Adeno-associated vector corneal gene therapy reverses corneal clouding in a feline model of mucopolysaccharidosis VI
Year: 2025
Type: article
Abstract: Mucopolysaccharidosis VI (MPS VI) is a rare, autosomal recessive lysosomal storage disease caused by mutations in the arylsulfatase B gene (ARSB). Ocular manifestations of MPS VI include progressive corneal clouding, leading to vision loss. Herein, an adeno-associated virus (AAV) ARSB corneal gene addition strategy was evaluated in a naturally occurring MPS VI feline model. The AAV serotype 8 capsid was packaged with a single-strand optimized human ARSB expression cassette (optARSB) and administered to MPS VI feline corneas at a dose of 1e9 vector genomes via intrastromal injection. All AAV8-optARSB injections were well tolerated, resulting in a complete reversal of pre-existing corneal clouding within 2-3 weeks, which was maintained throughout the study. Sequential dosing of the contralateral cornea 7 weeks after the first dose also cleared the storage disease with similar kinetics despite more advanced disease. Confocal microscopy, histological analyses, and electron microscopy revealed disorganization in the posterior corneal stroma in untreated animals with AAV8-optARSB-treated corneas demonstrating improved morphology and tissue organization. Human arylsulfatase B was observed throughout the corneal stroma with decreased smooth muscle actin staining following AAV8-optARSB treatment. The collective results demonstrate that reversing feline MPS VI corneal clouding using intrastromal low-dose AAV8-optARSB is safe and effective. Furthermore, as this strategy relied on the same AAV capsid, vector dose, genetic cassette context, injection type, and volume deemed safe and effective for the treatment of MPS I, the data derived herein support a standardized pipeline for AAV corneal gene therapy.
Source: PLoS ONE
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,382
Funders: Howard Hughes Medical Institute, American Cancer Society, Pharmaceutical Research and Manufacturers of America Foundation, Research to Prevent Blindness, St. Giles Foundation, American Lung Association, BrightFocus Foundation, National Research Centre, University of Oklahoma, Genome Canada, Deutsches Zentrum für Infektionsforschung, Botswana International University of Science and Technology, Fondation Brain Canada, Rockefeller University, Fondation du Souffle, Beijing Outstanding Young Talents, Tow Foundation, National MPS Society, Pershing Square Sohn Cancer Research Alliance, Innovative Research Group Project of the National Natural Science Foundation of China, NIHR Bristol Biomedical Research Centre, Midwest Athletes Against Childhood Cancer, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Institut des maladies génétiques Imagine, International Max Planck Research School for Environmental, Cellular and Molecular Microbiology, Emerson Collective, SCOR Corporate Foundation for Science, Saskatchewan Health Research Foundation, Cancer Research UK, Multiple Sclerosis Society of Canada, National Institute for Health and Care Research, European Commission, Trinity College Dublin, Deutsche Forschungsgemeinschaft, Volkswagen Foundation, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, AO Foundation, Fundação de Amparo à Pesquisa do Estado de São Paulo, National Natural Science Foundation of China, Chungnam National University, Sejong University, Canada Excellence Research Chairs, Government of Canada, China Postdoctoral Science Foundation, Ministry of Trade, Industry and Energy, Ministero della Salute, Natural Science Foundation of Fujian Province, Rural Development Administration, National Research Foundation of Korea, Natural Science Foundation of Hubei Province, Karen Elise Jensens Fond, Korea Drug Development Fund, Meiji Seika Pharma, Max-Planck-Gesellschaft, Stavros Niarchos Foundation, Vetenskapsrådet, Natural Science Foundation of Jiangsu Province, National Research Council of Thailand, Grand Challenges Canada, Ministerio de Ciencia e Innovación, Ahvaz Jundishapur University of Medical Sciences, Natural Science Foundation of Liaoning Province, Uniwersytet Medyczny w Bialymstoku, Kyoto University, Organization for Women in Science for the Developing World, Natural Science Foundation of Henan Province, Natural Science Foundation of Shandong Province, Fondation Bettencourt Schueller, Chulabhorn Research Institute, Taipei Tzu Chi Hospital, Tarbiat Modares University, Higher Education Commision, Pakistan, Uniwersytet Medyczny w Lublinie, African Union, Priority Academic Program Development of Jiangsu Higher Education Institutions, Nazarbayev University, Freistaat Sachsen, Seoul Metropolitan Government Seoul National University Boramae Medical Center, African Union Commission, Ministry of Higher Education, Science, Research and Innovation, Thailand, Bio-Based Industries Joint Undertaking, National Institutes of Health, Horizon 2020 Framework Programme, Intelligence Advanced Research Projects Activity, University of Michigan Center for Gastrointestinal Research, Institute on Aging, University of Pennsylvania, Chulabhorn Graduate Institute, Chulabhorn Royal Academy, Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, National Research Council Canada, Social Sciences and Humanities Research Council of Canada, Japan Society for the Promotion of Science, Science and Engineering Research Board, Korea Evaluation Institute of Industrial Technology, European Regional Development Fund, Canadian Glycomics Network, National Key Research and Development Program of China, Zhejiang Traditional Chinese Medicine Administration, Youth Innovation Promotion Association, Henan Provincial Science and Technology Research Project, Science and Technology Program of Suzhou, National Natural Science Foundation of China-China Academy of General Technology Joint Fund for Basic Research, Basic and Applied Basic Research Foundation of Guangdong Province, Institute for Life and Earth Sciences, Pan African University, National Institute on Aging, NIH Office of the Director, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Center for Research Resources, National Center for Advancing Translational Sciences, National Center for Complementary and Integrative Health, Institute of Neurosciences, Mental Health and Addiction, Medical Science and Technology Project of Zhejiang Province, Congressionally Directed Medical Research Programs, University of California - President's Postdoctoral Fellowship Program
Award: G9000064573
OpenAlex ID: W4417054853