery over long-term follow-up and had variable impact on the patients' visual function.
RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES
(2023)
Editorial Material
Ophthalmology
Yingjia Yang, Anthony Afanu, Peter Charbel Issa
Editorial Material
Ophthalmology
Mays Al-Nofal, Peter Charbel Issa
Editorial Material
Ophthalmology
Ariel Yuhan Ong, Katrina Fordwor, Peter Charbel Issa
GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY
(2023)
Article
Ophthalmology
Birgit Lorenz, Joana Tavares, L. Ingeborgh van den Born, Joao Pedro Marques, Elisabetta Pilotto, Katarina Stingl, Peter Charbel Issa, Dorothee Leroux, Helene Dollfus, Hendrik P. N. Scholl
Summary: This article investigates the management of RPE65-biallelic mutation-associated inherited retinal degeneration (RPE65-IRD) in Europe since the approval of Voretigene Neparvovec (VN) in 2018. The survey found that by July 2022, over 200 patients have been treated outside the USA, with about 90% in Europe. Among the surveyed centers, 26 follow RPE65-IRD patients and 8 centers have treated 57 cases, with 43 planned for treatment. The main reasons for non-treatment are advanced or mild disease and the absence of two class 4 or 5 mutations.
OPHTHALMIC RESEARCH
(2023)