Pub Date : 2025-10-22DOI: 10.1038/s41434-025-00571-4
Carolyn Riley Chapman, Ava Glazier, Emina Berbić, Barbara E Bierer
Guidance from the U.S. Food and Drug Administration and other regulatory agencies recommends long-term follow-up (LTFU) studies of gene therapy recipients. The primary objective of LTFU studies is to understand the long-term safety of gene therapy products; evaluation of efficacy outcomes may be a secondary goal. To learn more about LTFU study design and conduct, we conducted a descriptive study of key characteristics of LTFU gene therapy study protocols registered in ClinicalTrials.gov, including data about status and duration, funding source, enrollment, number of clinical trial sites per study, eligibility criteria, geographic location, and intent to monitor and report adverse events. This analysis enabled a better understanding of how registered LTFU studies are currently designed and stimulated ideas for improvement, which are discussed. Most notably, our results suggest that there is a lack of harmonization in how safety outcomes are monitored and reported across LTFU studies. Standardization and/or harmonization of outcome reporting for LTFU studies of GTs may increase their scientific value. The development of better guidance and innovative approaches for LTFU study design and conduct would help support best practices and the fulfillment of LTFU commitments to understand the overall long-term benefit-risk profile of GT products.
{"title":"Characteristics of long-term follow-up studies for gene therapies registered on ClinicalTrials.gov.","authors":"Carolyn Riley Chapman, Ava Glazier, Emina Berbić, Barbara E Bierer","doi":"10.1038/s41434-025-00571-4","DOIUrl":"https://doi.org/10.1038/s41434-025-00571-4","url":null,"abstract":"<p><p>Guidance from the U.S. Food and Drug Administration and other regulatory agencies recommends long-term follow-up (LTFU) studies of gene therapy recipients. The primary objective of LTFU studies is to understand the long-term safety of gene therapy products; evaluation of efficacy outcomes may be a secondary goal. To learn more about LTFU study design and conduct, we conducted a descriptive study of key characteristics of LTFU gene therapy study protocols registered in ClinicalTrials.gov, including data about status and duration, funding source, enrollment, number of clinical trial sites per study, eligibility criteria, geographic location, and intent to monitor and report adverse events. This analysis enabled a better understanding of how registered LTFU studies are currently designed and stimulated ideas for improvement, which are discussed. Most notably, our results suggest that there is a lack of harmonization in how safety outcomes are monitored and reported across LTFU studies. Standardization and/or harmonization of outcome reporting for LTFU studies of GTs may increase their scientific value. The development of better guidance and innovative approaches for LTFU study design and conduct would help support best practices and the fulfillment of LTFU commitments to understand the overall long-term benefit-risk profile of GT products.</p>","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-26DOI: 10.1038/s41434-025-00567-0
Beatrix Kovács, Viktória Szabó, Domonkos Horváth, Attila Balázs Dobos, Zoltán Zsolt Nagy, Wim Vanduffel, Zsuzsanna Szemlaky, Áron Szepesi, István Ulbert, Balázs Rózsa, Dániel Hillier
Sensitive quantification of adeno-associated virus (AAV) neutralizing antibodies (NAbs) is essential for gene therapy success. Conventional cell-based transduction inhibition assays often encounter matrix-induced artifacts resulting from variable serum content across dilutions, which artificially inflate transduction baselines and mask partial neutralization. To address this challenge, we developed the constant serum concentration (CSC) assay, which maintains constant serum levels across dilutions to stabilize assay baselines and enhance NAb detection sensitivity. Using human sera across multiple AAV serotypes, we demonstrated that CSC reclassified up to 21.7% of samples classified as non-neutralizing by a conventional variable serum concentration (VSC) assay format. This improved sensitivity was validated using monoclonal antibody and multi-species serum test benchmarks and enhanced the reliability of seronegative control pool selection. Importantly, CSC detected persistent seropositivity in preclinical seroreversion models up to one year longer than a conventional VSC assay. Since even low-level neutralizing antibodies can significantly impact gene therapy efficacy, these findings have direct implications for optimizing AAV redosing strategies and refining patient stratification. By addressing fundamental limitations in NAb quantification while maintaining procedural simplicity, the CSC assay provides crucial insights into antibody persistence with translational relevance across species and clinical settings.
{"title":"Overcoming matrix effects in AAV neutralization assays with a constant serum concentration approach","authors":"Beatrix Kovács, Viktória Szabó, Domonkos Horváth, Attila Balázs Dobos, Zoltán Zsolt Nagy, Wim Vanduffel, Zsuzsanna Szemlaky, Áron Szepesi, István Ulbert, Balázs Rózsa, Dániel Hillier","doi":"10.1038/s41434-025-00567-0","DOIUrl":"10.1038/s41434-025-00567-0","url":null,"abstract":"Sensitive quantification of adeno-associated virus (AAV) neutralizing antibodies (NAbs) is essential for gene therapy success. Conventional cell-based transduction inhibition assays often encounter matrix-induced artifacts resulting from variable serum content across dilutions, which artificially inflate transduction baselines and mask partial neutralization. To address this challenge, we developed the constant serum concentration (CSC) assay, which maintains constant serum levels across dilutions to stabilize assay baselines and enhance NAb detection sensitivity. Using human sera across multiple AAV serotypes, we demonstrated that CSC reclassified up to 21.7% of samples classified as non-neutralizing by a conventional variable serum concentration (VSC) assay format. This improved sensitivity was validated using monoclonal antibody and multi-species serum test benchmarks and enhanced the reliability of seronegative control pool selection. Importantly, CSC detected persistent seropositivity in preclinical seroreversion models up to one year longer than a conventional VSC assay. Since even low-level neutralizing antibodies can significantly impact gene therapy efficacy, these findings have direct implications for optimizing AAV redosing strategies and refining patient stratification. By addressing fundamental limitations in NAb quantification while maintaining procedural simplicity, the CSC assay provides crucial insights into antibody persistence with translational relevance across species and clinical settings.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"33 1","pages":"37-47"},"PeriodicalIF":4.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41434-025-00567-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145174670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-23DOI: 10.1038/s41434-025-00564-3
Sahana Kumar, Maria Corkran, Yahya Cheema, Margaret A. Scull, Gregg A. Duncan
The main structural components of mucus produced in the lung are mucin 5B (MUC5B) and mucin 5AC (MUC5AC) where a relatively higher expression of MUC5B is typical in health. In the lungs of individuals with asthma, there is a shift from MUC5B to MUC5AC as the predominantly secreted mucin which has been shown to impair mucociliary clearance (MCC) and increase airway mucus plug formation. Given its role in asthmatic lung disease, MUC5AC represents a potential therapeutic target where a gene delivery approach could be leveraged to modulate its expression. For these purposes, we explored adeno-associated virus serotype 6 (AAV6), as a viral gene vector to transduce airway epithelial cells and reduce MUC5AC expression via siRNA delivery. We confirmed that AAV6 was able to transduce epithelial cells in vitro as well as in the airways of healthy mice in vivo with high transgene expression in mucus-secreting goblet cells. Using multiple particle tracking analysis, we observed that AAV6 was capable of penetrating both normal and MUC5AC-enriched mucus barriers. AAV6 carrying MUC5AC-targeting siRNA was evaluated as a prophylactic treatment in HAE cell cultures before IL-13 challenge. IL-13 stimulated HAE cultures treated with AAV6-MUC5AC siRNA had significantly reduced MUC5AC mRNA and protein expression compared to untreated controls. Mucociliary transport in IL-13 stimulated HAE cultures was also maintained and comparable to healthy controls following AAV6-MUC5AC siRNA treatment. Together, these findings support that AAV6 may be used as an inhaled gene therapy to suppress MUC5AC overexpression and restore normal airway clearance function in asthma.
{"title":"AAV-mediated MUC5AC siRNA delivery to prevent mucociliary dysfunction in asthma","authors":"Sahana Kumar, Maria Corkran, Yahya Cheema, Margaret A. Scull, Gregg A. Duncan","doi":"10.1038/s41434-025-00564-3","DOIUrl":"10.1038/s41434-025-00564-3","url":null,"abstract":"The main structural components of mucus produced in the lung are mucin 5B (MUC5B) and mucin 5AC (MUC5AC) where a relatively higher expression of MUC5B is typical in health. In the lungs of individuals with asthma, there is a shift from MUC5B to MUC5AC as the predominantly secreted mucin which has been shown to impair mucociliary clearance (MCC) and increase airway mucus plug formation. Given its role in asthmatic lung disease, MUC5AC represents a potential therapeutic target where a gene delivery approach could be leveraged to modulate its expression. For these purposes, we explored adeno-associated virus serotype 6 (AAV6), as a viral gene vector to transduce airway epithelial cells and reduce MUC5AC expression via siRNA delivery. We confirmed that AAV6 was able to transduce epithelial cells in vitro as well as in the airways of healthy mice in vivo with high transgene expression in mucus-secreting goblet cells. Using multiple particle tracking analysis, we observed that AAV6 was capable of penetrating both normal and MUC5AC-enriched mucus barriers. AAV6 carrying MUC5AC-targeting siRNA was evaluated as a prophylactic treatment in HAE cell cultures before IL-13 challenge. IL-13 stimulated HAE cultures treated with AAV6-MUC5AC siRNA had significantly reduced MUC5AC mRNA and protein expression compared to untreated controls. Mucociliary transport in IL-13 stimulated HAE cultures was also maintained and comparable to healthy controls following AAV6-MUC5AC siRNA treatment. Together, these findings support that AAV6 may be used as an inhaled gene therapy to suppress MUC5AC overexpression and restore normal airway clearance function in asthma.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"32 5","pages":"508-516"},"PeriodicalIF":4.5,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41434-025-00564-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-22DOI: 10.1038/s41434-025-00563-4
Maria Stamataki, Julia Lüschow, Christina Schlumbohm, Malik Alawi, Lars Lunding, Eberhard Fuchs, Martin Trepel, Markus Schwaninger, Jakob Körbelin
The development of targeted vector systems for gene therapy has made impressive progress during the last decade. Promising vector candidates were identified by screening large pools of adeno-associated virus (AAV) mutants in small animal models. However, it became apparent that targeted AAV mutants isolated from rodents may not function in humans as the tropism of individual AAV mutants can differ between species. To identify novel vascular-targeted AAV capsid mutants suitable for treating human patients, we generated a set of AAV2 display peptide libraries and screened them in the common marmoset, a non-human primate. To evaluate the impact of different AAV library production methods, progress of the screening process was monitored by next generation sequencing. Particle distribution and enrichment was compared between different AAV libraries and selection rounds. We observed enrichment of AAV variants in the brain and other well-perfused organs (lung, heart, kidney) potentially mediated by high capsid affinity for the vascular endothelium in general. In vitro experiments on primary human microvascular endothelial cells isolated from a set of different organs (brain, heart, lung, liver, kidney and spleen) confirmed superior transduction of a selected AAV variant displaying the “DWP” amino acid sequence motif compared to natural AAV serotypes 1–9.
{"title":"Identification of AAV variants with improved transduction of human vascular endothelial cells by screening AAV capsid libraries in non-human primates","authors":"Maria Stamataki, Julia Lüschow, Christina Schlumbohm, Malik Alawi, Lars Lunding, Eberhard Fuchs, Martin Trepel, Markus Schwaninger, Jakob Körbelin","doi":"10.1038/s41434-025-00563-4","DOIUrl":"10.1038/s41434-025-00563-4","url":null,"abstract":"The development of targeted vector systems for gene therapy has made impressive progress during the last decade. Promising vector candidates were identified by screening large pools of adeno-associated virus (AAV) mutants in small animal models. However, it became apparent that targeted AAV mutants isolated from rodents may not function in humans as the tropism of individual AAV mutants can differ between species. To identify novel vascular-targeted AAV capsid mutants suitable for treating human patients, we generated a set of AAV2 display peptide libraries and screened them in the common marmoset, a non-human primate. To evaluate the impact of different AAV library production methods, progress of the screening process was monitored by next generation sequencing. Particle distribution and enrichment was compared between different AAV libraries and selection rounds. We observed enrichment of AAV variants in the brain and other well-perfused organs (lung, heart, kidney) potentially mediated by high capsid affinity for the vascular endothelium in general. In vitro experiments on primary human microvascular endothelial cells isolated from a set of different organs (brain, heart, lung, liver, kidney and spleen) confirmed superior transduction of a selected AAV variant displaying the “DWP” amino acid sequence motif compared to natural AAV serotypes 1–9.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"32 5","pages":"529-541"},"PeriodicalIF":4.5,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41434-025-00563-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vesicular glutamate transporter 3 (VGLUT3) is prominently expressed in the inner hair cells of the cochlea, playing a vital role in auditory signal transmission to the brain. Previous studies have shown that Vglut3 gene knockout in mice causes severe sensorineural hearing loss without affecting hair cell integrity. However, the cochlear structure of the aged Vglut3KO remains inadequately explored. In this study, we analyzed the cochlear structure of aged Vglut3KO mice, revealing significant degeneration of inner hair cells, synapses, and stereocilia. To explore the potential of gene therapy to restore cochlear structure, we employed AAV8 vectors to express Vglut3 in the cochleae of 5-week-old Vglut3KO mice. Twenty-seven weeks post-injection, we conducted a series of experiments to evaluate the efficacy of our gene therapy approach. Auditory brainstem response (ABR) testing demonstrated restoration of auditory function following gene therapy. Immunohistochemical staining and scanning electron microscopy (SEM) analysis revealed substantial recovery of inner hair cells and stereocilia post-injection. Our findings provide important insights into the development of novel therapeutic strategies for age-related hearing loss.
{"title":"Gene therapy restores auditory function and rescues damaged inner hair cells in an aged Vglut3 knockout mouse model","authors":"Xingle Zhao, Hongen Xu, Chengyu Lian, Shousen Hu, Yue Zhao, Jia Wang, Rongqun Zhai, Mihuan Yang, Yuanjing Zhang, Wei Lu, Wenxue Tang, Liang Wang","doi":"10.1038/s41434-025-00558-1","DOIUrl":"10.1038/s41434-025-00558-1","url":null,"abstract":"Vesicular glutamate transporter 3 (VGLUT3) is prominently expressed in the inner hair cells of the cochlea, playing a vital role in auditory signal transmission to the brain. Previous studies have shown that Vglut3 gene knockout in mice causes severe sensorineural hearing loss without affecting hair cell integrity. However, the cochlear structure of the aged Vglut3KO remains inadequately explored. In this study, we analyzed the cochlear structure of aged Vglut3KO mice, revealing significant degeneration of inner hair cells, synapses, and stereocilia. To explore the potential of gene therapy to restore cochlear structure, we employed AAV8 vectors to express Vglut3 in the cochleae of 5-week-old Vglut3KO mice. Twenty-seven weeks post-injection, we conducted a series of experiments to evaluate the efficacy of our gene therapy approach. Auditory brainstem response (ABR) testing demonstrated restoration of auditory function following gene therapy. Immunohistochemical staining and scanning electron microscopy (SEM) analysis revealed substantial recovery of inner hair cells and stereocilia post-injection. Our findings provide important insights into the development of novel therapeutic strategies for age-related hearing loss.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"32 5","pages":"542-552"},"PeriodicalIF":4.5,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-15DOI: 10.1038/s41434-025-00561-6
Katarzyna Chwalenia, Vivi-Yun Feng, Nicole Hemmer, Hans J. Friedrichsen, Ioulia Vorobieva, Matthew J. A. Wood, Thomas C. Roberts
Duchenne muscular dystrophy (DMD) is caused by pathogenic sequence variants occurring in the DMD gene which lead to the loss of the dystrophin protein, a molecular ‘shock absorber’ that protects muscle from contraction-induced injury. The large size of the dystrophin open reading frame precludes delivery of the full-length protein using a single adeno-associated virus (AAV) vector, which led to the development of internally-deleted dystrophin minigenes encoding partially-functional dystrophin. Indeed, five such microdystrophin therapies have been assessed in various clinical programmes. In 2023, Elevidys (Sarepta Therapeutics) received accelerated approval based on levels of dystrophin as a surrogate biomarker. In 2024, it received full approval despite unclear efficacy (i.e. not meeting primary or secondary outcomes in a phase 3 trial). Additionally, in 2025, two DMD individuals treated with Elevidys died after acute liver failure. A separate microdystrophin therapy, PF-06939926 (Pfizer) was discontinued for both efficacy and safety reasons (including the deaths of two clinical trial participants). Solid Biosciences, Genethon, REGENXBIO, and Insmed continue to develop microdystrophin therapies differing in transgene structure, promoter sequences, and AAV serotype. Here we describe recent progress in AAV-microdystrophin therapeutics development, and discuss the challenges facing such approaches, including pre-existing anti-capsid immunity, anti-transgene immunity, the unknown functionality of microdystrophin transgenes, transduction of muscle stem cells, and long-term transgene persistence.
{"title":"AAV microdystrophin gene replacement therapy for Duchenne muscular dystrophy: progress and prospects","authors":"Katarzyna Chwalenia, Vivi-Yun Feng, Nicole Hemmer, Hans J. Friedrichsen, Ioulia Vorobieva, Matthew J. A. Wood, Thomas C. Roberts","doi":"10.1038/s41434-025-00561-6","DOIUrl":"10.1038/s41434-025-00561-6","url":null,"abstract":"Duchenne muscular dystrophy (DMD) is caused by pathogenic sequence variants occurring in the DMD gene which lead to the loss of the dystrophin protein, a molecular ‘shock absorber’ that protects muscle from contraction-induced injury. The large size of the dystrophin open reading frame precludes delivery of the full-length protein using a single adeno-associated virus (AAV) vector, which led to the development of internally-deleted dystrophin minigenes encoding partially-functional dystrophin. Indeed, five such microdystrophin therapies have been assessed in various clinical programmes. In 2023, Elevidys (Sarepta Therapeutics) received accelerated approval based on levels of dystrophin as a surrogate biomarker. In 2024, it received full approval despite unclear efficacy (i.e. not meeting primary or secondary outcomes in a phase 3 trial). Additionally, in 2025, two DMD individuals treated with Elevidys died after acute liver failure. A separate microdystrophin therapy, PF-06939926 (Pfizer) was discontinued for both efficacy and safety reasons (including the deaths of two clinical trial participants). Solid Biosciences, Genethon, REGENXBIO, and Insmed continue to develop microdystrophin therapies differing in transgene structure, promoter sequences, and AAV serotype. Here we describe recent progress in AAV-microdystrophin therapeutics development, and discuss the challenges facing such approaches, including pre-existing anti-capsid immunity, anti-transgene immunity, the unknown functionality of microdystrophin transgenes, transduction of muscle stem cells, and long-term transgene persistence.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"32 5","pages":"447-461"},"PeriodicalIF":4.5,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41434-025-00561-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-15DOI: 10.1038/s41434-025-00562-5
Christina N. Heiss, Rebecca Riise, Eric Hanse, Stefanie Fruhwürth, Henrik Zetterberg, Andreas Björefeldt
{"title":"Correction: Expression of anti-amyloid CARs in microglia promotes efficient and selective phagocytosis of Aβ1‒42","authors":"Christina N. Heiss, Rebecca Riise, Eric Hanse, Stefanie Fruhwürth, Henrik Zetterberg, Andreas Björefeldt","doi":"10.1038/s41434-025-00562-5","DOIUrl":"10.1038/s41434-025-00562-5","url":null,"abstract":"","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"32 5","pages":"572-572"},"PeriodicalIF":4.5,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41434-025-00562-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Inherited retinal diseases are a devasting and incurable cause of blindness which frequently affect patients at a young age, and developing effective treatments has been an important research priority in recent decades. Treatments must be validated in randomised-control trials, which involve measuring benefit according to prospectively defined endpoints. A wide variety of conventional clinical endpoints and emerging anatomical, physiological, and functional biomarkers may be selected. Different options may be better or worse at capturing clinically significant differences and identifying real differences between experimental groups. This review provides an overview of some proven and potential endpoints for randomised-control trials involving inherited retinal disease patients. Clinical endpoints and biomarkers are discussed, and the work required to validate biomarkers for use in trials is outlined. Unlike in general medicine, ophthalmological clinical endpoints may all be conceptualised as surrogates for maintained vision. Selecting optimal endpoints is essential to ensure that treatments are assessed fairly, such that resources are directed towards interventions that stand to truly benefit patients with inherited retinal diseases.
{"title":"Visualising treatment effects in low-vision settings: proven and potential endpoints for clinical trials of inherited retinal disease therapies.","authors":"Arun J Thirunavukarasu, Shabnam Raji, Jasmina Cehajic Kapetanovic","doi":"10.1038/s41434-025-00552-7","DOIUrl":"10.1038/s41434-025-00552-7","url":null,"abstract":"<p><p>Inherited retinal diseases are a devasting and incurable cause of blindness which frequently affect patients at a young age, and developing effective treatments has been an important research priority in recent decades. Treatments must be validated in randomised-control trials, which involve measuring benefit according to prospectively defined endpoints. A wide variety of conventional clinical endpoints and emerging anatomical, physiological, and functional biomarkers may be selected. Different options may be better or worse at capturing clinically significant differences and identifying real differences between experimental groups. This review provides an overview of some proven and potential endpoints for randomised-control trials involving inherited retinal disease patients. Clinical endpoints and biomarkers are discussed, and the work required to validate biomarkers for use in trials is outlined. Unlike in general medicine, ophthalmological clinical endpoints may all be conceptualised as surrogates for maintained vision. Selecting optimal endpoints is essential to ensure that treatments are assessed fairly, such that resources are directed towards interventions that stand to truly benefit patients with inherited retinal diseases.</p>","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144798892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rod-cone dystrophies (RCD) are caused by mutations in over 100 genes associated with photoreceptor function, leading to progressive and sequential loss of rod and cone photoreceptors. These mutations generally disrupt retinal metabolism and oxidative stress response accelerating disease progression and vision loss. SPVN06 is an adeno-associated virus (AAV)-based gene- and mutation-agnostic investigational therapy designed to slow cone degeneration by delivering long-term expression of rod-derived cone viability factor (RdCVF) and its full-length isoform, thioredoxin RdCVFL, following a single subretinal administration. These proteins support cone survival by promoting glucose metabolism and reducing oxidative damage, respectively, providing a gene and mutation independent therapeutic approach for RCD. SPVN06 IND-enabling program included pharmacology evaluation in the rd10/rd10 mouse model of RCD (1.0 × 108 vector genomes (vg)/eye up to 1 month) along with systemic and ocular safety and biodistribution evaluation in non-human primates (NHPs, 6.0 × 109 to 3.0 × 1011 vg/eye up to 3 months). In the rd10/rd10 mice, SPVN06 showed preserved vision, as assessed by optokinetic tracking. In NHPs, SPVN06 was well-tolerated up to 6.0 × 1010 vg/eye, with high and stable RdCVF and RdCVFL mRNA expression levels in the retina and retinal pigment epithelium. These results supported the initiation of the ongoing Phase I/II PRODYGY trial with RCD (NCT05748873).
{"title":"Preclinical safety and biodistribution of SPVN06, a novel gene- and mutation-independent gene therapy for rod-cone dystrophies.","authors":"Mélanie Marie, Lucie Churet, Anne-Sophie Gautron, Rafal Farjo, Kensuke Mizuyoshi, Victoria Stevenson, Hanen Khabou, Thierry Léveillard, José-Alain Sahel, Florence Lorget","doi":"10.1038/s41434-025-00556-3","DOIUrl":"10.1038/s41434-025-00556-3","url":null,"abstract":"<p><p>Rod-cone dystrophies (RCD) are caused by mutations in over 100 genes associated with photoreceptor function, leading to progressive and sequential loss of rod and cone photoreceptors. These mutations generally disrupt retinal metabolism and oxidative stress response accelerating disease progression and vision loss. SPVN06 is an adeno-associated virus (AAV)-based gene- and mutation-agnostic investigational therapy designed to slow cone degeneration by delivering long-term expression of rod-derived cone viability factor (RdCVF) and its full-length isoform, thioredoxin RdCVFL, following a single subretinal administration. These proteins support cone survival by promoting glucose metabolism and reducing oxidative damage, respectively, providing a gene and mutation independent therapeutic approach for RCD. SPVN06 IND-enabling program included pharmacology evaluation in the rd10/rd10 mouse model of RCD (1.0 × 10<sup>8</sup> vector genomes (vg)/eye up to 1 month) along with systemic and ocular safety and biodistribution evaluation in non-human primates (NHPs, 6.0 × 10<sup>9</sup> to 3.0 × 10<sup>11</sup> vg/eye up to 3 months). In the rd10/rd10 mice, SPVN06 showed preserved vision, as assessed by optokinetic tracking. In NHPs, SPVN06 was well-tolerated up to 6.0 × 10<sup>10</sup> vg/eye, with high and stable RdCVF and RdCVFL mRNA expression levels in the retina and retinal pigment epithelium. These results supported the initiation of the ongoing Phase I/II PRODYGY trial with RCD (NCT05748873).</p>","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-28DOI: 10.1038/s41434-025-00557-2
Margareta Rybarikova, Maria Rey, Ed Hasanovic, Mélanie Sipion, Lukas Rambousek, Nicole Déglon
Spinocerebellar ataxia type 3 (SCA3) is a rare neurodegenerative disease caused by a CAG expansion of the ataxin-3 gene (ATXN3). SCA3 patients suffer from ataxia, spasticity and dystonia in mid-adulthood, with spinocerebellar dysfunction and degeneration. As a monogenic disease for which only symptomatic treatment is available, ATXN3 is an attractive target for gene editing. We used the KamiCas9, a self-inactivating gene editing system, to explore gene editing strategies suitable for all SCA3 patients. We first tested the deletion of exon 10 or the introduction of a premature stop codon into exon 9. High editing events were observed in vitro, but efficiency was very low in SCA3 transgenic mice. We then evaluated an ablate-and-replace strategy. The ablate experiments resulted in 55 ± 18% cerebellar editing of the ATXN3 gene. A human ATXN3L paralog, expressed in the brains of SCA3 patients, may act as a natural, CRISPR-resistant replacement gene. In a proof-of-principle study, ablate and ablate-and-replace strategies were evaluated in SCA3 transgenic mice. Two months after injection, similar editing efficiencies were obtained in the ablate and ablate-and-replace groups. Immunofluorescence and RT-qPCR analyses of cerebellar markers support the development of this strategy for SCA3 treatment.
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