Article
Medicine, Research & Experimental
Jinjie Ling, Laura A. Jenny, Ashley Zhou, Stephen H. Tsang
Summary: Since the development of CRISPR/Cas9 gene editing in 2012, therapeutic editing research has progressed through several phase 1-2a trials. This article provides an overview of the mechanisms and applications of various gene-editing technologies for the treatment of inherited retinal diseases (IRDs), including adeno-associated virus vectors, lentiviruses, CRISPR/Cas9 systems, base and prime editing, antisense oligonucleotides, short-hairpin RNAs, Cas13, and adenosine deaminase acting on RNA. The article also highlights the impact of these technologies on advancing the practice of medicine.
COLD SPRING HARBOR PERSPECTIVES IN MEDICINE
(2023)
Article
Neurosciences
Alexander L. Yan, Samuel W. Du, Krzysztof Palczewski
Summary: Gene augmentation and genome editing are hopeful strategies for the treatment of monogenic inherited retinal diseases. While gene augmentation treatments have shortcomings, innovative CRISPR-Cas9-based genome editing technologies have broadened the proportion of treatable genetic disorders and can have long-lasting treatment effects. Continued progress in precise gene correction and delivery strategies will establish genome editing as the preferred treatment for genetic retinal disorders.
Article
Ophthalmology
Lewis E. Fry, Michelle E. McClements, Robert E. MacLaren
Summary: This study revealed a high prevalence of pathogenic variants amenable to base editing in inherited retinal degeneration, suggesting a potential approach for developing base editing therapies to treat retinal degeneration not amenable to traditional gene therapy.
JAMA OPHTHALMOLOGY
(2021)
Article
Immunology
Andrea Nortey, Kimberly Garces, Tal Carmy-Bennun, Abigail S. Hackam
Summary: IL-27 has been found to reduce photoreceptor death, improve retinal function, and alleviate inflammation in a genetic model of retinal degeneration, highlighting its potential as an anti-inflammatory and neuroprotective therapy for retinal degenerative diseases.
JOURNAL OF NEUROINFLAMMATION
(2022)
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
Medicine, Research & Experimental
Jing Su, Kaiqin She, Li Song, Xiu Jin, Ruiting Li, Qinyu Zhao, Jianlu Xiao, Danian Chen, Hui Cheng, Fang Lu, Yuquan Wei, Yang Yang
Summary: Retinitis pigmentosa (RP) is a group of retinal diseases that cause progressive retinal photoreceptor cell death and ultimately blindness. A base editing approach using adeno-associated virus (AAV)-mediated adenine base editor (ABE) was used to correct the Pde6bmutation in a mouse model of RP, resulting in restored PDE6B expression, preserved photoreceptors, and rescued visual function with high efficiency.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2023)
Article
Medicine, General & Internal
Katarzyna Samelska, Jacek Pawel Szaflik, Maria Guszkowska, Anna Katarzyna Kurowska, Anna Zaleska-Zmijewska
Summary: This study examines the application of adaptive optics (AO) in the assessment of patients with inherited retinal dystrophies (IRDs). AO allows for detailed observation of retinal photoreceptor structures and quantitative analysis of parameters. The study found significant differences in DM, SM, REG, and N%6 parameters between healthy and IRD-affected eyes.
Article
Medicine, Research & Experimental
David M. Wu, Xuke Ji, Maryna Ivanchenko, Michelle Chung, Mary Piper, Parimal Rana, Sean K. Wang, Yunlu Xue, Emma West, Sophia R. Zhao, Hongbin Xu, Marcelo Cicconet, Wenjun Xiong, Constance L. Cepko
Summary: Overexpression of Nrf2 in the RPE can rescue RPE and cone photoreceptors in mice, improve visual acuity, and reverse declines in oxidative defense pathways. This method may be a potential therapy for diseases involving RPE degeneration.
Review
Ophthalmology
Dong Hyun Jo, Sangsu Bae, Hyongbum Henry Kim, Jin-Soo Kim, Jeong Hun Kim
Summary: Inherited retinal diseases (IRDs) are vision-threatening retinal disorders caused by gene variants related to vision. Current treatment options are limited, but genome editing using CRISPR-Cas9 technologies shows promise for correcting pathogenic variants and providing new treatment opportunities.
PROGRESS IN RETINAL AND EYE RESEARCH
(2023)
Article
Biology
Katarzyna Samelska, Jacek Pawel Szaflik, Barbara Smigielska, Anna Zaleska-Zmijewska
Summary: This study utilized adaptive optics to examine inherited retinal dystrophies affecting the macula and analyze the changes in cone parameters. The results showed significant changes in cone density and spacing over time, as well as deterioration in best corrected visual acuity.
Article
Multidisciplinary Sciences
Raghavi Sudharsan, Leonardo Murgiano, Hsin-Yao Tang, Timothy W. Olsen, Venkata R. M. Chavali, Gustavo D. Aguirre, William A. Beltran
Summary: A novel short PRL isoform lacking exon 1 was identified in the retinas of dogs with advanced photoreceptor disease, showing expression in photoreceptors of degenerating retinas and localization to the outer nuclear layer shortly after disease onset. Further investigations are needed to understand the role of this isoform in retinal degeneration.
SCIENTIFIC REPORTS
(2021)
Article
Medicine, Research & Experimental
Elliot H. Choi, Susie Suh, David E. Einstein, Henri Leinonen, Zhiqian Dong, Sriganesh Ramachandra Rao, Steven J. Fliesler, Seth Blackshaw, Minzhong Yu, Neal S. Peachey, Krzysztof Palczewski, Philip D. Kiser
Summary: This study presents a novel RPE-specific knockin mouse line with accurate introduction of the CreER(T2) gene into retinal pigment epithelial cells, demonstrating high efficiency and absolute RPE-specific recombination ability for studying gene function and pathophysiology in the RPE.
Article
Ophthalmology
Jingyu Yao, Tiantian Wang, Lin Jia, Yaoyan Qiu, David N. Zacks
Summary: This study found that a nonfunctional Fas receptor has a protective effect in two different mouse models of retinal degeneration, suggesting that the retina's response to different stressors appears to be shared and driven by Fas. Reducing Fas activity might represent a potential mutation-independent therapeutic approach to preserve retinal structure and function in patients with IRD.
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
(2022)
Review
Medicine, General & Internal
Yulia Haraguchi, Tsun-Kang Chiang, Minzhong Yu
Summary: Inherited retinal dystrophies are a group of disorders that affect the structure and function of the retina. Electrophysiology testing is a valuable tool for assessing and diagnosing these conditions, as well as guiding disease classification and management.
JOURNAL OF CLINICAL MEDICINE
(2023)
Article
Multidisciplinary Sciences
Manuela Voelkner, Felix Wagner, Lisa Maria Steinheuer, Madalena Carido, Thomas Kurth, Ali Yazbeck, Jana Schor, Stephanie Wieneke, Lynn J. A. Ebner, Claudia Del Toro Runzer, David Taborsky, Katja Zoschke, Marlen Vogt, Sebastian Canzler, Andreas Hermann, Shahryar Khattak, Joerg Hackermueller, Mike O. Karl
Summary: Human organoids can provide valuable insights into complex and incurable neuropathologies. In this study, researchers successfully established a human retinal organoid system that replicates various aspects of the human retina, including those within the macula. By combining TNF and HBEGF, the researchers induced the degeneration of photoreceptors, glial pathologies, dyslamination, and scar formation, uncovering a previously unknown pathomechanism. This research could have significant implications for age-related macular degeneration and other related diseases, offering potential therapeutic approaches.
NATURE COMMUNICATIONS
(2022)
Article
Biotechnology & Applied Microbiology
Beverly Y. Mok, Anna Kotrys, Aditya Raguram, Tony P. Huang, Vamsi K. Mootha, David R. Liu
Summary: Evolved DddA variants enhance the editing efficiency and expand the target compatibility of the all-protein base editor DdCBE, allowing efficient editing at non-T(C) target sites and broadening the sequence compatibility for mitochondrial and nuclear base editing.
NATURE BIOTECHNOLOGY
(2022)
Article
Biotechnology & Applied Microbiology
Monica E. Neugebauer, Alvin Hsu, Mandana Arbab, Nicholas A. Krasnow, Amber N. McElroy, Smriti Pandey, Jordan L. Doman, Tony P. Huang, Aditya Raguram, Samagya Banskota, Gregory A. Newby, Jakub Tolar, Mark J. Osborn, David R. Liu
Summary: Improved cytosine base editors are generated by phage-assisted evolution of a deoxyadenosine deaminase, which exhibit small size, low off-target activity, and high on-target activity. These modified base editors have significant application potential in cell and gene editing.
NATURE BIOTECHNOLOGY
(2023)
Editorial Material
Immunology
Samuel W. W. Du, Krzysztof Palczewski
Summary: CRISPR/Cas9 genome editing techniques have the potential to treat previously untreatable inherited genetic disorders of vision by correcting mutations that cause these afflictions. Using a prime editor, Qin et al. (2023. J. Exp. Med. https://doi.org/10.1084/jem.20220776) restored visual functions in a mouse model (rd10) of retinitis pigmentosa.
JOURNAL OF EXPERIMENTAL MEDICINE
(2023)
Article
Biotechnology & Applied Microbiology
Zackery A. Ely, Nicolas Mathey-Andrews, Santiago Naranjo, Samuel I. Gould, Kim L. Mercer, Gregory A. Newby, Christina M. Cabana, William M. Rideout III, Grissel Cervantes Jaramillo, Jennifer M. Khirallah, Katie Holland, Peyton B. Randolph, William A. Freed-Pastor, Jessie R. Davis, Zachary Kulstad, Peter M. K. Westcott, Lin Lin, Andrew V. Anzalone, Brendan L. Horton, Nimisha B. Pattada, Sean-Luc Shanahan, Zhongfeng Ye, Stefani Spranger, Qiaobing Xu, Francisco J. Sanchez-Rivera, David R. Liu, Tyler Jacks
Summary: Genetically engineered mouse models have limitations in capturing the full range of genetic lesions that drive human cancer. However, a new CRISPR-Cas9 model has been developed to expand this scope through in vivo prime editing. This system allows for precise engineering of various mutations in cell lines and organoids derived from primary tissues, making it possible to study cancer-associated mutations and complex genetic combinations that are challenging with traditional models.
NATURE BIOTECHNOLOGY
(2023)
Article
Biotechnology & Applied Microbiology
Jessie R. Davis, Samagya Banskota, Jonathan M. Levy, Gregory A. Newby, Xiao Wang, Andrew V. Anzalone, Andrew T. Nelson, Peter J. Chen, Andrew D. Hennes, Meirui An, Heejin Roh, Peyton B. Randolph, Kiran Musunuru, David R. Liu
Summary: Efficient methods for delivering prime editors (PEs) in vivo are needed to realize the promise of prime editing for the study and treatment of genetic disorders. This study describes the identification of bottlenecks limiting adeno-associated virus (AAV)-mediated prime editing in vivo and the development of AAV-PE vectors with increased efficiency. The optimized PE-AAV systems support high levels of in vivo prime editing and enable therapeutically relevant editing in mouse organs.
NATURE BIOTECHNOLOGY
(2023)
Article
Multidisciplinary Sciences
Jennings C. Luu, Aicha Saadane, Henri Leinonen, Elliot H. Choi, Fangyuan Gao, Dominik Lewandowski, Maximilian Halabi, Christopher L. Sander, Arum Wu, Jacob M. Wang, Rupesh Singh, Songqi Gao, Emma M. Lessieur, Zhiqian Dong, Grazyna Palczewska, Robert F. Mullins, Neal S. Peachey, Philip D. Kiser, Marcin Tabaka, Timothy S. Kern, Krzysztof Palczewski
Summary: Chronic, progressive retinal diseases result from disruptions in cellular and tissue homeostasis, leading to vision impairment and blindness. Existing therapeutic options are limited for these diseases, especially in the early stages. A systems pharmacology approach was used to identify molecular mechanisms and develop targeted pharmacological inhibition of cyclic nucleotide phosphodiesterases (PDEs), resulting in enhanced resilience and preservation of retinal structure and function. This approach shows promise for the treatment and prevention of common causes of blindness.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Mandana Arbab, Zaneta Matuszek, Kaitlyn M. Kray, Ailing Du, Gregory A. Newby, Anton J. Blatnik, Aditya Raguram, Michelle F. Richter, Kevin T. Zhao, Jonathan M. Levy, Max W. Shen, W. David Arnold, Dan Wang, Jun Xie, Guangping Gao, Arthur H. M. Burghes, David R. Liu
Summary: Spinal muscular atrophy (SMA), a leading genetic cause of infant mortality, can be treated by genome editing of SMN2 to restore SMN protein levels and rescue SMA phenotypes, demonstrating the potential of a one-time base editing treatment for SMA.
Article
Engineering, Biomedical
Kelcee A. Everette, Gregory A. Newby, Rachel M. Levine, Kalin Mayberry, Yoonjeong Jang, Thiyagaraj Mayuranathan, Nikitha Nimmagadda, Erin Dempsey, Yichao Li, Senthil Velan Bhoopalan, Xiong Liu, Jessie R. Davis, Andrew T. Nelson, Peter J. Chen, Alexander A. Sousa, Yong Cheng, John F. Tisdale, Mitchell J. Weiss, Jonathan S. Yen, David R. Liu
Summary: Prime editing efficiently corrects the sickle-cell allele in patient haematopoietic stem cells, resulting in erythrocytes resistant to hypoxia-induced sickling. This correction was achieved at frequencies of 15%-41% in patients with sickle-cell disease. After transplantation into mice, the prime-edited cells maintained normal gene expression and displayed similar differentiation and maturation as unedited stem cells from healthy donors.
NATURE BIOMEDICAL ENGINEERING
(2023)
Article
Genetics & Heredity
Thiyagaraj Mayuranathan, Gregory A. Newby, Ruopeng Feng, Yu Yao, Kalin D. Mayberry, Cicera R. Lazzarotto, Yichao Li, Rachel M. Levine, Nikitha Nimmagadda, Erin Dempsey, Guolian Kang, Shaina N. Porter, Phillip A. Doerfler, Jingjing Zhang, Yoonjeong Jang, Jingjing Chen, Henry W. Bell, Merlin Crossley, Senthil Velan Bhoopalan, Akshay Sharma, John F. Tisdale, Shondra M. Pruett-Miller, Yong Cheng, Shengdar Q. Tsai, David R. Liu, Mitchell J. Weiss, Jonathan S. Yen
Summary: A comparison of gene editing strategies using sickle cell disease cells and in vivo transplantation reveals that adenine base editing of the -175A>G site in the γ-globin gene promoters yields durable and potent expression. This approach provides insights into γ-globin gene regulation and offers a potential strategy for inducing HbF. The study also highlights the unexpected phenotypic variation caused by Cas9-generated diverse indels, which can be avoided by base editing.
Article
Medicine, Research & Experimental
Meha Kabra, Pawan K. Shahi, Yuyuan Wang, Divya Sinha, Allison Spillane, Gregory A. Newby, Shivani Saxena, Yao Tong, Yu Chang, Amr A. Abdeen, Kimberly L. Edwards, Cole O. Theisen, David R. Liu, David M. Gamm, Shaoqin Gong, Krishanu Saha, Bikash R. Pattnaik
Summary: Clinical genome editing is being used to treat rare diseases, but the delivery of CRISPR editors remains a challenge. In this study, we used silica nanocapsules to deliver base editors to the retinal pigmented epithelium for the treatment of retinal degeneration. The base editor effectively corrected point mutations in the KCNJ13 gene and restored functional channels. This preclinical validation of targeted ion channel functional rescue demonstrates the effectiveness of nonviral genome-editing therapy for rare inherited disorders.
JOURNAL OF CLINICAL INVESTIGATION
(2023)
Meeting Abstract
Ophthalmology
Elliot H. Choi, Susie Suh, Andrzej Foik, Henri Olavi Leinonen, Gregory Newby, Samagya Banskota, Thanh V. Hoang, Samuel W. Du, Xin D. Gao, Zhiqian Dong, Aditya Raguram, Sajeev Kohil, Seth Blackshaw, David Lyon, David R. Liu, Krzysztof Palczewski
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
(2022)
Meeting Abstract
Ophthalmology
Dominik Lewandowski, Andrzej Foik, Roman Smidak, Elliot H. Choi, Jianye Zhang, Thanh Hoang, Aleksander Tworak, Susie Suh, Zhiqian Dong, Antonio F. M. Pinto, Emily Tom, Seth Blackshaw, David Lyon, Dorota Skowronska-Krawczyk, Marcin Tabaka, Krzysztof Palczewski
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
(2022)