Pub Date : 2024-11-18DOI: 10.1038/s44321-024-00159-2
Alastair Copland, Gillian M Mackie, Lisa Scarfe, Elizabeth Jinks, David A J Lecky, Nancy Gudgeon, Riahne McQuade, Masahiro Ono, Manja Barthel, Wolf-Dietrich Hardt, Hiroshi Ohno, Wilma H M Hoevenaar, Sarah Dimeloe, David Bending, Kendle M Maslowski
Bacterial cancer therapy (BCT) is a promising therapeutic for solid tumours. Salmonella enterica Typhimurium (STm) is well-studied amongst bacterial vectors due to advantages in genetic modification and metabolic adaptation. A longstanding paradox is the redundancy of T cells for treatment efficacy; instead, STm BCT depends on innate phagocytes for tumour control. Here, we used distal T cell receptor (TCR) and IFNγ reporter mice (Nr4a3-Tocky-Ifnγ-YFP) and a colorectal cancer (CRC) model to interrogate T cell activity during BCT with attenuated STm. We found that colonic tumour infiltrating lymphocytes (TILs) exhibited a variety of activation defects, including IFN-γ production decoupled from TCR signalling, decreased polyfunctionality and reduced central memory (TCM) formation. Modelling of T-cell-tumour interactions with a tumour organoid platform revealed an intact TCR signalosome, but paralysed metabolic reprogramming due to inhibition of the master metabolic controller, c-Myc. Restoration of c-Myc by deletion of the bacterial asparaginase ansB reinvigorated T cell activation, but at the cost of decreased metabolic control of the tumour by STm. This work shows for the first time that T cells are metabolically defective during BCT, but also that this same phenomenon is inexorably tied to intrinsic tumour suppression by the bacterial vector.
细菌癌症疗法(BCT)是一种治疗实体瘤的前景广阔的疗法。在细菌载体中,鼠伤寒沙门氏菌(STm)因其在基因修饰和代谢适应方面的优势而受到广泛研究。一个长期存在的悖论是T细胞对治疗效果的冗余性;相反,STm BCT依赖于先天性吞噬细胞来控制肿瘤。在这里,我们使用远端 T 细胞受体(TCR)和 IFNγ 报告小鼠(Nr4a3-Tocky-Ifnγ-YFP)以及结肠直肠癌(CRC)模型来研究 STm BCT 期间 T 细胞的活性。我们发现结肠肿瘤浸润淋巴细胞(TILs)表现出多种活化缺陷,包括IFN-γ的产生与TCR信号脱钩、多功能性降低和中心记忆(TCM)形成减少。利用肿瘤类器官平台建立的T细胞-肿瘤相互作用模型显示,TCR信号体完好无损,但由于主代谢控制器c-Myc受到抑制,导致代谢重编程瘫痪。通过删除细菌天冬酰胺酶ansB恢复c-Myc可重新激活T细胞,但代价是STm对肿瘤的代谢控制能力下降。这项研究首次表明,T细胞在BCT期间存在代谢缺陷,而且这一现象与细菌载体对肿瘤的内在抑制有着不可分割的联系。
{"title":"Salmonella cancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity.","authors":"Alastair Copland, Gillian M Mackie, Lisa Scarfe, Elizabeth Jinks, David A J Lecky, Nancy Gudgeon, Riahne McQuade, Masahiro Ono, Manja Barthel, Wolf-Dietrich Hardt, Hiroshi Ohno, Wilma H M Hoevenaar, Sarah Dimeloe, David Bending, Kendle M Maslowski","doi":"10.1038/s44321-024-00159-2","DOIUrl":"10.1038/s44321-024-00159-2","url":null,"abstract":"<p><p>Bacterial cancer therapy (BCT) is a promising therapeutic for solid tumours. Salmonella enterica Typhimurium (STm) is well-studied amongst bacterial vectors due to advantages in genetic modification and metabolic adaptation. A longstanding paradox is the redundancy of T cells for treatment efficacy; instead, STm BCT depends on innate phagocytes for tumour control. Here, we used distal T cell receptor (TCR) and IFNγ reporter mice (Nr4a3-Tocky-Ifnγ-YFP) and a colorectal cancer (CRC) model to interrogate T cell activity during BCT with attenuated STm. We found that colonic tumour infiltrating lymphocytes (TILs) exhibited a variety of activation defects, including IFN-γ production decoupled from TCR signalling, decreased polyfunctionality and reduced central memory (T<sub>CM</sub>) formation. Modelling of T-cell-tumour interactions with a tumour organoid platform revealed an intact TCR signalosome, but paralysed metabolic reprogramming due to inhibition of the master metabolic controller, c-Myc. Restoration of c-Myc by deletion of the bacterial asparaginase ansB reinvigorated T cell activation, but at the cost of decreased metabolic control of the tumour by STm. This work shows for the first time that T cells are metabolically defective during BCT, but also that this same phenomenon is inexorably tied to intrinsic tumour suppression by the bacterial vector.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667155","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 : 2024-11-14DOI: 10.1038/s44321-024-00169-0
Ze-Rong Cai, Wen Wang, Di Chen, Hao-Jie Chen, Yan Hu, Xiao-Jing Luo, Yi-Ting Wang, Yi-Qian Pan, Hai-Yu Mo, Shu-Yu Luo, Kun Liao, Zhao-Lei Zeng, Shan-Shan Li, Xin-Yuan Guan, Xin-Juan Fan, Hai-Long Piao, Rui-Hua Xu, Huai-Qiang Ju
Early detection is warranted to improve prognosis of gastric cancer (GC) but remains challenging. Liquid biopsy combined with machine learning will provide new insights into diagnostic strategies of GC. Lipid metabolism reprogramming plays a crucial role in the initiation and development of tumors. Here, we integrated the lipidomics data of three cohorts (n = 944) to develop the lipid metabolic landscape of GC. We further constructed the serum lipid metabolic signature (SLMS) by machine learning, which showed great performance in distinguishing GC patients from healthy donors. Notably, the SLMS also held high efficacy in the diagnosis of early-stage GC. Besides, by performing unsupervised consensus clustering analysis on the lipid metabolic matrix of patients with GC, we generated the gastric cancer prognostic subtypes (GCPSs) with significantly different overall survival. Furthermore, the lipid metabolic disturbance in GC tissues was demonstrated by multi-omics analysis, which showed partially consistent with that in GC serums. Collectively, this study revealed an innovative strategy of liquid biopsy for the diagnosis of GC on the basis of the serum lipid metabolic fingerprints.
{"title":"Diagnosis and prognosis prediction of gastric cancer by high-performance serum lipidome fingerprints.","authors":"Ze-Rong Cai, Wen Wang, Di Chen, Hao-Jie Chen, Yan Hu, Xiao-Jing Luo, Yi-Ting Wang, Yi-Qian Pan, Hai-Yu Mo, Shu-Yu Luo, Kun Liao, Zhao-Lei Zeng, Shan-Shan Li, Xin-Yuan Guan, Xin-Juan Fan, Hai-Long Piao, Rui-Hua Xu, Huai-Qiang Ju","doi":"10.1038/s44321-024-00169-0","DOIUrl":"10.1038/s44321-024-00169-0","url":null,"abstract":"<p><p>Early detection is warranted to improve prognosis of gastric cancer (GC) but remains challenging. Liquid biopsy combined with machine learning will provide new insights into diagnostic strategies of GC. Lipid metabolism reprogramming plays a crucial role in the initiation and development of tumors. Here, we integrated the lipidomics data of three cohorts (n = 944) to develop the lipid metabolic landscape of GC. We further constructed the serum lipid metabolic signature (SLMS) by machine learning, which showed great performance in distinguishing GC patients from healthy donors. Notably, the SLMS also held high efficacy in the diagnosis of early-stage GC. Besides, by performing unsupervised consensus clustering analysis on the lipid metabolic matrix of patients with GC, we generated the gastric cancer prognostic subtypes (GCPSs) with significantly different overall survival. Furthermore, the lipid metabolic disturbance in GC tissues was demonstrated by multi-omics analysis, which showed partially consistent with that in GC serums. Collectively, this study revealed an innovative strategy of liquid biopsy for the diagnosis of GC on the basis of the serum lipid metabolic fingerprints.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616840","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 : 2024-11-11DOI: 10.1038/s44321-024-00162-7
Pranav Preman, Daan Moechars, Emre Fertan, Leen Wolfs, Lutgarde Serneels, Disha Shah, Jochen Lamote, Suresh Poovathingal, An Snellinx, Renzo Mancuso, Sriram Balusu, David Klenerman, Amaia M Arranz, Mark Fiers, Bart De Strooper
The major genetic risk factor for Alzheimer's disease (AD), APOE4, accelerates beta-amyloid (Aβ) plaque formation, but whether this is caused by APOE expressed in microglia or astrocytes is debated. We express here the human APOE isoforms in astrocytes in an Apoe-deficient AD mouse model. This is not only sufficient to restore the amyloid plaque pathology but also induces the characteristic transcriptional pathological responses in Apoe-deficient microglia surrounding the plaques. We find that both APOE4 and the protective APOE2 from astrocytes increase fibrillar plaque deposition, but differentially affect soluble Aβ aggregates. Microglia and astrocytes show specific alterations in function of APOE genotype expressed in astrocytes. Our experiments indicate a central role of the astrocytes in APOE mediated amyloid plaque pathology and in the induction of associated microglia responses.
阿尔茨海默病(AD)的主要遗传风险因子--APOE4--会加速β-淀粉样蛋白(Aβ)斑块的形成,但这究竟是由小胶质细胞还是星形胶质细胞中表达的APOE引起的还存在争议。在这里,我们在载脂蛋白缺陷型 AD 小鼠模型的星形胶质细胞中表达了人类 APOE 异构体。这不仅足以恢复淀粉样蛋白斑块的病理变化,而且还能诱导斑块周围的载脂蛋白缺陷小胶质细胞产生特征性的转录病理反应。我们发现,来自星形胶质细胞的APOE4和保护性APOE2都会增加纤维斑块的沉积,但对可溶性Aβ聚集体的影响不同。小胶质细胞和星形胶质细胞中表达的 APOE 基因型显示出特定的功能改变。我们的实验表明,星形胶质细胞在 APOE 介导的淀粉样斑块病理学和诱导相关小胶质细胞反应中起着核心作用。
{"title":"APOE from astrocytes restores Alzheimer's Aβ-pathology and DAM-like responses in APOE deficient microglia.","authors":"Pranav Preman, Daan Moechars, Emre Fertan, Leen Wolfs, Lutgarde Serneels, Disha Shah, Jochen Lamote, Suresh Poovathingal, An Snellinx, Renzo Mancuso, Sriram Balusu, David Klenerman, Amaia M Arranz, Mark Fiers, Bart De Strooper","doi":"10.1038/s44321-024-00162-7","DOIUrl":"https://doi.org/10.1038/s44321-024-00162-7","url":null,"abstract":"<p><p>The major genetic risk factor for Alzheimer's disease (AD), APOE4, accelerates beta-amyloid (Aβ) plaque formation, but whether this is caused by APOE expressed in microglia or astrocytes is debated. We express here the human APOE isoforms in astrocytes in an Apoe-deficient AD mouse model. This is not only sufficient to restore the amyloid plaque pathology but also induces the characteristic transcriptional pathological responses in Apoe-deficient microglia surrounding the plaques. We find that both APOE4 and the protective APOE2 from astrocytes increase fibrillar plaque deposition, but differentially affect soluble Aβ aggregates. Microglia and astrocytes show specific alterations in function of APOE genotype expressed in astrocytes. Our experiments indicate a central role of the astrocytes in APOE mediated amyloid plaque pathology and in the induction of associated microglia responses.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616835","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 : 2024-11-09DOI: 10.1038/s44321-024-00166-3
Karoline Strobl, Jörg Klufa, Regina Jin, Lena Artner-Gent, Dana Krauß, Philipp Novoszel, Johanna Strobl, Georg Stary, Igor Vujic, Johannes Griss, Martin Holcmann, Matthias Farlik, Bernhard Homey, Maria Sibilia, Thomas Bauer
The hair follicle stem cell niche is an immune-privileged microenvironment, characterized by reduced antigen presentation, thus shielding against permanent immune-mediated tissue damage. In this study, we demonstrated the protective role of hair follicle-specific epidermal growth factor receptor (EGFR) against scarring hair follicle destruction. Mechanistically, disruption of EGFR signaling generated a cell-intrinsic hypersensitivity within the JAK-STAT1 pathway, which, synergistically with interferon gamma expressing CD8 T-cell and NK-cell-mediated inflammation, compromised the stem cell niche. Hair follicle-specific genetic depletion of either JAK1/2 or STAT1 or therapeutic inhibition of JAK1/2 ameliorated the inflammation, restored skin barrier function and activated the residual stem cells to resume hair growth in mouse models of epidermal and hair follicle-specific EGFR deletion. Skin biopsies from EGFR inhibitor-treated and cicatricial alopecia patients revealed an active JAK-STAT1 signaling signature along with upregulation of antigen presentation and downregulation of key components of the EGFR pathway. Our findings offer molecular insights and highlight a mechanism-based therapeutic strategy for addressing chronic folliculitis associated with EGFR-inhibitor anti-cancer therapy and cicatricial alopecia.
{"title":"JAK-STAT1 as therapeutic target for EGFR deficiency-associated inflammation and scarring alopecia.","authors":"Karoline Strobl, Jörg Klufa, Regina Jin, Lena Artner-Gent, Dana Krauß, Philipp Novoszel, Johanna Strobl, Georg Stary, Igor Vujic, Johannes Griss, Martin Holcmann, Matthias Farlik, Bernhard Homey, Maria Sibilia, Thomas Bauer","doi":"10.1038/s44321-024-00166-3","DOIUrl":"https://doi.org/10.1038/s44321-024-00166-3","url":null,"abstract":"<p><p>The hair follicle stem cell niche is an immune-privileged microenvironment, characterized by reduced antigen presentation, thus shielding against permanent immune-mediated tissue damage. In this study, we demonstrated the protective role of hair follicle-specific epidermal growth factor receptor (EGFR) against scarring hair follicle destruction. Mechanistically, disruption of EGFR signaling generated a cell-intrinsic hypersensitivity within the JAK-STAT1 pathway, which, synergistically with interferon gamma expressing CD8 T-cell and NK-cell-mediated inflammation, compromised the stem cell niche. Hair follicle-specific genetic depletion of either JAK1/2 or STAT1 or therapeutic inhibition of JAK1/2 ameliorated the inflammation, restored skin barrier function and activated the residual stem cells to resume hair growth in mouse models of epidermal and hair follicle-specific EGFR deletion. Skin biopsies from EGFR inhibitor-treated and cicatricial alopecia patients revealed an active JAK-STAT1 signaling signature along with upregulation of antigen presentation and downregulation of key components of the EGFR pathway. Our findings offer molecular insights and highlight a mechanism-based therapeutic strategy for addressing chronic folliculitis associated with EGFR-inhibitor anti-cancer therapy and cicatricial alopecia.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616775","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 : 2024-11-09DOI: 10.1038/s44321-024-00170-7
Joseph S Durgin, Sunny Y Wong
{"title":"Hair follicle stem cells and the collapse of self-tolerance in alopecia: the interplay of barrier function, the microbiome, and immunity.","authors":"Joseph S Durgin, Sunny Y Wong","doi":"10.1038/s44321-024-00170-7","DOIUrl":"https://doi.org/10.1038/s44321-024-00170-7","url":null,"abstract":"","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616770","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 : 2024-11-07DOI: 10.1038/s44321-024-00165-4
Partho Protim Adhikary, Temilolu Idowu, Zheng Tan, Christopher Hoang, Selina Shanta, Malti Dumbani, Leah Mappalakayil, Bhuwan Awasthi, Marcel Bermudez, January Weiner, Dieter Beule, Gerhard Wolber, Brent D G Page, Sarah Hedtrich
{"title":"Author Correction: Disrupting TSLP-TSLP receptor interactions via putative small molecule inhibitors yields a novel and efficient treatment option for atopic diseases.","authors":"Partho Protim Adhikary, Temilolu Idowu, Zheng Tan, Christopher Hoang, Selina Shanta, Malti Dumbani, Leah Mappalakayil, Bhuwan Awasthi, Marcel Bermudez, January Weiner, Dieter Beule, Gerhard Wolber, Brent D G Page, Sarah Hedtrich","doi":"10.1038/s44321-024-00165-4","DOIUrl":"https://doi.org/10.1038/s44321-024-00165-4","url":null,"abstract":"","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602303","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 : 2024-11-04DOI: 10.1038/s44321-024-00154-7
Richard R Meehan, Sari Pennings
{"title":"Rett syndrome: interferon-γ to the rescue?","authors":"Richard R Meehan, Sari Pennings","doi":"10.1038/s44321-024-00154-7","DOIUrl":"https://doi.org/10.1038/s44321-024-00154-7","url":null,"abstract":"","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575652","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 : 2024-11-01Epub Date: 2024-10-28DOI: 10.1038/s44321-024-00155-6
Louise Nuyttens, Jolien Vandewalle, Claude Libert
Sepsis is a heterogeneous syndrome resulting from a dysregulated host response to infection. It is considered as a global major health priority. Sepsis is characterized by significant metabolic perturbations, leading to increased circulating metabolites such as lactate. In mammals, pyruvate is the primary substrate for lactate production. It plays a critical role in metabolism by linking glycolysis, where it is produced, with the mitochondrial oxidative phosphorylation pathway, where it is oxidized. Here, we provide an overview of all cytosolic and mitochondrial enzymes involved in pyruvate metabolism and how their activities are disrupted in sepsis. Based on the available data, we also discuss potential therapeutic strategies targeting these pyruvate-related enzymes leading to enhanced survival.
{"title":"Sepsis-induced changes in pyruvate metabolism: insights and potential therapeutic approaches.","authors":"Louise Nuyttens, Jolien Vandewalle, Claude Libert","doi":"10.1038/s44321-024-00155-6","DOIUrl":"10.1038/s44321-024-00155-6","url":null,"abstract":"<p><p>Sepsis is a heterogeneous syndrome resulting from a dysregulated host response to infection. It is considered as a global major health priority. Sepsis is characterized by significant metabolic perturbations, leading to increased circulating metabolites such as lactate. In mammals, pyruvate is the primary substrate for lactate production. It plays a critical role in metabolism by linking glycolysis, where it is produced, with the mitochondrial oxidative phosphorylation pathway, where it is oxidized. Here, we provide an overview of all cytosolic and mitochondrial enzymes involved in pyruvate metabolism and how their activities are disrupted in sepsis. Based on the available data, we also discuss potential therapeutic strategies targeting these pyruvate-related enzymes leading to enhanced survival.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2678-2698"},"PeriodicalIF":9.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521394","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 : 2024-11-01Epub Date: 2024-10-02DOI: 10.1038/s44321-024-00148-5
Jessica P Wiseman, Joseph M Scarrott, João Alves-Cruzeiro, Afshin Saffari, Cedric Böger, Evangelia Karyka, Emily Dawes, Alexandra K Davies, Paolo M Marchi, Emily Graves, Fiona Fernandes, Zih-Liang Yang, Ian Coldicott, Jennifer Hirst, Christopher P Webster, J Robin Highley, Neil Hackett, Adrienn Angyal, Thushan de Silva, Adrian Higginbottom, Pamela J Shaw, Laura Ferraiuolo, Darius Ebrahimi-Fakhari, Mimoun Azzouz
Spastic paraplegia 47 (SPG47) is a neurological disorder caused by mutations in the adaptor protein complex 4 β1 subunit (AP4B1) gene leading to AP-4 complex deficiency. SPG47 is characterised by progressive spastic paraplegia, global developmental delay, intellectual disability and epilepsy. Gene therapy aimed at restoring functional AP4B1 protein levels is a rational therapeutic strategy to ameliorate the disease phenotype. Here we report that a single delivery of adeno-associated virus serotype 9 expressing hAP4B1 (AAV9/hAP4B1) into the cisterna magna leads to widespread gene transfer and restoration of various hallmarks of disease, including AP-4 cargo (ATG9A) mislocalisation, calbindin-positive spheroids in the deep cerebellar nuclei, anatomical brain defects and motor dysfunction, in an SPG47 mouse model. Furthermore, AAV9/hAP4B1-based gene therapy demonstrated a restoration of plasma neurofilament light (NfL) levels of treated mice. Encouraged by these preclinical proof-of-concept data, we conducted IND-enabling studies, including immunogenicity and GLP non-human primate (NHP) toxicology studies. Importantly, NHP safety and biodistribution study revealed no significant adverse events associated with the therapeutic intervention. These findings provide evidence of both therapeutic efficacy and safety, establishing a robust basis for the pursuit of an IND application for clinical trials targeting SPG47 patients.
{"title":"Pre-clinical development of AP4B1 gene replacement therapy for hereditary spastic paraplegia type 47.","authors":"Jessica P Wiseman, Joseph M Scarrott, João Alves-Cruzeiro, Afshin Saffari, Cedric Böger, Evangelia Karyka, Emily Dawes, Alexandra K Davies, Paolo M Marchi, Emily Graves, Fiona Fernandes, Zih-Liang Yang, Ian Coldicott, Jennifer Hirst, Christopher P Webster, J Robin Highley, Neil Hackett, Adrienn Angyal, Thushan de Silva, Adrian Higginbottom, Pamela J Shaw, Laura Ferraiuolo, Darius Ebrahimi-Fakhari, Mimoun Azzouz","doi":"10.1038/s44321-024-00148-5","DOIUrl":"10.1038/s44321-024-00148-5","url":null,"abstract":"<p><p>Spastic paraplegia 47 (SPG47) is a neurological disorder caused by mutations in the adaptor protein complex 4 β1 subunit (AP4B1) gene leading to AP-4 complex deficiency. SPG47 is characterised by progressive spastic paraplegia, global developmental delay, intellectual disability and epilepsy. Gene therapy aimed at restoring functional AP4B1 protein levels is a rational therapeutic strategy to ameliorate the disease phenotype. Here we report that a single delivery of adeno-associated virus serotype 9 expressing hAP4B1 (AAV9/hAP4B1) into the cisterna magna leads to widespread gene transfer and restoration of various hallmarks of disease, including AP-4 cargo (ATG9A) mislocalisation, calbindin-positive spheroids in the deep cerebellar nuclei, anatomical brain defects and motor dysfunction, in an SPG47 mouse model. Furthermore, AAV9/hAP4B1-based gene therapy demonstrated a restoration of plasma neurofilament light (NfL) levels of treated mice. Encouraged by these preclinical proof-of-concept data, we conducted IND-enabling studies, including immunogenicity and GLP non-human primate (NHP) toxicology studies. Importantly, NHP safety and biodistribution study revealed no significant adverse events associated with the therapeutic intervention. These findings provide evidence of both therapeutic efficacy and safety, establishing a robust basis for the pursuit of an IND application for clinical trials targeting SPG47 patients.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2882-2917"},"PeriodicalIF":9.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364850","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}