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)
Article
Medicine, Research & Experimental
Maximilian Pfau, Catherine A. Cukras, Laryssa A. Huryn, Wadih M. Zein, Ehsan Ullah, Marisa P. Boyle, Amy Turriff, Michelle A. Chen, Aarti S. Hinduja, Hermann Ea Siebel, Robert B. Hufnagel, Brett G. Jeffrey, Brian P. Brooks
Summary: This study aimed to analyze eye changes in patients with ABCA4-associated retinopathy. The study found that photoreceptors degenerate beyond EZ-loss in these patients, and there is an association between genotype, age, and photoreceptor degeneration.
Article
Cell Biology
Qing Zhu, Xue Rui, Ya Li, Ya You, Xun-Lun Sheng, Bo Lei
Summary: The study aimed to describe the genetic and clinical features of 17 patients with ABCA4-related inherited retinal degenerations (IRDs) and define the phenotype-genotype correlations. Four novel ABCA4 variants were identified, expanding the spectrum of disease-causing variants in ABCA4 for future genetic counseling.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
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
Chemistry, Medicinal
Jiaxin Bian, Hongyu Chen, Junhui Sun, Yuqing Cao, Jianhong An, Qing Pan, Ming Qi
Summary: The study established an Rdh12-IRD mouse model and found that early gene therapy can delay retinal degeneration and maintain visual function.
DRUG DESIGN DEVELOPMENT AND THERAPY
(2021)
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)
Review
Biochemistry & Molecular Biology
Leyao Li, Lakshmy Vasan, Bryan Kartono, Kevan Clifford, Ahmadreza Attarpour, Raghav Sharma, Matthew Mandrozos, Ain Kim, Wenda Zhao, Ari Belotserkovsky, Claire Verkuyl, Gerold Schmitt-Ulms
Summary: This review introduces the use of recombinant adeno-associated virus (rAAV) vectors in the treatment of neurodegenerative diseases, highlighting recent research advancements and challenges. It provides a reference for newcomers to the field and directs researchers struggling to keep up with the literature towards important studies. The review covers early milestones, current clinical trials, gene editing applications, and payload elements of rAAV vectors, as well as discusses the risks and mitigation strategies associated with off-target effects and immunogenicity.
Article
Biochemistry & Molecular Biology
Tomasz Z. Tomkiewicz, Nuria Suarez-Herrera, Frans P. M. Cremers, Rob W. J. Collin, Alejandro Garanto
Summary: The discovery of novel intronic variants in the ABCA4 locus has contributed significantly to solving the missing heritability in Stargardt disease (STGD1). Testing 26 AONs in vitro, the study observed partial or complete splicing correction for certain variants, indicating the high potential of AONs for developing future RNA therapies to correct splicing defects causing STGD1.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Genetics & Heredity
R. Villafuerte-De la Cruz, O. F. Chacon-Camacho, A. C. Rodriguez-Martinez, N. Xilotl-De Jesus, R. Arce-Gonzalez, C. Rodriguez-De la Torre, J. E. Valdez-Garcia, A. Rojas-Martinez, J. C. Zenteno
Summary: This study describes an IRD patient with ABCA4 and USH2A pathogenic biallelic mutations resulting from paternal uniparental disomy on chromosome 1. This is the first known case of a patient with confirmed UPD for two recessively mutated IRD genes, expanding on the genetic heterogeneity of IRDs and highlighting the importance of UPD as a mechanism of autosomal recessive disease in non-consanguineous parents.
FRONTIERS IN GENETICS
(2022)
Article
Ophthalmology
Lorenzo Bianco, Alessandro Arrigo, Alessio Antropoli, Maria Pia Manitto, Elisabetta Martina, Emanuela Aragona, Francesco Bandello, Maurizio Battaglia Parodi
Summary: This study investigated the correlation between genotypes and phenotypes in ABCA4-associated retinopathy. The results showed significant differences in disease severity among different genotypes. These findings are important for prognostication of patients and the design of future clinical trials.
JAMA OPHTHALMOLOGY
(2023)
Article
Ophthalmology
Lorenzo Bianco, Alessandro Arrigo, Alessio Antropoli, Maria Pia Manitto, Elisabetta Martina, Emanuela Aragona, Francesco Bandello, Maurizio Battaglia Parodi
Summary: This study reveals significant correlations between genotypes and phenotypes in ABCA4-associated retinopathy, providing valuable insights for prognosis and guiding the design of future clinical trials.
JAMA OPHTHALMOLOGY
(2023)
Editorial Material
Multidisciplinary Sciences
Ambroise Wonkam
Summary: Despite being the epicentre of sickle-cell disease, Africa is underrepresented in genome-wide association studies.
Article
Biochemistry & Molecular Biology
Fabian A. Garces, Jessica F. Scortecci, Robert S. Molday
Summary: This study investigated the molecular properties of ABCA4 variants with disease-causing missense mutations, categorizing them into three classes based on their expression levels, ATPase activities, and substrate binding capabilities. Understanding these classifications can provide insights into genotype-phenotype correlations and aid in evaluating therapeutic options for Stargardt macular degeneration.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Genetics & Heredity
Andrea Sodi, Sandro Banfi, Francesco Testa, Michele Della Corte, Ilaria Passerini, Elisabetta Pelo, Settimio Rossi, Francesca Simonelli
Summary: This study established recommendations on clinical and genetic characteristics necessary for gene supplementation with voretigene neparvovec through expert steering committee and multiple rounds of Delphi process. The guidelines aim to guide pediatricians and general ophthalmologists in making informed clinical decisions regarding eligibility for gene therapy for RPE65-associated IRD, ensuring the best outcome for the patient based on expert opinion, literature, and practical experience.
ORPHANET JOURNAL OF RARE DISEASES
(2021)
Article
Cell Biology
Patrizia Tornabene, Ivana Trapani, Renato Minopoli, Miriam Centrulo, Mariangela Lupo, Sonia de Simone, Paola Tiberi, Fabio Dell'Aquila, Elena Marrocco, Carolina Iodice, Antonella Iuliano, Carlo Gesualdo, Settimio Rossi, Laura Giaquinto, Silvia Albert, Carel B. Hoyng, Elena Polishchuk, Frans P. M. Cremers, Enrico M. Surace, Francesca Simonelli, Maria A. De Matteis, Roman Polishchuk, Alberto Auricchio
SCIENCE TRANSLATIONAL MEDICINE
(2019)
Article
Biotechnology & Applied Microbiology
Patrizia Tornabene, Ivana Trapani
HUMAN GENE THERAPY
(2020)
Article
Biochemistry & Molecular Biology
Federica Naso, Daniela Intartaglia, Danila Falanga, Chiara Soldati, Elena Polishchuk, Giuliana Giamundo, Paola Tiberi, Elena Marrocco, Paolo Scudieri, Chiara Di Malta, Ivana Trapani, Edoardo Nusco, Francesco Giuseppe Salierno, Enrico Maria Surace, Luis J. Galietta, Sandro Banfi, Alberto Auricchio, Andrea Ballabio, Diego Luis Medina, Ivan Conte
Editorial Material
Biochemistry & Molecular Biology
Ivana Trapani, Patrizia Tornabene, Alberto Auricchio
Article
Medicine, Research & Experimental
Patrizia Tornabene, Ivana Trapani, Miriam Centrulo, Elena Marrocco, Renato Minopoli, Mariangela Lupo, Carolina Iodice, Carlo Gesualdo, Francesca Simonelli, Enrico M. Surace, Alberto Auricchio
Summary: The study found that by optimizing inteins, the capacity of AAV vectors was expanded, improving the effectiveness of gene therapy, and success was achieved in a mouse model of Stargardt disease. This provides a new approach for treating STGD1 and other diseases requiring the transfer of large genes.
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
(2021)
Article
Multidisciplinary Sciences
Patrizia Tornabene, Rita Ferla, Manel Llado-Santaeularia, Miriam Centrulo, Margherita Dell'Anno, Federica Esposito, Elena Marrocco, Emanuela Pone, Renato Minopoli, Carolina Iodice, Edoardo Nusco, Settimio Rossi, Hristiana Lyubenova, Anna Manfredi, Lucio Di Filippo, Antonella Iuliano, Annalaura Torella, Giulio Piluso, Francesco Musacchia, Enrico Maria Surace, Davide Cacchiarelli, Vincenzo Nigro, Alberto Auricchio
Summary: The study introduces a novel gene therapy approach, AAV-HITI, to overcome challenges in gene therapy. The results show that AAV-HITI enables efficient gene integration in both retina and liver, leading to therapeutic benefits for genetic diseases.
NATURE COMMUNICATIONS
(2022)
Review
Biotechnology & Applied Microbiology
Emmanuel J. Simons, Ivana Trapani
Summary: Inherited forms of blindness and deafness are significant global health issues, and gene therapy is showing promise as a potential treatment. While some progress has been made, challenges remain and further development of innovative techniques is needed to overcome current limitations.
HUMAN GENE THERAPY
(2023)
Meeting Abstract
Biotechnology & Applied Microbiology
E. N. Pugni, P. Tiberi, M. Lupo, C. Iodice, C. Gesualdo, S. Rossi, F. Simonelli, M. L. Bacci, C. Galli, A. Auricchio, I. Trapani
HUMAN GENE THERAPY
(2022)
Meeting Abstract
Biotechnology & Applied Microbiology
E. Pone, V. Temas, A. Ferrara, F. Olasz, A. Furiano, I. Trapani, Z. Zoltan, A. Auricchio
HUMAN GENE THERAPY
(2022)
Meeting Abstract
Biochemistry & Molecular Biology
Eugenio Nahuel Pugni, Mariangela Lupo, Carolina Iodice, Carlo Gesualdo, Settimio Rossi, Francesca Simonelli, Maria Laura Bacci, Cesare Galli, Alberto Auricchio, Ivana Trapani
EUROPEAN JOURNAL OF HUMAN GENETICS
(2022)
Meeting Abstract
Biotechnology & Applied Microbiology
P. Tornabene, I. Trapani, M. Centrulo, E. Marrocco, R. Minopoli, M. Lupo, C. Iodice, C. Gesualdo, F. Simonelli, E. M. Surace, A. Auricchio
HUMAN GENE THERAPY
(2021)
Meeting Abstract
Biotechnology & Applied Microbiology
Rita Ferla, Fabio Dell'Aquila, Monica Doria, Ivana Trapani, Maria Ferraiuolo, Alessia Noto, Fabiana Grazioli, Virginia Ammendola, Stefano Colloca, Alberto Auricchio
Meeting Abstract
Biotechnology & Applied Microbiology
Patrizia Tornabene, Ivana Trapani, Miriam Centrulo, Elena Marrocco, Renato Minopoli, Mariangela Lupo, Carolina Iodice, Carlo Gesualdo, Francesca Simonelli, Enrico Maria Surace, Alberto Auricchio
Meeting Abstract
Biotechnology & Applied Microbiology
Ivana Trapani, Mariangela Lupo, Edoardo Nusco, Arjun Padmanabhan, Alberto Auricchio