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Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI184043.
Abstract
Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment (TME) and dampen the immune response, negatively affecting patient survival. Therefore, targeting TAMs could address the limitations of current cancer treatments. However, drug development in this area remains limited. The Leukocyte-associated Immunoglobulin-like Receptor-1 (LAIR1), also called CD305, is prominently expressed on the surface of TAMs. We have uncovered a previously unrecognized immunosuppressive LAIR1 → Factor XIII A (FXIII-A) → Collagen IV pathway across various cancer types. Inhibition of LAIR1, either through knockout (Lair1–/–), antibody blockade (aLAIR1), or a chimeric antigen receptor (CAR) design (3-in-1 CAR by combining tumor targeting, T cell trafficking, and remodeling of the immunosuppressive TME in one CAR construct) provides enhanced antitumor response. LAIR1 inhibition enhances peripheral and intratumoral CD8 memory T-cell populations, induces a phenotypic shift of M2-like Macrophages towards M1, and normalizes tumor collagen IV and structural components in the TME, facilitating effective tumor-T cell interactions and tumor suppression. Enhanced antitumor responses were observed when Lair1–/– or aLAIR1 was used alone or combined with CAR T cells or when the 3-in-1 CAR T cells were used solely in chemotherapy-radiation-PD-1 blockade-resistant tumor models. These findings position LAIR1 inhibition as a promising strategy for cancer immunotherapies.
Authors
Haipeng Tao, Dongjiang Chen, Changlin Yang, Duy T. Nguyen, Georges Abboud, Ruixuan Liu, Tianyi Liu, Avirup Chakraborty, Alicia Y. Hou, Nicole A. Petit, Muhammad Abbas, Robert W. Davis, Janie Zhang, Christina Von Roemeling, Mohammed O. Gbadamosi, Linchun Jin, Tongjun Gu, Tuo Lin, Pengchen Wang, Alfonso Pepe, Diego Ivan Pedro, Hector R. Mendez-Gomez, Chao Xie, Aida Karachi, Frances Weidert, Dan Jin, Chenggang Wang, Kaytora Long-James, Elizabeth K. Molchan, Paul Castillo, John A. Ligon, Ashley P. Ghiaseddin, Elias J. Sayour, Maryam Rahman, Loic P. Deleyrolle, Betty Y.S. Kim, Duane A. Mitchell, W. Gregory Sawyer, Jianping Huang
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI181881.
Abstract
Facioscapulohumeral muscular dystrophy (FSHD) is a genetic muscle disease caused by ectopic expression of the toxic protein DUX4, resulting in muscle weakness. However, the mechanism by which DUX4 exerts its toxicity remains unclear. In this study, we observed abnormal iron accumulation in muscles of patients with FSHD and in muscle-specific DUX4-expressing (DUX4-Tg) mice. Treatment with iron chelators, an iron-deficient diet, and genetic modifications inhibiting intracellular uptake of iron did not improve but rather exacerbated FSHD pathology in DUX4-Tg mice. Unexpectedly, however, iron supplementation, either from a high-iron diet or intravenous iron administration, resulted in remarkable improvement in grip strength and running performance in DUX4-Tg mice. Iron supplementation suppressed abnormal iron accumulation and the ferroptosis-related pathway involving increased lipid peroxidation in DUX4-Tg muscle. Muscle-specific DUX4 expression led to retinal vasculopathy, a part of FSHD pathology, which was prevented by iron administration. Furthermore, high-throughput compound screening of the ferroptosis pathway identified drug candidates including Ferrostatin-1 (Fer-1), a potent inhibitor of lipid peroxidation. Treatment with Fer-1 dramatically improved physical function in DUX4-Tg mice. Our findings demonstrate that DUX4-provoked toxicity is involved in the activation of the ferroptosis-related pathway and that supplementary iron could be a promising and readily available therapeutic option for FSHD.
Authors
Kodai Nakamura, Huascar-Pedro Ortuste-Quiroga, Naoki Horii, Shin Fujimaki, Toshiro Moroishi, Keiichi I. Nakayama, Shinjiro Hino, Yoshihiko Saito, Ichizo Nishino, Yusuke Ono
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI190180.
Abstract
Elevated cholesterol poses cardiovascular risks. The glucocorticoid receptor (GR) harbors a still undefined role in cholesterol regulation. Here, we report that a coding single nucleotide polymorphism (SNP) in the gene en-coding the GR, rs6190, associated with increased cholesterol in women according to UK Biobank and All Of Us datasets. In SNP-genocopying mice, we found that the SNP enhanced hepatic GR activity to transactivate Pcsk9 and Bhlhe40, negative regulators of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) re-ceptors respectively. In mice, the SNP was sufficient to elevate circulating cholesterol across all lipoprotein frac-tions and the risk and severity of atherosclerotic lesions on the pro-atherogenic hAPOE*2/*2 background. The SNP effect on atherosclerosis was blocked by in vivo liver knockdown of Pcsk9 and Bhlhe40. Also, corti-costerone and testosterone were protective against the mutant GR program in cholesterol and atherosclerosis in male mice, while the SNP effect was additive to estrogen loss in females. Remarkably, we found that the mu-tant GR program was conserved in human hepatocyte-like cells using CRISPR-engineered, SNP-genocopying human induced pluripotent stem cells (hiPSCs). Taken together, our study leverages a non-rare human variant to uncover a novel GR-dependent mechanism contributing to atherogenic risk, particularly in women.
Authors
Hima Bindu Durumutla, April Haller, Greta Noble, Ashok Daniel Prabakaran, Kevin McFarland, Hannah Latimer, Akanksha Rajput, Olukunle Akinborewa, Bahram Namjou-Khales, David Y. Hui, Mattia Quattrocelli
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI188530.
Abstract
Authors
James G. Krueger, Mrinal K. Sarkar, Mark G. Lebwohl, Akimichi Morita, Kenneth Gordon, Rachael Bogle, Christopher Cole, Anthony Coon, Richard G. Langley, Richard B. Warren, Arash Mostaghimi, Bruce Strober, A. David Burden, Min Zheng, Aaron R. Mangold, Milan J. Anadkat, Jonathan N. Barker, Joseph F. Merola, Lam C. Tsoi, Ming Tang, Kolja Becker, Denis Delic, Christian Thoma, Johann E. Gudjonsson
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI190539.
Abstract
Neuropathic pain is often comorbid with affective disorders. Synaptic plasticity in anterior cingulate cortex (ACC) is assumed to be a crucial interface for pain perception and emotion. Laminin β1 (LAMB1), a key element of extracellular matrix (ECM) in ACC was recently revealed to convey extracellular alterations to intracellular synaptic plasticity and underlie neuropathic pain and aversive emotion. However, it remains elusive what triggers activity-dependent changes of LAMB1 and ECM remodeling after nerve injury. Here, we uncovered a key role of retinoic acid (RA)/RARB signaling in neuropathic pain and associated anxiodepression via regulation of ECM homeostasis. We showed that nerve injury reduced RA level in the serum and ACC in mice and human, which brought about downregulation of its corresponding receptor, RARB. Overexpressing RARB relieved pain hypersensitivity and comorbid anxiodepression, while silencing RARB exacerbated pain sensitivity and induced anxiodepression. Further mechanistic analysis revealed that RARB maintained ECM homeostasis via transcriptional regulation of LAMB1, reversing abnormal synaptic plasticity and eventually improved neuropathic pain and aversive emotion. Taken together with our previous study, we revealed an intracellular-extracellular-intracellular feedforward regulatory network in modulating pain plasticity. Moreover, we identified cingulate RA/RARB signaling as a promising therapeutic target for treatment of neuropathic pain and associated anxiodepression.
Authors
Zhen-Zhen Li, Wan-Neng Liu, Ke-Xin Liu, Zhi-Wei Dou, Rui Zhao, Yun Chen, Meng-Meng Wang, Tao-Zhi Wang, Fei Wang, Wen-Juan Han, Wen-Guang Chu, Xing-Xing Zheng, Rou-Gang Xie, Hua Yuan, Xiao-Fan Jiang, Xiao-Long Sun, Ceng Luo, Shengxi Wu
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI190374.
Abstract
Esophageal adenocarcinoma (EA) is increasingly prevalent and is thought to arise from Barrett’s esophagus (BE), a metaplastic condition in which chronic acid and bile reflux transforms the esophageal squamous epithelium into a gastric-intestinal glandular mucosa. The molecular determinants driving this metaplasia are poorly understood. We developed a human BE organoid biobank that recapitulates BE’s molecular heterogeneity. Bulk and single-cell transcriptomics, supported by patient tissue analysis, revealed that BE differentiation reflects a balance between SOX2 (foregut/esophageal) and CDX2 (hindgut/intestinal) transcription factors. Using squamous-specific inducible Sox2 knockout (Krt5CreER/+; Sox2∆/∆; ROSA26tdTomato/+) mice, we observed increased basal proliferation, reduced squamous differentiation, and expanded metaplastic glands at the squamocolumnar junction, some tracing back to Krt5-expressing cells. CUT&RUN analysis showed SOX2 bound and promoted differentiation-associated (e.g., Krt13) and repressed proliferation-associated (e.g., Mki67) targets. Thus, SOX2 is critical for foregut squamous epithelial differentiation and its decreased expression is likely an initiating step in progression to BE and thence to EA.
Authors
Ramon U. Jin, Yuanwei Xu, Tung-Shing Lih, Yang-Zhe Huang, Toni M. Nittolo, Blake E. Sells, Olivia M. Dres, Jean S. Wang, Qing Kay Li, Hui Zhang, Jason C. Mills
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI180252.
Abstract
COPA syndrome is a monogenic disorder of immune dysregulation that leads to interstitial lung disease and high-titer autoantibodies. Constitutive activation of the innate immune molecule STING is centrally involved in disease. However, the mechanisms by which STING results in autoimmunity is not well understood in COPA syndrome and other STING-associated diseases. Prior studies show a cell autonomous role for STING in thymocyte development. Single cell data of human thymus demonstrates STING is highly expressed in medullary thymic epithelial cells (mTECs) and at levels much greater than T cells. Here, we show that in certain contexts activated STING exerts a functional role in the thymic epithelium to alter thymocyte selection and predisposes to autoimmunity. In CopaE241K/+ mice, activated STING in mTECs amplified interferon signaling, impaired macroautophagy and caused a defect in negative selection of T cell precursors. Wild-type mice given a systemic STING agonist phenocopied the selection defect and showed enhanced thymic escape of a T cell clone targeting a self-antigen also expressed in melanoma. Our work demonstrates STING activation in TECs shapes the T cell repertoire and contributes to autoimmunity, findings important for conditions that activate thymic STING.
Authors
Zimu Deng, Christopher S. Law, Santosh Kurra, Noa Simchoni, Anthony K. Shum
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI180913.
Abstract
The balance of hematopoietic stem cell (HSC) self-renewal versus differentiation is essential to ensure long-term repopulation capacity while allowing response to events that require increased hematopoietic output. Proliferation and differentiation of HSCs and their progeny is controlled by the JAK/STAT pathway downstream of cytokine signaling. E3 ubiquitin ligases, like Cullin 5 (Cul5), can regulate JAK/STAT signaling by degrading signaling intermediates. Here we report that mice lacking Cul5 in hematopoietic cells (Cul5Vav-Cre) have increased numbers of HSPCs, splenomegaly, and extramedullary hematopoiesis. Differentiation in Cul5Vav-Cre mice is myeloid- and megakaryocyte-biased, resulting in leukocytosis, anemia and thrombocytosis. Cul5Vav-Cre mice increased HSC proliferation and circulation, associated with a decrease in CXCR4 surface expression. In bone marrow cells, we identified LRRC41 co-immunoprecipitated with CUL5, and vice versa, supporting that CRL5 forms a complex with LRRC41. We identified an accumulation of LRRC41 and STAT5 in Cul5Vav-Cre HSCs during IL-3 stimulation, supporting their regulation by Cul5. Whole cell proteome (WCP) analysis of HSPCs from Cul5Vav-Cre bone marrow identified upregulation of many STAT5 target genes and associated pathways. Finally, JAK1/2 inhibition with ruxolitinib normalized hematopoiesis in Cul5Vav-Cre mice. These studies demonstrate the function of Cul5 in HSC function, stem cell fate decisions, and regulation of IL-3 signaling.
Authors
Siera A. Tomishima, Dale D. Kim, Nadia Porter, Ipsita Guha, Asif A. Dar, Yohaniz Ortega-Burgos, Jennifer Roof, Hossein Fazelinia, Lynn A. Spruce, Christopher S. Thom, Robert L. Bowman, Paula M. Oliver
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI190736.
Abstract
BACKGROUND. Reversal reactions (RR) in leprosy are acute immune episodes marked by inflammation and bacterial clearance, offering a model to study the dynamics of host responses to Mycobacterium leprae. These episodes are often severe and difficult to treat, frequently progressing to permanent disabilities. We aimed to characterize the immune mechanisms and identify antimicrobial effectors during RR. METHODS. We performed RNA sequencing on paired skin biopsy specimens from nine leprosy patients collected before and at RR diagnosis, followed by differential gene expression and functional analysis. A machine learning classifier was applied to predict membrane-permeabilizing proteins. Antimicrobial activity was assessed in M. leprae-infected macrophages and axenic cultures. RESULTS. In the paired pre-RR and RR biopsy specimens, a 64-gene antimicrobial response signature was upregulated during RR and correlated with reduced M. leprae burden. Predicted upstream regulators included IL-1β, TNF, IFN-γ, and IL-17, indicating activation of both Th1 and Th17 pathways. A machine learning classifier identified 28 genes with predicted membrane-permeabilizing antimicrobial activity, including S100A8. Four proteins (S100A7, S100A8, CCL17, CCL19) demonstrated antimicrobial activity against M. leprae in vitro. Scanning electron microscopy revealed membrane damage in bacteria exposed to these proteins. CONCLUSION. RR is associated with a robust antimicrobial gene program regulated by Th1/Th17 cytokines. We identified potentially novel host antimicrobial effectors that exhibit activity against M. leprae, suggesting potential strategies to bolster Th1/Th17 responses for combating intracellular mycobacterial infections. FUNDING. NIH grants R01 AI022553, R01 AR040312, R01 AR073252, R01 AI166313, R01 AI169526, P50 AR080594, 4R37 AI052453-21, and NSF grant DMR2325840.
Authors
Priscila R. Andrade, Feiyang Ma, Jing Lu, Jaime de Anda, Ernest Y. Lee, George W. Agak, Craig J. Dobry, Bruno J. de Andrade Silva, Rosane M.B. Teles, Lilah A. Mansky, Jonathan Perrie, Dennis J. Montoya, Bryan D. Bryson, Johann E. Gudjonsson, Gerard C.L. Wong, Euzenir N. Sarno, Matteo Pellegrini, Robert L. Modlin
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI188138.
Abstract
Cytoplasmic TDP43 mislocalization and aggregation are pathological hallmarks of amyotrophic lateral sclerosis (ALS). However, the initial cellular insults that lead to TDP43 mislocalization remain unclear. In this study, we demonstrate that Nemo-like kinase (NLK) — a proline-directed serine/threonine kinase — promotes the mislocalization of TDP43 and other RNA-binding proteins by disrupting nuclear import. NLK levels are selectively elevated in neurons exhibiting TDP43 mislocalization in ALS patient tissues, while genetic reduction of NLK reduces toxicity in human neuron models of ALS. Our findings suggest that NLK is a promising therapeutic target for neurodegenerative diseases.
Authors
Michael E. Bekier II, Emile S. Pinarbasi, Gopinath Krishnan, Jack J. Mesojedec, Madelaine Hurley, Harisankar Harikumar Sheela, Catherine A. Collins, Layla T. Ghaffari, Martina de Majo, Erik M. Ullian, Mark Koontz, Sarah Coleman, Xingli Li, Elizabeth M.H. Tank, Jacob Waksmacki, Fen-Biao Gao, Sami J. Barmada
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI180378.
Abstract
A subgroup (~20-30%) of castration-resistant prostate cancer (CRPC) aberrantly expresses a gastrointestinal (GI) transcriptome governed by two GI-lineage-restricted transcription factors, HNF1A and HNF4G. In this study, we found that expression of GI transcriptome in CRPC correlates with adverse clinical outcomes to androgen receptor signaling inhibitor treatment and shorter overall survival. Bromo- and extra-terminal domain inhibitors (BETi) downregulated HNF1A, HNF4G, and the GI transcriptome in multiple CRPC models, including cell lines, patient-derived organoids, and patient-derived xenografts, while AR and the androgen-dependent transcriptome were largely spared. Accordingly, BETi selectively inhibited growth of GI transcriptome-positive preclinical models of prostate cancer. Mechanistically, BETi inhibited BRD4 binding at enhancers globally, including both AR and HNF4G bound enhancers while gene expression was selectively perturbed. Restoration of HNF4G expression in the presence of BETi rescued target gene expression without rescuing BRD4 binding. This suggests that inhibition of master transcription factors expression underlies the selective transcriptional effects of BETi.
Authors
Shipra Shukla, Dan Li, Woo Hyun Cho, Dana M. Schoeps, Holly M. Nguyen, Jennifer L. Conner, Marjorie L. Roskes, Anisha Tehim, Gabriella Bayshtok, Mohini R. Pachai, Juan Yan, Nicholas A. Teri, Eric Campeau, Sarah Attwell, Patrick Trojer, Irina Ostrovnaya, Anuradha Gopalan, Ekta Khurana, Eva Corey, Ping Chi, Yu Chen
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI191070.
Abstract
Since the lung is a mucosal barrier organ with a unique immunologic environment, mechanisms of immunoregulation in lung cancer may differ from those of other malignancies. Consistent with this notion, we found that CD8+ T cells play a paradoxical role in facilitating, rather than ameliorating, the growth of multiple lung adenocarcinoma models. These include spontaneous, carcinogen-induced, and transplantable tumor cell line models. Specifically, we found that CD8+ T cells promote homing of CD4+Foxp3+ T regulatory cells to the tumor bed by increasing levels of CCR5 chemokines in the tumor microenvironment in an IFN-γ and TNF-α dependent manner. Contrary to their canonical role, these Th1 cytokines contributed to accelerated growth of murine lung adenocarcinomas while suppressing the growth of other malignancies. Surprisingly, lung cancer cells themselves can serve as a dominant source of IFN-γ, and deletion of this cytokine from cancer cells using CRISPR/Cas-9 decreases tumor growth. Importantly for translational applications, a high level of IFN-γ was also found in human lung cancer patients at both the mRNA and protein level. Our data outlines what we deem a novel and previously undefined lung cancer specific immunoregulatory pathway that may be harnessed to tailor immune based therapy specifically for this malignancy.
Authors
Christina Kratzmeier, Mojtaba Taheri, Zhongcheng Mei, Isabelle Lim, May A. Khalil, Brandon Carter-Cooper, Rachel E. Fanaroff, Chin S. Ong, Eric B. Schneider, Stephanie Chang, Erica Leyder, Dongge Li, Irina G. Luzina, Anirban Banerjee, Alexander Sasha Krupnick
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI191008.
Abstract
Up to 10% of patients with severe early-onset obesity carry pathogenic variants in known obesity-related genes, mostly affecting the leptin-melanocortin pathway. Studying children with severe obesity from consanguineous populations provides a unique opportunity to uncover novel molecular mechanisms. Using whole-exome sequencing, followed by a rigorous analytical and filtration strategy, we identified three different homozygous missense variants in SREK1 (encoding Splicing Regulatory glutamic acid and lysine rich protein) in Pakistani children with severe obesity, from three unrelated consanguineous pedigrees. The wild type SREK1 gene of human induced pluripotent stem cell (iPSC)-derived hypothalamic neurons was individually replaced by each of the three variants and the impact of these changes on global gene expression was studied. Neurons expressing the two variants in the SREK1 RNA recognition domain p.P95L and p.T194M, but not the C-terminally located p.E601K, had markedly reduced expression of the small nucleolar RNA clusters SNORD115 and SNORD116, deficiency of which has been implicated in Prader-Willi syndrome (PWS). In addition to hyperphagic obesity the carriers of these two variants had other features of PWS, such as neonatal hypotonia. In conclusion, homozygous variants in SREK1 result in a subtype of severe early onset obesity sharing features with PWS.
Authors
Sadia Saeed, Anna-Maria Siegert, YC Loraine Tung, Roohia Khanam, Qasim M. Janjua, Jaida Manzoor, Mehdi Derhourhi, Bénédicte Toussaint, Brian Y. H. Lam, Sherine Awad, Emmanuel Vaillant, Emmanuel Buse Falay, Souhila Amanzougarene, Hina Ayesha, Waqas Imran Khan, Nosheen Ramzan, Vladimir Saudek, Stephen O'Rahilly, Anthony P. Goldstone, Muhammad Arslan, Amélie Bonnefond, Philippe Froguel, Giles S.H. Yeo
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI187868.
Abstract
The dystrophin-glycoprotein complex (DGC) is composed of peripheral and integral membrane proteins at the muscle cell membrane that link the extracellular matrix with the intracellular cytoskeleton. While it is well-established that genetic mutations that disrupt the structural integrity of DGC result in numerous muscular dystrophies, the three-dimensional structure of the complex has remained elusive. Two recent elegant cryoEM structures of DGC illuminate its molecular architecture and reveal the unique structural placement of sarcospan (SSPN) within the complex. SSPN, a 25-kDa tetraspanin-like protein, anchors beta-dystroglycan to the beta-, gamma- and delta-sarcoglycan trimer, supporting biochemical studies that SSPN is a core element for DGC assembly and stabilization. Here, we advance these studies by revealing that SSPN provides scaffolding in gamma-sarcoglycanopathies enabling substitution of gamma-sarcoglycan by its homolog, zeta-sarcoglycan, leading to the structural integrity of the DGC and prevention of limb-girdle muscular dystrophy R5. Three-dimensional modeling reveals that zeta-sarcoglycan preserves protein-protein interactions with the sarcospan, sarcoglycans, dystroglycan, and dystrophin. The structural integrity of the complex maintains myofiber attachment to the extracellular matrix and protect the cell membrane from contraction-induced damage. These findings demonstrate that sarcospan prevents limb-girdle muscular dystrophy R5 by remodeling of the sarcoglycan complex composition.
Authors
Ekaterina I. Mokhonova, Daniel Helzer, Ravinder Malik, Hafsa Mamsa, Jackson Walker, Mark Maslanka, Tess S. Fleser, Mohammad H. Afsharinia, Shiheng Liu, Johan Holmberg, Z. Hong Zhou, Eric J. Deeds, Kirk C. Hansen, Elizabeth M. McNally, Rachelle H. Crosbie
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI177123.
Abstract
Vasculopathy is a common hallmark of various fibrotic disorders including systemic sclerosis (SSc), yet its underlying etiology and contribution to fibrogenesis remain ill-defined. In SSc the vasculopathy typically precedes the onset of fibrosis and we observed that this phenomenon is recapitulated in the Snail transgenic mouse model of SSc. The vascular anomalies manifest as deformed vessels, endothelial cell dysfunction and vascular leakage. Our investigation into the underlying mechanism of this phenotype revealed that angiopoietin-like protein 2 (ANGPTL2), secreted by the Snail transgenic keratinocytes, is a principal driver of fibrotic vasculopathy. In endothelial cells, ANGPTL2 upregulates pro-fibrotic genes, downregulates various junctional proteins, and prompts the acquisition of mesenchymal characteristics. Inhibiting endothelial cell junctional instability and consequently vascular leakage with a synthetic analog of the microbial metabolite Urolithin A (UAS03) effectively mitigated the vasculopathy and inhibited fibrogenesis. Thus, ANGPTL2 emerges as a promising early biomarker of the disease and inhibiting the vasculopathy inducing effects of this protein with agents such as UAS03 presents an appealing therapeutic avenue to reduce disease severity. These insights hold the potential to revolutionize the approach to the treatment of fibrotic diseases by targeting the vascular defects.
Authors
Dyuti Saha, Ravi Kiran Annadorai, Sujaya Thannimangalath, Neha P. Shroff, Sunny Kataria, Binita Dam, Abhik Dutta, Akshay Hegde, Ankita Hiwale, Venkatesh Ravula, Shagnik Saha, Lekshmi Minikumari Rahulan, Neha Nigam, Neha Singh, Vikas Agarwal, Praveen K. Vemula, Colin Jamora
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI177430.
Abstract
Mucopolysaccharidoses (MPS) are lysosomal storage diseases caused by defects in catabolism of glycosaminoglycans. MPS I, II, III and VII, associated with lysosomal accumulation of heparan sulphate (HS), manifest with neurological deterioration and currently lack effective treatments. We report that neuraminidase 1 (NEU1) activity is drastically reduced in brain tissues of neurological MPS patients and mouse models but not in neurological lysosomal disorders without HS storage. Accumulated HS disrupts the lysosomal multienzyme complex of NEU1 with cathepsin A (CTSA), β-galactosidase (GLB1) and glucosamine-6-sulfate sulfatase (GALNS) leading to NEU1 deficiency and partial GLB1 and GALNS deficiencies in cortical tissues and iPSC-derived cortical neurons of neurological MPS patients. Increased sialylation of N-linked glycans in brains of MPS patients and mice implicated insufficient processing of sialylated glycans, except for polysialic acid. Correction of NEU1 activity in MPS IIIC mice by lentiviral gene transfer ameliorated previously identified hallmarks of the disease, including memory impairment, behavioural traits, and reduced levels of excitatory synapse markers VGLUT1 and PSD95. Overexpression of NEU1 also restored levels of VGLUT1/PSD95-positive puncta in cortical iPSC-derived MPS IIIA neurons. Our results demonstrate that HS-induced secondary NEU1 deficiency and aberrant sialylation of brain glycoproteins constitute what we believe to be a novel pathological pathway in neurological MPS spectrum crucially contributing to CNS pathology.
Authors
TianMeng Xu, Rachel Heon-Roberts, Travis Moore, Patricia Dubot, Xuefang Pan, Tianlin Guo, Christopher W. Cairo, Rebecca J. Holley, Brian Bigger, Thomas M. Durcan, Thierry Levade, Jerôme Ausseil, Bénédicte Amilhon, Alexei Gorelik, Bhushan Nagar, Shaukat Khan, Shunji Tomatsu, Luisa Sturiale, Angelo Palmigiano, Iris Röckle, Hauke Thiesler, Herbert Hildebrandt, Domenico Garozzo, Alexey V. Pshezhetsky
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI185001.
Abstract
Metachromatic leukodystrophy (MLD) is an autosomal recessive neurodegenerative disorder caused by mutations in the arylsulfatase A (ARSA) gene, resulting in lower sulfatase activity and the toxic accumulation of sulfatides in the central and peripheral nervous system. Children account for 70% of cases and become progressively disabled with death occurring within 10 years of disease onset. Gene therapy approaches to restore ARSA expression via adeno-associated viral vectors (AAV) have been promising but hampered by limited brain biodistribution. We report the development of an engineered capsid AAV.GMU01, demonstrating superior biodistribution and transgene expression in the central nervous system of non-human primates (NHPs). Next, we show that AAV.GMU01-ARSA treated MLD mice exhibit persistent, normal levels of sulfatase activity and a concomitant reduction in toxic sulfatides. Treated mice also show a reduction in MLD-associated pathology and auditory dysfunction. Lastly, we demonstrate that treatment with AAV.GMU01-ARSA in NHPs is well-tolerated and results in potentially therapeutic ARSA expression in the brain. In summary, we propose AAV.GMU01-ARSA mediated gene replacement as a clinically viable approach to achieve broad and therapeutic levels of ARSA.
Authors
Shyam Ramachandran, Jeffery Ardinger, Jie Bu, MiAngela Ramos, Lilu Guo, Dhiman Ghosh, Mahmud Hossain, Shih-Ching Chou, Yao Chen, Erik Wischhof, Swathi Ayloo, Roger Trullo, Yuxia Luo, Jessica M. Hogestyn, Daniel M. DuBreuil, Emily Crosier, Johanna G. Flyer-Adams, Amy M. Richards, Michael Tsabar, Giorgio Gaglia, Shelley Nass, Bindu Nambiar, Denise Woodcock, Catherine O'Riordan, Qi Tang, Bradford Elmer, Bailin Zhang, Martin Goulet, Christian Mueller
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI181893.
Abstract
BACKGROUND. Axicabtagene ciloleucel (axi-cel), anti-CD19 chimeric antigen receptor (CAR) T-cell therapy demonstrated remarkable efficacy with manageable toxicity in relapsed/refractory indolent B-cell lymphomas in the ZUMA-5 trial. METHODS. Here, we report associations of product attributes, serum biomarkers, clinical features, and tumor characteristics with outcome in 124 follicular lymphoma (FL) patients. RESULTS. In univariate and multivariate analyses, pre-treatment inflammatory markers, including TNFα and IL12p40, as well as total metabolic tumor volume (TMTV) associated with disease progression. Conversely, T-naïve-like product phenotype associated with improved outcome, particularly in high TMTV patients. These covariates improved risk stratification when combined with the FL International Prognostic Index. Post-infusion, CAR T-cell expansion associated with improved outcome, while serum inflammatory and immuno-modulatory markers, including TNFα associated with disease progression and occurrence of high-grade cytokine release syndrome or neurologic events, presenting targets to improve the therapeutic index of axi-cel in FL. Tumor gene expression profiling revealed that both type I and II IFN signaling associated with disease progression and higher expression of T cell exhaustion markers, including TIM3 and LAG3. Pre- or post-treatment CD19 expression on tumor was not associated with outcome. CONCLUSION. These findings offer insights into mechanisms of resistance and toxicity, risk stratification, and strategies for development of next generation CAR-T approaches. TRIAL REGISTRATION. ClinicalTrials.gov NCT03105336. FUNDING. Kite, a Gilead Company.
Authors
Soumya Poddar, Jiali Yan, Gayatri Tiwari, Darawan Rinchai, Justin Budka, Wangshu Zhang, Weixin Peng, Shruti Salunkhe, Madison Davis, Qinghua Song, Sara Beygi, Harry Miao, Mike Mattie, Rhine S. Shen, Caron A. Jacobson, Davide Bedognetti, Simone Filosto, Sattva S. Neelapu
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI191256.
Abstract
Authors
Caitlin M. Stewart, Sonya Parpart-Li, James R. White, Mitesh Patel, Oliver Artz, Michael B. Foote, Erika Gedvilaite, Michelle F. Lamendola-Essel, Drew Gerber, Rohini Bhattacharya, Justin M. Haseltine, Kety Huberman, Kelly L. Bolton, Ross L. Levine, Luis A. Diaz, Jr.
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI181034.
Abstract
Lupus nephritis (LN) is a frequent manifestation of systemic lupus erythematosus, and fewer than half of patients achieve complete renal response with standard immunosuppressants. Identifying non-invasive, blood-based immune alterations associated with renal injury could aid therapeutic decisions. Here, we used mass cytometry immunophenotyping of peripheral blood mononuclear cells in 145 patients with biopsy-proven LN and 40 healthy controls to evaluate the heterogeneity of immune activation and identify correlates of renal parameters. Unbiased analysis identified three immunologically distinct groups of patients that were associated with different patterns of histopathology, renal cell infiltrates, urine proteomic profiles, and treatment response at one year. Patients with enriched circulating granzyme B+ T cells showed more active disease and increased numbers of activated CD8 T cells in the kidney, yet they had the highest likelihood of treatment response. A second group characterized by a high type I interferon signature had a lower likelihood of response to therapy, while a third group appeared immunologically inactive but with chronic renal injuries. The major immunologic axes of variation could be distilled down to five simple cytometric parameters that recapitulate several clinical associations, highlighting the potential for blood immunoprofiling to translate to clinically useful non-invasive metrics to assess immune-mediated disease in LN.
Authors
Alice Horisberger, Alec Griffith, Joshua Keegan, Arnon Arazi, John Pulford, Ekaterina Murzin, Kaitlyn Howard, Brandon Hancock, Andrea Fava, Takanori Sasaki, Tusharkanti Ghosh, Jun Inamo, Rebecca Beuschel, Ye Cao, Katie Preisinger, Maria Gutierrez-Arcelus, Thomas M. Eisenhaure, Joel Guthridge, Paul J. Hoover, Maria Dall'Era, David Wofsy, Diane L. Kamen, Kenneth C. Kalunian, Richard Furie, Michael Belmont, Peter Izmirly, Robert Clancy, David Hildeman, E. Steve Woodle, William Apruzzese, Maureen A. McMahon, Jennifer Grossman, Jennifer L. Barnas, Fernanda Payan-Schober, Mariko Ishimori, Michael Weisman, Matthias Kretzler, Celine C. Berthier, Jeffrey B. Hodgin, Dawit S. Demeke, Chaim Putterman, Michael B. Brenner, Jennifer H. Anolik, Soumya Raychaudhuri, Nir Hacohen, Judith A. James, Anne Davidson, Michelle A. Petri, Jill P. Buyon, Betty Diamond, Fan Zhang, James A. Lederer, Deepak A. Rao
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ISSN: 0021-9738 (print), 1558-8238 (online)