Review
Biochemistry & Molecular Biology
Young Gun Park, Yong Soo Park, In-Beom Kim
Summary: Age-related macular degeneration (AMD) is a complex disease characterized by neovascularization or geographic atrophy. The complement system plays a crucial role in AMD and has become a therapeutic target. Further research is needed to fully understand the mechanism of complement disease propagation in AMD.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Angela Armento, Marius Ueffing, Simon J. Clark
Summary: Age-related macular degeneration (AMD) is a complex disease with genetic, aging, and lifestyle factors all playing a role in its onset and progression. Therapeutic attempts targeting the complement system have not been successful, highlighting the complexity of AMD beyond genetic factors.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Review
Immunology
Sarah de Jong, Jiaqi Tang, Simon J. Clark
Summary: Age-related macular degeneration (AMD) is a major cause of vision impairment, but currently there is no effective treatment for the majority of patients. Studies have shown that the complement system and remodeling of the extracellular matrix play a significant role in AMD. Excessive activation of the complement system can lead to tissue damage and complement-associated diseases like AMD. The latest findings suggest abnormal activation of the alternative pathway in AMD patients, which has important implications for future clinical trials and treatment prospects.
IMMUNOLOGICAL REVIEWS
(2023)
Article
Oncology
Andrea P. Cabrera, Jonathan Stoddard, Irene Santiago Tierno, Nikolaos Matisioudis, Mahesh Agarwal, Lauren Renner, Neha Palegar, Martha Neuringer, Trevor McGill, Kaustabh Ghosh
Summary: The study found differences in the characteristics of choroidal endothelial cells in young and old monkey eyes, with cells in older eyes being stiffer and more susceptible to complement activation-induced damage. These differences may be related to the activities of the mechanical structure regulators Rac and Rho in the cells. These findings offer new mechanistic insights into choroidal vascular loss in early AMD and warrant further investigation for translational potential.
JOURNAL OF PATHOLOGY
(2022)
Review
Ophthalmology
Shenouda Girgis, Lawrence R. Lee
Summary: Age-related macular degeneration is a global disease with a significant social impact, and the treatment of neovascular AMD has been revolutionized by the advent of anti-VEGF therapy. Currently, investigations are being conducted for possible therapeutic options for dry AMD. Various treatments, including complement pathway inhibitors, visual cycle modulators, antioxidative therapy, gene therapy, and stem cell therapy, are undergoing clinical trials. Two intravitreal anti-complement factors have shown promising results in reducing the growth of geographic atrophy.
CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Niloofar Piri, Henry J. Kaplan
Summary: AMD is a progressive degenerative disease that severely affects central vision in people over age 50, impacting their ability to read, write, drive, and recognize faces. The disease is complex and multifactorial, involving age, genetics, and environmental factors. The role of complement system in the development of AMD is reviewed. Understanding the pathophysiology of AMD and its risk factors is crucial for drug discovery.
Review
Biochemistry & Molecular Biology
Prem N. Patel, Parth A. Patel, Matthew R. Land, Ibrahim Bakerkhatib-Taha, Harris Ahmed, Veeral Sheth
Summary: Age-related macular degeneration (AMD) is a common cause of vision loss in elderly individuals. The pathophysiology of dry AMD is associated with key proteins in the complement cascade, providing potential therapeutic targets. Early intervention may prevent disease progression.
Article
Medicine, General & Internal
Jonathan B. Lin, Stylianos Serghiou, Joan W. Miller, Demetrios G. Vavvas
Summary: Complement dysregulation is observed in early/intermediate nonexudative AMD, but not in patients with geographic atrophy. These findings provide insights into the mechanism of AMD and inform future clinical trials.
JOURNAL OF CLINICAL MEDICINE
(2022)
Review
Pharmacology & Pharmacy
Chloe N. Thomas, Dawn A. Sim, Wen Hwa Lee, Nada Alfahad, Andrew D. Dick, Alastair K. Denniston, Lisa J. Hill
Summary: Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world, with the need for new therapies to address disease progression and treatment challenges at different stages.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Ophthalmology
John T. Demirs, Junzheng Yang, Maura A. Crowley, Michael Twarog, Omar Delgado, Yubin Qiu, Stephen Poor, Dennis S. Rice, Thaddeus P. Dryja, Karen Anderson, Sha-Mei Liao
Summary: The dysregulation of the alternative complement pathway is a major pathogenic mechanism in age-related macular degeneration. Complement mRNA and protein expression levels were found to be significantly higher in macular retinal pigment epithelium/choroid tissue than in the neural retina, regardless of AMD grade status. The study suggests that the RPE/choroid is the primary site for complement inhibition to treat geographic atrophy or earlier stages of the disease.
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
(2021)
Review
Pharmacology & Pharmacy
Matteo Stravalaci, Mariantonia Ferrara, Varun Pathak, Francesca Davi, Barbara Bottazzi, Alberto Mantovani, Reinhold J. Medina, Mario R. Romano, Antonio Inforzato
Summary: Age related macular degeneration (AMD) and diabetic retinopathy (DR) are neurodegenerative and inflammatory diseases of the eye. Both diseases involve cellular components of the blood-retina barrier (BRB) and share common drivers, such as chronic inflammation. Long pentraxin 3 (PTX3), a soluble pattern recognition molecule, is emerging as a potential therapeutic target in retinal diseases, as it plays a role in trapping complement and modulating inflammation at the BRB.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Immunology
Yingbo Ma, Xueqing Ding, Mingxi Shao, Yichao Qiu, Shengjie Li, Wenjun Cao, Gezhi Xu
Summary: This study investigated the association between serum complement components and AMD. The results showed that higher levels of C1q and lower levels of C3 were associated with increased risk of AMD in female patients. This suggests that the complement classical pathway may be involved in the development of AMD, especially in females.
JOURNAL OF INFLAMMATION RESEARCH
(2022)
Review
Medicine, General & Internal
Sarah Hammadi, Nikolaos Tzoumas, Mariantonia Ferrara, Ingrid Porpino Meschede, Katharina Lo, Claire Harris, Majlinda Lako, David H. Steel
Summary: The complement system is essential for the body's defense against pathogens, but dysregulation can lead to diseases such as age-related macular degeneration (AMD). Complement activation occurs in various parts of the eye, including the choriocapillaris and the subretinal and retinal pigment epithelium spaces. The barrier of Bruch's membrane impedes complement protein diffusion and its dysfunction contributes to AMD pathogenesis. This review examines the structure of Bruch's membrane, its age-related changes, and the potential of different delivery routes for complement inhibitors in treating AMD.
JOURNAL OF CLINICAL MEDICINE
(2023)
Review
Cell Biology
Aniket Ramshekar, Haibo Wang, M. Elizabeth Hartnett
Summary: AMD is a major cause of blindness worldwide, with neovascular AMD leading to vision loss. The current standard of care with anti-angiogenic agents is only effective in around 50% of AMD cases. Studies have shown that Rac1 activation plays a crucial role in the invasion of choroidal endothelial cells into the neural retina in AMD.
Review
Ophthalmology
Sarah de Jong, Giuliana Gagliardi, Alejandro Garanto, Anita de Breuk, Yara T. E. Lechanteur, Suresh Katti, Lambert P. van den Heuvel, Elena B. Volokhina, Anneke I. den Hollander
Summary: AMD is a major cause of vision loss in elderly individuals in the Western world. The complement system plays a crucial role in disease risk associated with AMD. Despite ongoing research on complement inhibitors in clinical trials, the success has been limited, leaving many AMD patients without effective treatment options.
PROGRESS IN RETINAL AND EYE RESEARCH
(2021)
Article
Ophthalmology
Timothy M. Boyce, S. Scott Whitmore, Katayoun Varzavand, Stephen R. Russell, Elliott H. Sohn, James C. Folk, Edwin M. Stone, Ian C. Han
Summary: Patients with ADNIV have a high lifetime risk of severe vision loss, with tractional retinal detachment being an important risk factor for poor vision.
AMERICAN JOURNAL OF OPHTHALMOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Budd A. Tucker, Erin R. Burnight, Cathryn M. Cranston, Mallory J. Ulferts, Meagan A. Luse, Trudi Westfall, C. Anthony Scott, Autumn Marsden, Katherine Gibson-Corley, Luke A. Wiley, Ian C. Han, Diane C. Slusarski, Robert F. Mullins, Edwin M. Stone
Summary: A study identified a genetic mutation in the MAK gene leading to retinitis pigmentosa, and explored the feasibility of using a viral gene augmentation strategy for treatment.
Article
Oncology
Kelly Mulfaul, Nathaniel K. Mullin, Joseph C. Giacalone, Andrew P. Voigt, Melette DeVore, Edwin M. Stone, Budd A. Tucker, Robert F. Mullins
Summary: Activation of the alternative complement pathway is a crucial event in the development of age-related macular degeneration (AMD). Uncontrolled complement activation leads to the formation of the membrane attack complex (MAC). This study demonstrates that reduced levels of complement factor H (FH) in the choroid can contribute to MAC deposition on choroidal endothelial cells (CECs), while overexpression of FH can protect against MAC deposition. These findings highlight the importance of local FH production in preventing MAC deposition in AMD.
JOURNAL OF PATHOLOGY
(2022)
Review
Ophthalmology
Bharatendu Chandra, Moon Ley Tung, Ying Hsu, Todd Scheetz, Val C. Sheffield
Summary: The primary cilium is a specialized organelle in eukaryotes that plays an important role in cell signaling and transportation. Ciliopathies are a group of disorders caused by ciliary dysfunction or abnormal ciliogenesis, with multiorgan involvement. Understanding the genetics and clinical features of ciliopathies, such as Bardet-Biedl syndrome, is challenging but crucial for therapeutic development. This review discusses the structure and function of primary cilia, their role in retinal photoreceptors, and the progress made in understanding ciliopathies.
PROGRESS IN RETINAL AND EYE RESEARCH
(2022)
Article
Ophthalmology
Lola P. Lozano, Budd A. Tucker, Connie J. Hinz, H. Culver Boldt, Elaine M. Binkley
Summary: Von Hippel-Lindau (VHL) disease is a rare inherited cancer syndrome that leads to the development of tumors in multiple systems. This case report highlights the importance of being aware that rare diagnoses can co-exist, as seen in a patient with both retinopathy of prematurity (ROP) and VHL.
CASE REPORTS IN OPHTHALMOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Ian C. Han, Luke A. Wiley, Dalyz Ochoa, Mallory J. Lang, Brynnon E. Harman, Katie M. Sheehan, Robert F. Mullins, Edwin M. Stone, Budd A. Tucker
Summary: In this study, a novel Pde6b-deficient rat model was generated using CRISPR-Cas9 genome editing. The model exhibited rapid photoreceptor degeneration and adeno-associated viral vectors were successfully manufactured to drive human PDE6B expression. Subretinal gene therapy using these vectors was able to delay photoreceptor loss in the rat model.
Article
Cell Biology
Guillermo L. Lehmann, Michael Ginsberg, Daniel J. Nolan, Cristina Rodriguez, Jose Martinez-Gonzalez, Shemin Zeng, Andrew P. Voigt, Robert F. Mullins, Shahin Rafii, Enrique Rodriguez-Boulan, Ignacio Benedicto
Summary: A2M, a protease inhibitor, is found to be expressed in endothelial cells of the human eye choroid. The expression of A2M is induced by retinal pigment epithelium (RPE)-conditioned medium, with VEGF-A playing a key role. Furthermore, the inhibition of A2M leads to the restoration of gelatinase activity in culture supernatants. This study provides important insights into the alterations in choroidal ECM and visual function due to dysfunctional RPE or choroidal blood vessels.
Article
Ophthalmology
Eli A. Perez, David A. Ramirez, Jared D. Peterson, Elaine M. Binkley, H. Culver Boldt, Karen M. Gehrs, Ian C. Han, Stephen R. Russell, Elliott H. Sohn, Scott A. Larson, Jonathan F. Russell
Summary: This study aimed to compare visual outcomes after open-globe injury (OGI) with those predicted by the Ocular Trauma Score (OTS), and to investigate the effect of treatment with pars plana vitrectomy (PPV). The study found that severe OGI had better visual outcomes than predicted by the OTS, and secondary PPV surgery significantly improved visual acuity despite poor prognostic predictions.
OPHTHALMOLOGY RETINA
(2023)
Article
Biotechnology & Applied Microbiology
Luke A. Wiley, Timothy M. Boyce, Emily E. Meyering, Dalyz Ochoa, Katie M. Sheehan, Edwin M. Stone, Robert F. Mullins, Budd A. Tucker, Ian C. Han
Summary: Adeno-associated virus (AAV)-mediated gene therapy has the potential to treat retinal degenerative diseases, but recent evidence of AAV-associated inflammation has raised concerns. This study characterizes the severity and distribution of AAV-induced inflammation in rats, testing five different AAV vectors and three different routes of ocular delivery. The results show that AAV2 and AAV6 induce the most inflammation, with AAV6 causing the highest levels when delivered suprachoroidally. AAV8 and AAV9 induce minimal inflammation. These findings highlight the importance of considering ocular inflammation when developing gene therapy strategies.
HUMAN GENE THERAPY
(2023)
Article
Multidisciplinary Sciences
S. Scott Whitmore, Adam P. DeLuca, Jeaneen L. Andorf, Justine L. Cheng, Mahsaw Mansoor, Christopher R. Fortenbach, D. Brice Critser, Jonathan F. Russell, Edwin M. Stone, Ian C. Han
Summary: Many retinal diseases lead to the loss of light-sensing photoreceptor cells (rods and cones), and characterizing the degree and pattern of this loss can help understand the pathology and prognosis of these diseases. While current technology like adaptive optics can visualize individual photoreceptors, it has limitations and is not widely used. In contrast, optical coherence tomography (OCT) is commonly used for retinal structure visualization but cannot distinguish between rod and cone loss. This study presents a computational model that can estimate rod and cone loss using OCT data alone, providing a powerful tool for research and clinical care.
SCIENTIFIC REPORTS
(2023)
Article
Cell & Tissue Engineering
Jessica A. Cooke, Andrew P. Voigt, Michael A. Collingwood, Nicholas E. Stone, S. Scott Whitmore, Adam P. DeLuca, Erin R. Burnight, Kristin R. Anfinson, Christopher A. Vakulskas, Austin J. Reutzel, Heather T. Daggett, Jeaneen L. Andorf, Edwin M. Stone, Robert F. Mullins, Budd A. Tucker
Summary: Before using iPSC, thorough validation should be conducted. Although there are excellent validation and release testing assays for potency, genetic integrity, and sterility, they cannot predict cell type-specific differentiation capacity. Selecting iPSC lines with limited capacity to produce high-quality transplantable cells strains clinical manufacturing resources.
STEM CELLS TRANSLATIONAL MEDICINE
(2023)
Article
Medicine, Research & Experimental
Nathaniel K. Mullin, Andrew P. Voigt, Miles J. Flamme-Wiese, Xiuying Liu, Megan J. Riker, Katayoun Varzavand, Edwin M. Stone, Budd A. Tucker, Robert F. Mullins
Summary: Variants in the high copy number mitochondrial genome can disrupt organelle function and lead to severe multisystem disease. Heteroplasmy, the uneven distribution of abnormal mtDNA molecules in different cells and tissues, contributes to the wide range of manifestations observed in patients with mitochondrial disease. This study reveals the nonrandom nature of mitochondrial variant distribution in human mitochondrial disease, highlighting its importance for understanding pathogenesis and developing treatments.