Pub Date : 2025-12-03DOI: 10.1126/scitranslmed.adw7428
Tanya N. Weerakkody, Hanna Sabelström, Shan V. Andrews, Jean Paul Chadarevian, Marcus Y. Chin, David Tatarakis, Nicholas E. Propson, Do Jin Kim, Richard Theolis, Gian Carlo G. Parico, Hiwot Misker, Jennifer E. Kung, Abira Bandyopadhyay, Yaneth Robles Colmenares, Taggra-Nicole Jackson, Ahlam N. Qerqez, Srijana Balasundar, Sonnet S. Davis, Connie Ha, Rajarshi Ghosh, Ritesh Ravi, Anil Rana, Kyla Germain, Arnold Tao, Ken Xiong, Dylan Braun, Karthik Raju, Kang-Chieh Huang, Lihong Zhan, Jing L. Guo, Hoda Safari Yazd, Lily Sarrafha, Joia Kai Capocchi, Jonathan Hasselmann, Alina L. Chadarevian, Christina Tu, Kimiya Mansour, Ghazaleh Eskandari-Sedighi, Niccolò Tesi, Sven van der Lee, Marc Hulsman, Georgii Oshegov, Yolande Pijnenburg, Meredith Calvert, Henne Holstege, Jung H. Suh, Gilbert Di Paolo, Hayk Davtyan, Joseph W. Lewcock, Mathew Blurton-Jones, Kathryn M. Monroe
The Alzheimer’s disease (AD) genetic landscape identified microglia as a key disease-modifying cell type. Paired immunoglobulin-like type 2 receptor alpha (PILRA) is an immunoreceptor tyrosine–based inhibitory motif domain–containing inhibitory receptor, expressed by myeloid cells such as microglia. The known protective PILRA G78R gene variant reduces AD risk in apolipoprotein E4 (APOE4) carriers and is enriched in a cohort of healthy centenarians. However, mechanisms underlying protective effects in microglia are undefined. Here, we identified biological functions of PILRA in human induced pluripotent stem cell–derived microglia (iMG) and chimeric AD mice. PILRA knockout (KO) in iMG rescued ApoE4-mediated immunometabolic deficits and prevented lipotoxicity through increased lipid storage, improved mitochondrial bioenergetics, and antioxidant activity. PILRA KO also enhanced microglial chemotaxis and attenuated inflammation. With pharmacological inhibitor studies, we showed that peroxisome proliferator–activated receptor and signal transducer and activator of transcription 1/3 mediated PILRA-dependent microglial functions. AD mice transplanted with human PILRA KO microglia exhibited reduced amyloid pathology and rescued synaptic markers. A high-affinity ligand blocking PILRA antibody phenocopied PILRA KO iMG. These findings suggest that PILRA is a pharmacologically tractable therapeutic target for AD.
阿尔茨海默病（AD）的遗传景观确定小胶质细胞是一种关键的疾病修饰细胞类型。配对免疫球蛋白样2型受体α (PILRA)是一种基于酪氨酸的抑制基序结构域的抑制受体，由髓样细胞如小胶质细胞表达。已知的保护性PILRA G78R基因变异可降低载脂蛋白E4 （APOE4）携带者的AD风险，并在健康百岁老人队列中富集。然而，小胶质细胞保护作用的机制尚不明确。在这里，我们确定了PILRA在人诱导多能干细胞衍生小胶质细胞（iMG）和嵌合AD小鼠中的生物学功能。iMG中的PILRA基因敲除（KO）挽救了apoe4介导的免疫代谢缺陷，并通过增加脂质储存、改善线粒体生物能量学和抗氧化活性来防止脂肪毒性。PILRA KO还能增强小胶质细胞趋化性和减轻炎症。通过药物抑制剂研究，我们发现过氧化物酶体增殖物激活受体和转录1/3的信号换能器和激活因子介导了PILRA依赖性小胶质细胞的功能。移植了人类PILRA KO小胶质细胞的AD小鼠表现出淀粉样蛋白病理减少和突触标志物恢复。一种高亲和力配体阻断PILRA抗体对PILRA KO iMG进行表型复制。这些发现表明PILRA是一种药理学上可行的治疗AD的靶点。
{"title":"Loss of PILRA promotes microglial immunometabolism to reduce amyloid pathology in cell and mouse models of Alzheimer’s disease","authors":"Tanya N. Weerakkody, Hanna Sabelström, Shan V. Andrews, Jean Paul Chadarevian, Marcus Y. Chin, David Tatarakis, Nicholas E. Propson, Do Jin Kim, Richard Theolis, Gian Carlo G. Parico, Hiwot Misker, Jennifer E. Kung, Abira Bandyopadhyay, Yaneth Robles Colmenares, Taggra-Nicole Jackson, Ahlam N. Qerqez, Srijana Balasundar, Sonnet S. Davis, Connie Ha, Rajarshi Ghosh, Ritesh Ravi, Anil Rana, Kyla Germain, Arnold Tao, Ken Xiong, Dylan Braun, Karthik Raju, Kang-Chieh Huang, Lihong Zhan, Jing L. Guo, Hoda Safari Yazd, Lily Sarrafha, Joia Kai Capocchi, Jonathan Hasselmann, Alina L. Chadarevian, Christina Tu, Kimiya Mansour, Ghazaleh Eskandari-Sedighi, Niccolò Tesi, Sven van der Lee, Marc Hulsman, Georgii Oshegov, Yolande Pijnenburg, Meredith Calvert, Henne Holstege, Jung H. Suh, Gilbert Di Paolo, Hayk Davtyan, Joseph W. Lewcock, Mathew Blurton-Jones, Kathryn M. Monroe","doi":"10.1126/scitranslmed.adw7428","DOIUrl":"10.1126/scitranslmed.adw7428","url":null,"abstract":"<div >The Alzheimer’s disease (AD) genetic landscape identified microglia as a key disease-modifying cell type. Paired immunoglobulin-like type 2 receptor alpha (PILRA) is an immunoreceptor tyrosine–based inhibitory motif domain–containing inhibitory receptor, expressed by myeloid cells such as microglia. The known protective <i>PILRA</i> G78R gene variant reduces AD risk in <i>apolipoprotein E4</i> (<i>APOE4</i>) carriers and is enriched in a cohort of healthy centenarians. However, mechanisms underlying protective effects in microglia are undefined. Here, we identified biological functions of PILRA in human induced pluripotent stem cell–derived microglia (iMG) and chimeric AD mice. <i>PILRA</i> knockout (KO) in iMG rescued ApoE4-mediated immunometabolic deficits and prevented lipotoxicity through increased lipid storage, improved mitochondrial bioenergetics, and antioxidant activity. <i>PILRA</i> KO also enhanced microglial chemotaxis and attenuated inflammation. With pharmacological inhibitor studies, we showed that peroxisome proliferator–activated receptor and signal transducer and activator of transcription 1/3 mediated <i>PILRA</i>-dependent microglial functions. AD mice transplanted with human <i>PILRA</i> KO microglia exhibited reduced amyloid pathology and rescued synaptic markers. A high-affinity ligand blocking PILRA antibody phenocopied <i>PILRA</i> KO iMG. These findings suggest that PILRA is a pharmacologically tractable therapeutic target for AD.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 827","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145658271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-03DOI: 10.1126/scitranslmed.adr2277
Sang-Hun Kim, Jessica Nouws, Jannik Ruwisch, Gavitt A. Woodard, Joseph Cooley, Johad Khoury, Huanxing Sun, Edward Doherty, Marta Piecychna, Edward P. Manning, Min-Jong Kang, Emanuela M. Bruscia, Huanhuan Wei, Yuening Zhang, Timur O. Yarovinsky, John Hwa, William J. Zacharias, Jennifer Ingram, Chun Geun Lee, Jack A. Elias, Naftali Kaminski, Elizabeth F. Redente, Erica L. Herzog, Antje Prasse, Richard Bucala, Maor Sauler
Aberrant proteostasis in alveolar type 2 epithelial cells (AEC2s) contributes to idiopathic pulmonary fibrosis (IPF), but the role of the ubiquitin-proteasome system (UPS) is unclear. Here, we show that UPS disruption in AEC2s amplifies profibrotic signaling to macrophages through macrophage migration inhibitory factor (MIF) family proteins in several models. Modeling UPS disruption with an AEC2-specific cullin 3 (Cul3) deletion produced spontaneous fibrosis in a physiological aging mouse model and exacerbated fibrosis in the bleomycin-induced lung injury model. This was accompanied by expansion of transitional epithelial states and increased MIF and MIF-2 in lung tissue and bronchoalveolar lavage fluid (BALF) in the model. Global or conditional AEC2-specific deletions of Mif or Mif-2 attenuated fibrosis in the bleomycin-treated mouse model, as did conditional deletions of Cd74, the cognate receptor for MIF and MIF-2, in C-X3-C motif chemokine receptor 1 (Cx3cr1)–expressing and platelet factor 4 (Pf4)–expressing cells. Pharmacological inhibition of MIF attenuated fibrosis in bleomycin-treated and transforming growth factor–β1 (TGFB1) transgenic mouse models and in ex vivo human precision-cut lung slices treated with fibrotic cocktail. In study participants with IPF, BALF MIF was elevated compared with that in study participants without IPF. In participants with IPF, BALF MIF greater than 4000 picograms per milliliter was associated with increased mortality compared with participants with IPF with lower MIF. Together, these findings define a UPS-sensitive epithelial-macrophage signaling connection and identify MIF-CD74 cross-talk as a potential therapeutic target in fibrotic lung disease.
{"title":"Dysregulated alveolar type 2 epithelial cell proteostasis promotes fibrogenic macrophage migration inhibitory factor–CD74 signaling","authors":"Sang-Hun Kim, Jessica Nouws, Jannik Ruwisch, Gavitt A. Woodard, Joseph Cooley, Johad Khoury, Huanxing Sun, Edward Doherty, Marta Piecychna, Edward P. Manning, Min-Jong Kang, Emanuela M. Bruscia, Huanhuan Wei, Yuening Zhang, Timur O. Yarovinsky, John Hwa, William J. Zacharias, Jennifer Ingram, Chun Geun Lee, Jack A. Elias, Naftali Kaminski, Elizabeth F. Redente, Erica L. Herzog, Antje Prasse, Richard Bucala, Maor Sauler","doi":"10.1126/scitranslmed.adr2277","DOIUrl":"10.1126/scitranslmed.adr2277","url":null,"abstract":"<div >Aberrant proteostasis in alveolar type 2 epithelial cells (AEC2s) contributes to idiopathic pulmonary fibrosis (IPF), but the role of the ubiquitin-proteasome system (UPS) is unclear. Here, we show that UPS disruption in AEC2s amplifies profibrotic signaling to macrophages through macrophage migration inhibitory factor (MIF) family proteins in several models. Modeling UPS disruption with an AEC2-specific cullin 3 (<i>Cul3</i>) deletion produced spontaneous fibrosis in a physiological aging mouse model and exacerbated fibrosis in the bleomycin-induced lung injury model. This was accompanied by expansion of transitional epithelial states and increased MIF and MIF-2 in lung tissue and bronchoalveolar lavage fluid (BALF) in the model. Global or conditional AEC2-specific deletions of <i>Mif</i> or <i>Mif-2</i> attenuated fibrosis in the bleomycin-treated mouse model, as did conditional deletions of <i>Cd74</i>, the cognate receptor for MIF and MIF-2, in C-X3-C motif chemokine receptor 1 (<i>Cx3cr1</i>)–expressing and platelet factor 4 (<i>Pf4</i>)–expressing cells. Pharmacological inhibition of MIF attenuated fibrosis in bleomycin-treated and transforming growth factor–β1 (<i>TGFB1</i>) transgenic mouse models and in ex vivo human precision-cut lung slices treated with fibrotic cocktail. In study participants with IPF, BALF MIF was elevated compared with that in study participants without IPF. In participants with IPF, BALF MIF greater than 4000 picograms per milliliter was associated with increased mortality compared with participants with IPF with lower MIF. Together, these findings define a UPS-sensitive epithelial-macrophage signaling connection and identify MIF-CD74 cross-talk as a potential therapeutic target in fibrotic lung disease.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 827","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145658270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-03DOI: 10.1126/scitranslmed.ads0982
Eva Conde, Emma Lamanna, Aurélie Mougel, Jasper B. J. Kamphuis, Alexia Loste, Julien Stackowicz, Ophélie Godon, Emilie Mauré, Cyprien Pecalvel, William P. M. Worrall, Léna Andrieux, Edouard Leveque, Zohra Benmessaoud, Pol-André Apoil, Marija Backovic, Bruno Iannascoli, Jonathan Bonnefoy, Samir Hamdi, Fabien Colaone, Friederike Jönsson, Patrick England, Laurent Guilleminault, Bernard Malissen, Frédéric Fiore, Lara Linnemann, Minka Breloer, Nicolas Gaudenzio, Béatrice Drouet, Katia Lemdani, Vincent Serra, Pierre Bruhns, Laurent L. Reber
Immunoglobulin E (IgE) antibodies play a key role in allergy and its most dangerous and life-threatening manifestation, anaphylaxis. Anti-IgE monoclonal antibodies (mAbs) have been developed to treat IgE-dependent diseases such as allergic asthma, food allergy, and chronic spontaneous urticaria. However, their use is still restricted to a minority of patients suffering from the most severe symptoms because treatment is costly and requires repeated administration. Therefore, we developed a conjugate vaccine against human IgE as a potential alternative therapy for long-term protection from IgE-dependent diseases. The IgE conjugate vaccine was generated by coupling a mutated fragment containing the Cε3-4 domains of human IgE with the carrier protein diphtheria cross-reactive material 197 (CRM197) using kinoid technology to raise autoantibodies against a self-antigen by engrafting it onto the highly immunogenic CRM197 carrier. To assess the efficacy of IgE-kinoid (IgE-K) vaccination, we generated a mouse model humanized for IgE and its high-affinity receptor FcεRI. IgE-K vaccination induced long-term production of anti–human IgE neutralizing antibodies without any detectable adverse effect. Anti-IgE antibodies were detected in the sera of IgE-K–immunized mice for up to 12 months postvaccination with a similar avidity as the approved anti-IgE mAb omalizumab. Furthermore, IgE-K vaccination protected against both IgE-mediated cutaneous and severe systemic anaphylaxis in IgE/FcεRI-humanized mice. Our results demonstrate that long-term reduction in IgE activity can be achieved through vaccination with human kinoids and can protect against anaphylaxis in humanized mice. This may represent a cost-effective, long-term therapeutic strategy for the treatment of IgE-mediated diseases.
{"title":"A vaccine targeting human IgE induces long-term protection against anaphylaxis in humanized mice","authors":"Eva Conde, Emma Lamanna, Aurélie Mougel, Jasper B. J. Kamphuis, Alexia Loste, Julien Stackowicz, Ophélie Godon, Emilie Mauré, Cyprien Pecalvel, William P. M. Worrall, Léna Andrieux, Edouard Leveque, Zohra Benmessaoud, Pol-André Apoil, Marija Backovic, Bruno Iannascoli, Jonathan Bonnefoy, Samir Hamdi, Fabien Colaone, Friederike Jönsson, Patrick England, Laurent Guilleminault, Bernard Malissen, Frédéric Fiore, Lara Linnemann, Minka Breloer, Nicolas Gaudenzio, Béatrice Drouet, Katia Lemdani, Vincent Serra, Pierre Bruhns, Laurent L. Reber","doi":"10.1126/scitranslmed.ads0982","DOIUrl":"10.1126/scitranslmed.ads0982","url":null,"abstract":"<div >Immunoglobulin E (IgE) antibodies play a key role in allergy and its most dangerous and life-threatening manifestation, anaphylaxis. Anti-IgE monoclonal antibodies (mAbs) have been developed to treat IgE-dependent diseases such as allergic asthma, food allergy, and chronic spontaneous urticaria. However, their use is still restricted to a minority of patients suffering from the most severe symptoms because treatment is costly and requires repeated administration. Therefore, we developed a conjugate vaccine against human IgE as a potential alternative therapy for long-term protection from IgE-dependent diseases. The IgE conjugate vaccine was generated by coupling a mutated fragment containing the Cε3-4 domains of human IgE with the carrier protein diphtheria cross-reactive material 197 (CRM<sub>197</sub>) using kinoid technology to raise autoantibodies against a self-antigen by engrafting it onto the highly immunogenic CRM<sub>197</sub> carrier. To assess the efficacy of IgE-kinoid (IgE-K) vaccination, we generated a mouse model humanized for IgE and its high-affinity receptor FcεRI. IgE-K vaccination induced long-term production of anti–human IgE neutralizing antibodies without any detectable adverse effect. Anti-IgE antibodies were detected in the sera of IgE-K–immunized mice for up to 12 months postvaccination with a similar avidity as the approved anti-IgE mAb omalizumab. Furthermore, IgE-K vaccination protected against both IgE-mediated cutaneous and severe systemic anaphylaxis in IgE/FcεRI-humanized mice. Our results demonstrate that long-term reduction in IgE activity can be achieved through vaccination with human kinoids and can protect against anaphylaxis in humanized mice. This may represent a cost-effective, long-term therapeutic strategy for the treatment of IgE-mediated diseases.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 827","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.ads0982","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145658252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-03DOI: 10.1126/scitranslmed.adw9578
Laura Seldeslachts, Sirima Kraisin, Intan M. W. Dewi, Simon Feys, Frederik Staels, Marina Gkountzinopoulou, Cato Jacobs, Birger Tielemans, Eliane Vanhoffelen, Agustin Reséndiz-Sharpe, Lander De Herdt, Oswin Kwan, Niels Vandamme, Jana Roels, Julika Neumann, Teresa Prezzemolo, Bert Malengier-Devlies, Mathias Stroobants, Agostinho Carvalho, Patrick Matthys, Lieve Naesens, Katrien Lagrou, Mona Khan, Peter Mombaerts, Erik Verbeken, Kimberly Martinod, Joost Wauters, Frank L. van de Veerdonk, Greetje Vande Velde, Stephanie Humblet-Baron
Influenza-associated pulmonary aspergillosis (IAPA) is a severe fungal superinfection affecting critically ill patients with influenza. Current treatments target the causative pathogens but do not address the dysregulated host immune responses that drive morbidity. Host-directed immunotherapies could overcome this treatment gap. Here, we studied the host-pathogen factors driving IAPA using patient samples and an IAPA mouse model. We identified interleukin-1 (IL-1)–mediated inflammation, neutrophil activation, and neutrophil extracellular trap (NET) release as crucial features in IAPA pathogenesis. This inflammation led to an immunological imbalance with defective neutrophil effector functions, including impaired reactive oxygen production (ROS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, thereby impairing the fungal host immune response toward a permissive environment for Aspergillus fumigatus. Blocking the IL-1 receptor with anakinra reduced inflammation and NET release, restored ROS production in neutrophils, and rescued influenza virus–infected mice from invasive pulmonary aspergillosis. Our findings underscore the crucial role of IL-1–driven inflammation in the immunological misfiring that drives IAPA and suggest anakinra as a promising immunomodulatory therapy for patients with IAPA.
{"title":"Anakinra restores immunological misfiring that drives influenza-associated pulmonary aspergillosis","authors":"Laura Seldeslachts, Sirima Kraisin, Intan M. W. Dewi, Simon Feys, Frederik Staels, Marina Gkountzinopoulou, Cato Jacobs, Birger Tielemans, Eliane Vanhoffelen, Agustin Reséndiz-Sharpe, Lander De Herdt, Oswin Kwan, Niels Vandamme, Jana Roels, Julika Neumann, Teresa Prezzemolo, Bert Malengier-Devlies, Mathias Stroobants, Agostinho Carvalho, Patrick Matthys, Lieve Naesens, Katrien Lagrou, Mona Khan, Peter Mombaerts, Erik Verbeken, Kimberly Martinod, Joost Wauters, Frank L. van de Veerdonk, Greetje Vande Velde, Stephanie Humblet-Baron","doi":"10.1126/scitranslmed.adw9578","DOIUrl":"10.1126/scitranslmed.adw9578","url":null,"abstract":"<div >Influenza-associated pulmonary aspergillosis (IAPA) is a severe fungal superinfection affecting critically ill patients with influenza. Current treatments target the causative pathogens but do not address the dysregulated host immune responses that drive morbidity. Host-directed immunotherapies could overcome this treatment gap. Here, we studied the host-pathogen factors driving IAPA using patient samples and an IAPA mouse model. We identified interleukin-1 (IL-1)–mediated inflammation, neutrophil activation, and neutrophil extracellular trap (NET) release as crucial features in IAPA pathogenesis. This inflammation led to an immunological imbalance with defective neutrophil effector functions, including impaired reactive oxygen production (ROS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, thereby impairing the fungal host immune response toward a permissive environment for <i>Aspergillus fumigatus</i>. Blocking the IL-1 receptor with anakinra reduced inflammation and NET release, restored ROS production in neutrophils, and rescued influenza virus–infected mice from invasive pulmonary aspergillosis. Our findings underscore the crucial role of IL-1–driven inflammation in the immunological misfiring that drives IAPA and suggest anakinra as a promising immunomodulatory therapy for patients with IAPA.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 827","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145658272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-03DOI: 10.1126/scitranslmed.adp1338
Ahmed Gamal-Eldin Ibrahim, Alessandra Ciullo, Hiroaki Komuro, Kazutaka Miyamoto, Xaviar M. Jones, Shukuro Yamaguchi, Kara Tsi, Jessica Anderson, Joshua Godoy Coto, Diana Kitka, Ke Liao, Chang Li, Alice Rannou, Asma Nawaz, Ashley Morris, Cristina H. Marbán, Jamie Lee, Nancy Manriquez, Yeojin Hong, Arati Naveen Kumar, James F. Dawkins, Russell G. Rogers, Eduardo Marbán
Noncoding RNAs (ncRNAs) are increasingly recognized as promising therapeutic candidates. Here, we report the development of therapeutic Y RNA 1 (TY1), a synthetic ncRNA bioinspired by a naturally occurring human small Y RNA with immunomodulatory properties. TY1 up-regulates three-prime DNA exonuclease 1 (TREX1), an exonuclease that rapidly degrades cytosolic DNA. In preclinical models of myocardial infarction (MI) induced by ischemia-reperfusion, TY1 reduced scar size. The cardioprotective effect of TY1 was abrogated by prior depletion of macrophages and mimicked by adoptive transfer of macrophages exposed to either TY1 or Trex1 overexpression. Inhibition of Trex1 in macrophages blocked TY1 cardioprotection. Consistent with a central role for Trex1, TY1 attenuated DNA damage in the post-MI heart. The key beneficial effects appear to be mediated by extracellular vesicles secreted by TY1-conditioned macrophages. This previously undescribed mechanism—pharmacological up-regulation of Trex1 in macrophages—establishes TY1 as the prototype for a new class of ncRNA drugs with disease-modifying bioactivity. We refer to this potential new class of ncRNA drugs as exomers because of the identification of their parent molecules in extracellular vesicles.
{"title":"Augmentation of DNA exonuclease TREX1 in macrophages as a therapy for cardiac ischemic injury","authors":"Ahmed Gamal-Eldin Ibrahim, Alessandra Ciullo, Hiroaki Komuro, Kazutaka Miyamoto, Xaviar M. Jones, Shukuro Yamaguchi, Kara Tsi, Jessica Anderson, Joshua Godoy Coto, Diana Kitka, Ke Liao, Chang Li, Alice Rannou, Asma Nawaz, Ashley Morris, Cristina H. Marbán, Jamie Lee, Nancy Manriquez, Yeojin Hong, Arati Naveen Kumar, James F. Dawkins, Russell G. Rogers, Eduardo Marbán","doi":"10.1126/scitranslmed.adp1338","DOIUrl":"10.1126/scitranslmed.adp1338","url":null,"abstract":"<div >Noncoding RNAs (ncRNAs) are increasingly recognized as promising therapeutic candidates. Here, we report the development of therapeutic Y RNA 1 (TY1), a synthetic ncRNA bioinspired by a naturally occurring human small Y RNA with immunomodulatory properties. TY1 up-regulates three-prime DNA exonuclease 1 (TREX1), an exonuclease that rapidly degrades cytosolic DNA. In preclinical models of myocardial infarction (MI) induced by ischemia-reperfusion, TY1 reduced scar size. The cardioprotective effect of TY1 was abrogated by prior depletion of macrophages and mimicked by adoptive transfer of macrophages exposed to either TY1 or <i>Trex1</i> overexpression. Inhibition of <i>Trex1</i> in macrophages blocked TY1 cardioprotection. Consistent with a central role for <i>Trex1</i>, TY1 attenuated DNA damage in the post-MI heart. The key beneficial effects appear to be mediated by extracellular vesicles secreted by TY1-conditioned macrophages. This previously undescribed mechanism—pharmacological up-regulation of <i>Trex1</i> in macrophages—establishes TY1 as the prototype for a new class of ncRNA drugs with disease-modifying bioactivity. We refer to this potential new class of ncRNA drugs as exomers because of the identification of their parent molecules in extracellular vesicles.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 827","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145658268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Metabolic dysfunction–associated fatty liver disease (MAFLD), a leading cause of hepatocellular carcinoma (HCC), poses a formidable therapeutic challenge because of the metabolic stress–induced aberrant immune microenvironment. However, no effective pharmacological therapies for the liver microenvironment remodeling in MAFLD are now available. Here, we developed a lipid nanoparticle (Def-LNP) that incorporates vitamin E–derived phosphatidylcholine (VEPC). Def-LNP effectively ameliorated the hepatic oxidative microenvironment to achieve sustained localized expression of target mRNA in hepatocytes in preclinical models, outperforming a commercially used LNP formulation. In vivo delivery efficiency, stability, and biosafety of Def-LNP were validated in various mammalian models, including mice, pigs, and nonhuman primates. Using clinical samples, we identified a pronounced correlation between T cell protein tyrosine phosphatase (TCPTP) and MAFLD pathogenesis. The administration of Def-LNP loaded with TCPTP-encoding mRNA (Def-LNP@mRNATCPTP) suppressed signal transducer and activator of transcription signaling in the hepatocytes of MAFLD mice, leading to hepatic metabolic reprogramming and immunological reconfiguration, a characteristic that is prominently lacking in conventional mRNA-based protein replacement therapy. In preclinical models, the administration of Def-LNP@mRNATCPTP successfully eliminated steatohepatitis, impeded hepatocarcinogenesis, and improved the therapeutic responsiveness of HCC to cancer vaccine and immune checkpoint blockade therapy. Def-LNP@mRNATCPTP represents a potential therapeutic strategy for MAFLD and MAFLD-related HCC, potentially offering treatment paradigms for immunotherapy for HCC and metabolic liver diseases.
{"title":"Metabolism-programming mRNA-lipid nanoparticles remodel the immune microenvironment to improve immunotherapy against MAFLD","authors":"Xinyang Yu, Shaolong Qi, Wanyue Cao, Meiqi Cheng, Wenjie Zhang, Yangfan Wang, Rujia Zheng, Gaowei Jin, Xiaomin Gao, Meixin Lu, Jiaqi Lei, Kun Peng, Xinhui Su, Qi Zhang, Guocan Yu","doi":"10.1126/scitranslmed.adv2293","DOIUrl":"10.1126/scitranslmed.adv2293","url":null,"abstract":"<div >Metabolic dysfunction–associated fatty liver disease (MAFLD), a leading cause of hepatocellular carcinoma (HCC), poses a formidable therapeutic challenge because of the metabolic stress–induced aberrant immune microenvironment. However, no effective pharmacological therapies for the liver microenvironment remodeling in MAFLD are now available. Here, we developed a lipid nanoparticle (Def-LNP) that incorporates vitamin E–derived phosphatidylcholine (VEPC). Def-LNP effectively ameliorated the hepatic oxidative microenvironment to achieve sustained localized expression of target mRNA in hepatocytes in preclinical models, outperforming a commercially used LNP formulation. In vivo delivery efficiency, stability, and biosafety of Def-LNP were validated in various mammalian models, including mice, pigs, and nonhuman primates. Using clinical samples, we identified a pronounced correlation between T cell protein tyrosine phosphatase (TCPTP) and MAFLD pathogenesis. The administration of Def-LNP loaded with TCPTP-encoding mRNA (Def-LNP@mRNA<sup>TCPTP</sup>) suppressed signal transducer and activator of transcription signaling in the hepatocytes of MAFLD mice, leading to hepatic metabolic reprogramming and immunological reconfiguration, a characteristic that is prominently lacking in conventional mRNA-based protein replacement therapy. In preclinical models, the administration of Def-LNP@mRNA<sup>TCPTP</sup> successfully eliminated steatohepatitis, impeded hepatocarcinogenesis, and improved the therapeutic responsiveness of HCC to cancer vaccine and immune checkpoint blockade therapy. Def-LNP@mRNA<sup>TCPTP</sup> represents a potential therapeutic strategy for MAFLD and MAFLD-related HCC, potentially offering treatment paradigms for immunotherapy for HCC and metabolic liver diseases.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 827","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145658269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-26DOI: 10.1126/scitranslmed.aea2531
Rebecca Webster, Damian A. Oyong, Stacey Llewellyn, Azrin N. Abd-Rahman, Adam J. Potter, Reena Mukhiya, Nischal Sahai, Indika Leelasena, Eniko Ujvary, Sue Mathison, Dean W. Andrew, Luzia Bukali, Fabian de Labastida Rivera, Jessica Engel, Megan S. F. Soon, Teija Frame, Julianne Hamelink, Mayimuna Nalubega, Nicholas L. Dooley, Jessica R. Loughland, Tran Nguyen, Yael Rosenberg-Hasson, Sofia Maysel-Auslender, Natalia Sigal, Kira Foygel, Jeremy Gower, Jenny Peters, Ria Woo, Fiona Amante, Timothy N. C. Wells, Stephan Chalon, Joerg J. Moehrle, James S. McCarthy, Geoffrey W. Birrell, Michael D. Edstein, Michael Leipold, Gerlinde Obermoser, Holden Maecker, Christian R. Engwerda, Bridget E. Barber, Michelle J. Boyle
Inhibiting the inflammatory response to malaria offers a promising strategy to improve clinical outcomes and overcome immunoregulatory barriers that hinder development of antiparasitic immunity. We conducted a double-blind, randomized, placebo-controlled trial assessing whether ruxolitinib, a Janus-activated kinase (JAK) 1/2 inhibitor, can reduce inflammatory responses and enhance antiparasitic immunity in malaria-naïve volunteers inoculated with blood-stage Plasmodium falciparum. Twenty participants were inoculated and, on day 8, randomized to receive artemether-lumefantrine with either ruxolitinib or placebo. Ninety days later, participants underwent a second inoculation. Ruxolitinib was safe and well tolerated; moreover, it attenuated inflammatory responses to the initial infection, with reduced posttreatment increases in C-reactive protein and markers of disease severity, including angiopoietin-2 and intercellular adhesion molecule-1. Ruxolitinib also enhanced immune memory after the second infection, with elevated human leukocyte antigen–DRA and 4-1BB, consistent with increased T cell activation. These data support the further evaluation of ruxolitinib as an adjunctive treatment to improve clinical outcomes and boost antiparasitic immunity in clinical malaria.
{"title":"Adjunctive ruxolitinib attenuates inflammation and enhances immunity in volunteers experimentally infected with Plasmodium falciparum","authors":"Rebecca Webster, Damian A. Oyong, Stacey Llewellyn, Azrin N. Abd-Rahman, Adam J. Potter, Reena Mukhiya, Nischal Sahai, Indika Leelasena, Eniko Ujvary, Sue Mathison, Dean W. Andrew, Luzia Bukali, Fabian de Labastida Rivera, Jessica Engel, Megan S. F. Soon, Teija Frame, Julianne Hamelink, Mayimuna Nalubega, Nicholas L. Dooley, Jessica R. Loughland, Tran Nguyen, Yael Rosenberg-Hasson, Sofia Maysel-Auslender, Natalia Sigal, Kira Foygel, Jeremy Gower, Jenny Peters, Ria Woo, Fiona Amante, Timothy N. C. Wells, Stephan Chalon, Joerg J. Moehrle, James S. McCarthy, Geoffrey W. Birrell, Michael D. Edstein, Michael Leipold, Gerlinde Obermoser, Holden Maecker, Christian R. Engwerda, Bridget E. Barber, Michelle J. Boyle","doi":"10.1126/scitranslmed.aea2531","DOIUrl":"10.1126/scitranslmed.aea2531","url":null,"abstract":"<div >Inhibiting the inflammatory response to malaria offers a promising strategy to improve clinical outcomes and overcome immunoregulatory barriers that hinder development of antiparasitic immunity. We conducted a double-blind, randomized, placebo-controlled trial assessing whether ruxolitinib, a Janus-activated kinase (JAK) 1/2 inhibitor, can reduce inflammatory responses and enhance antiparasitic immunity in malaria-naïve volunteers inoculated with blood-stage <i>Plasmodium falciparum</i>. Twenty participants were inoculated and, on day 8, randomized to receive artemether-lumefantrine with either ruxolitinib or placebo. Ninety days later, participants underwent a second inoculation. Ruxolitinib was safe and well tolerated; moreover, it attenuated inflammatory responses to the initial infection, with reduced posttreatment increases in C-reactive protein and markers of disease severity, including angiopoietin-2 and intercellular adhesion molecule-1. Ruxolitinib also enhanced immune memory after the second infection, with elevated human leukocyte antigen–DRA and 4-1BB, consistent with increased T cell activation. These data support the further evaluation of ruxolitinib as an adjunctive treatment to improve clinical outcomes and boost antiparasitic immunity in clinical malaria.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 826","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.aea2531","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145600095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-26DOI: 10.1126/scitranslmed.ads5813
Nader Sanai, Artak Tovmasyan, An-Chi Tien, Yu-Wei Chang, Tigran Margaryan, William Knight, Kristin Hendrickson, Jennifer Eschbacher, Jocelyn Harmon, Amy Hong, Wonsuk Yoo, Charuta Furey, Stuart L. Marcus, Lea Alhilali, Igor Barani, Zaman Mirzadeh, Shwetal Mehta
Systemic administration of 5-aminolevulinic acid (5-ALA) results in accumulation of the sonosensitizing compound protoporphyrin IX in tumor cells because of their aberrant metabolism. Activation of protoporphyrin IX by noninvasive, magnetic resonance–guided focused ultrasound (MRgFUS) sonodynamic therapy (SDT) induces production of reactive oxygen species and tumor cytotoxicity. In this first-in-human, open-label, early clinical study (NCT04559685), safety and biological efficacy of ascending doses of MRgFUS combined with intravenous administration of 5-ALA (SONALA-001) were assessed in nine patients with recurrent high-grade glioma. The safety assessment revealed no drug-related or device-related toxicities. Pharmacokinetic analysis provided quantitative information on the concentration of 5-ALA and protoporphyrin IX in plasma, blood, and brain tissue. Comparison of pharmacodynamic markers between half of the tumor region treated with MRgFUS compared with the untreated tumor provided information on dose-related changes in markers of oxidative stress and cell death for each patient’s tumor. This early phase clinical trial demonstrates proof of principle for 5-ALA SDT as a therapeutic modality for glioma. Further research is needed to optimize treatment parameters for clinical efficacy and to explore the potential of 5-ALA SDT in other types of cancer.
{"title":"An early clinical trial of 5-ALA sonodynamic therapy in recurrent high-grade glioma","authors":"Nader Sanai, Artak Tovmasyan, An-Chi Tien, Yu-Wei Chang, Tigran Margaryan, William Knight, Kristin Hendrickson, Jennifer Eschbacher, Jocelyn Harmon, Amy Hong, Wonsuk Yoo, Charuta Furey, Stuart L. Marcus, Lea Alhilali, Igor Barani, Zaman Mirzadeh, Shwetal Mehta","doi":"10.1126/scitranslmed.ads5813","DOIUrl":"10.1126/scitranslmed.ads5813","url":null,"abstract":"<div >Systemic administration of 5-aminolevulinic acid (5-ALA) results in accumulation of the sonosensitizing compound protoporphyrin IX in tumor cells because of their aberrant metabolism. Activation of protoporphyrin IX by noninvasive, magnetic resonance–guided focused ultrasound (MRgFUS) sonodynamic therapy (SDT) induces production of reactive oxygen species and tumor cytotoxicity. In this first-in-human, open-label, early clinical study (NCT04559685), safety and biological efficacy of ascending doses of MRgFUS combined with intravenous administration of 5-ALA (SONALA-001) were assessed in nine patients with recurrent high-grade glioma. The safety assessment revealed no drug-related or device-related toxicities. Pharmacokinetic analysis provided quantitative information on the concentration of 5-ALA and protoporphyrin IX in plasma, blood, and brain tissue. Comparison of pharmacodynamic markers between half of the tumor region treated with MRgFUS compared with the untreated tumor provided information on dose-related changes in markers of oxidative stress and cell death for each patient’s tumor. This early phase clinical trial demonstrates proof of principle for 5-ALA SDT as a therapeutic modality for glioma. Further research is needed to optimize treatment parameters for clinical efficacy and to explore the potential of 5-ALA SDT in other types of cancer.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 826","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145600142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-26DOI: 10.1126/scitranslmed.adp5849
Philipp Gobrecht, Jeannette Gebel, Günter Gisselmann, Kirsten Haastert-Talini, Dietmar Fischer
Diabetes mellitus impairs axon regeneration, leading to chronic functional deficits after nerve injury. Here, we used a streptozotocin-induced model of type 1 diabetes and leptin receptor–deficient db/db mice representing type 2 diabetes to identify a key molecular mechanism underlying this failure and propose targeted strategies to restore regenerative capacity. As determined by Western blotting and immunohistochemistry, sensory neurons from diabetic mice displayed elevated p35 abundance, leading to cyclin-dependent kinase 5 (CDK5) hyperactivation and glycogen synthase kinase 3β (GSK3β)–dependent inhibitory phosphorylation of collapsin response mediator protein 2 (CRMP2), a critical regulator of axon growth. These changes, coinciding with impaired axon regeneration in injured sciatic nerves, occurred before the onset of diabetes-induced neuropathy in mice. Disrupting this pathway, through expression of constitutively active CRMP2, p35 knockdown, or blockade of the p35-CDK5 interaction by expression of the inhibitory protein CIP or injection of a TAT (transactivator of transcription) peptide, restored axon regeneration of cultured adult sensory neurons and accelerated motor and sensory recovery of diabetic mice. These manipulations did not affect nerve regeneration in nondiabetic mice. Similarly, GSK3β knockout prevented CRMP2 inactivation and rescued growth in diabetic neurons. Systemic administration of the peptide also enhanced motor and sensory nerve repair in long-term diabetic mice with established neuropathy. These findings identify p35 and CRMP2 as central effectors of diabetes-induced regenerative failure in mice, suggesting that the p35-CDK5-CRMP2 axis and GSK3β are promising therapeutic targets for promoting nerve repair in patients with diabetes.
{"title":"Failure of nerve regeneration in mouse models of diabetes is caused by p35-mediated CDK5 hyperactivity","authors":"Philipp Gobrecht, Jeannette Gebel, Günter Gisselmann, Kirsten Haastert-Talini, Dietmar Fischer","doi":"10.1126/scitranslmed.adp5849","DOIUrl":"10.1126/scitranslmed.adp5849","url":null,"abstract":"<div >Diabetes mellitus impairs axon regeneration, leading to chronic functional deficits after nerve injury. Here, we used a streptozotocin-induced model of type 1 diabetes and leptin receptor–deficient <i>db/db</i> mice representing type 2 diabetes to identify a key molecular mechanism underlying this failure and propose targeted strategies to restore regenerative capacity. As determined by Western blotting and immunohistochemistry, sensory neurons from diabetic mice displayed elevated p35 abundance, leading to cyclin-dependent kinase 5 (CDK5) hyperactivation and glycogen synthase kinase 3β (GSK3β)–dependent inhibitory phosphorylation of collapsin response mediator protein 2 (CRMP2), a critical regulator of axon growth. These changes, coinciding with impaired axon regeneration in injured sciatic nerves, occurred before the onset of diabetes-induced neuropathy in mice. Disrupting this pathway, through expression of constitutively active CRMP2, p35 knockdown, or blockade of the p35-CDK5 interaction by expression of the inhibitory protein CIP or injection of a TAT (transactivator of transcription) peptide, restored axon regeneration of cultured adult sensory neurons and accelerated motor and sensory recovery of diabetic mice. These manipulations did not affect nerve regeneration in nondiabetic mice. Similarly, GSK3β knockout prevented CRMP2 inactivation and rescued growth in diabetic neurons. Systemic administration of the peptide also enhanced motor and sensory nerve repair in long-term diabetic mice with established neuropathy. These findings identify p35 and CRMP2 as central effectors of diabetes-induced regenerative failure in mice, suggesting that the p35-CDK5-CRMP2 axis and GSK3β are promising therapeutic targets for promoting nerve repair in patients with diabetes.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 826","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145600112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-26DOI: 10.1126/scitranslmed.adt8617
Giulia Hardouin, Pierre Martinucci, Samantha Scaramuzza, Panagiotis Antoniou, Federico Corradi, Alexandra Tachtsidi, Guillaume Corre, Margaux Mombled, Jessika Chermont, Sandra Manceau, Cécile Rouillon, Cécile Masson, Laure Joseph, Isabelle Thuret, Catherine Badens, Sarah Szepetowsky, Eric Allemand, Mario Amendola, Oriana Romano, Giuliana Ferrari, Annarita Miccio
Gene therapy has emerged as a promising curative treatment for β-hemoglobinopathies, the most common genetic disorders worldwide. However, current approved approaches still have some limitations in terms of safety and efficacy. Here, we used highly processive adenine base editor (ABE) variants to precisely correct some of the most prevalent and severe β-thalassemia–causing mutations in the β-globin–encoding HBB gene, including CD39 and IVS2-1, using NRCH-ABE8e and SpRY-ABE8e, respectively. More than 90% of editing of hematopoietic stem and progenitor cells (HSPCs) led to improved β-globin expression in their erythroid progeny and persistent correction of both β-thalassemia and sickle cell–β-thalassemia phenotypes. The safety of this strategy was confirmed in HSPCs in vitro and in vivo through the absence of gene dysregulation and any meaningful impact on the DNA mutational burden, RNA deamination, β-globin gene locus integrity, and the clonality of the HSPC graft, as assessed by RNA sequencing, whole-exome sequencing, long-read sequencing, and human HSPC transplantation in immunodeficient mice. Overall, these preclinical studies suggest that base editing–mediated gene correction may be a safe and effective strategy for treating β-hemoglobinopathies.
{"title":"Base editing of β0-thalassemia mutations as a therapeutic strategy for severe β-hemoglobinopathies","authors":"Giulia Hardouin, Pierre Martinucci, Samantha Scaramuzza, Panagiotis Antoniou, Federico Corradi, Alexandra Tachtsidi, Guillaume Corre, Margaux Mombled, Jessika Chermont, Sandra Manceau, Cécile Rouillon, Cécile Masson, Laure Joseph, Isabelle Thuret, Catherine Badens, Sarah Szepetowsky, Eric Allemand, Mario Amendola, Oriana Romano, Giuliana Ferrari, Annarita Miccio","doi":"10.1126/scitranslmed.adt8617","DOIUrl":"10.1126/scitranslmed.adt8617","url":null,"abstract":"<div >Gene therapy has emerged as a promising curative treatment for β-hemoglobinopathies, the most common genetic disorders worldwide. However, current approved approaches still have some limitations in terms of safety and efficacy. Here, we used highly processive adenine base editor (ABE) variants to precisely correct some of the most prevalent and severe β-thalassemia–causing mutations in the β-globin–encoding <i>HBB</i> gene, including CD39 and IVS2-1, using NRCH-ABE8e and SpRY-ABE8e, respectively. More than 90% of editing of hematopoietic stem and progenitor cells (HSPCs) led to improved β-globin expression in their erythroid progeny and persistent correction of both β-thalassemia and sickle cell–β-thalassemia phenotypes. The safety of this strategy was confirmed in HSPCs in vitro and in vivo through the absence of gene dysregulation and any meaningful impact on the DNA mutational burden, RNA deamination, β-globin gene locus integrity, and the clonality of the HSPC graft, as assessed by RNA sequencing, whole-exome sequencing, long-read sequencing, and human HSPC transplantation in immunodeficient mice. Overall, these preclinical studies suggest that base editing–mediated gene correction may be a safe and effective strategy for treating β-hemoglobinopathies.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 826","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145600115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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