Molecular TherapyPub Date : 2025-07-02Epub Date: 2025-03-28DOI: 10.1016/j.ymthe.2025.03.044
Julie Bejoy, Richard C Welch, Eddie S Qian, Felisha M Williams, Katherine N Gibson-Corley, Matthew H Wilson, Neal Paragas, Lauren E Woodard
{"title":"Urine-derived stem cells display homing, incorporation, and regeneration in human organoid and mouse models of acute kidney injury.","authors":"Julie Bejoy, Richard C Welch, Eddie S Qian, Felisha M Williams, Katherine N Gibson-Corley, Matthew H Wilson, Neal Paragas, Lauren E Woodard","doi":"10.1016/j.ymthe.2025.03.044","DOIUrl":"10.1016/j.ymthe.2025.03.044","url":null,"abstract":"<p><p>Urine-derived stem cells (USCs) are adult human stem cells that can be collected noninvasively from urine and cultured in vitro. Because of their renal origin and reported therapeutic effects, we hypothesized that USCs would home to the injured kidney in acute kidney injury (AKI) models. We used mouse models of glycerol-induced rhabdomyolysis or unilateral nephrectomy with clamping ischemia reperfusion injury to model AKI. To track USC homing by live animal imaging, we administered luciferase-expressing (Luc) USCs to mice by intraperitoneal injection. We observed USC localization to both the tubules and glomeruli of injured mice within 3 h by histology. We confirmed the presence of Luc-USCs in the kidney at 3 h, 24 h, and 48 h after the injection using biodistribution analysis of quantitative bioluminescence tomography imaging. We performed immunostaining for kidney injury molecule-1 (KIM-1/HAVCR1/TIM-1) for kidney injury and found reduced expression in USC-treated group at 24 h after injection. To evaluate the effects of the human USCs on injured human nephrons, we injured human kidney organoids with the nephrotoxin cisplatin (5 μM) followed by 5 × 10<sup>4</sup> USC treatment. USCs were incorporated and lowered expression of KIM-1 in the organoids. USCs home to injured nephrons and reduce measures of kidney injury.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3307-3320"},"PeriodicalIF":12.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12266040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753684","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}
Molecular TherapyPub Date : 2025-07-02Epub Date: 2025-03-12DOI: 10.1016/j.ymthe.2025.03.012
Rahul Mallick, Ahmed B Montaser, Henna Komi, Greta Juusola, Annakaisa Tirronen, Erika Gurzeler, Maria Barbiera, Petra Korpisalo, Tetsuya Terasaki, Tiina Nieminen, Seppo Ylä-Herttuala
{"title":"VEGF-B is a novel mediator of ER stress which induces cardiac angiogenesis via RGD-binding integrins independent of VEGFR1/NRP activities.","authors":"Rahul Mallick, Ahmed B Montaser, Henna Komi, Greta Juusola, Annakaisa Tirronen, Erika Gurzeler, Maria Barbiera, Petra Korpisalo, Tetsuya Terasaki, Tiina Nieminen, Seppo Ylä-Herttuala","doi":"10.1016/j.ymthe.2025.03.012","DOIUrl":"10.1016/j.ymthe.2025.03.012","url":null,"abstract":"<p><p>Vascular endothelial growth factor B186 (VEGF-B186), a ligand for VEGF receptor 1 (VEGFR1) and neuropilin (NRP), promotes vascular growth in healthy and ischemic myocardium. However, the mechanisms and signaling of VEGF-B186 to support angiogenesis have remained unclear. We studied the effects of VEGF-B186 and its variant, VEGF-B186R127S, which cannot bind to NRPs, using VEGFR1 tyrosine kinase knockout (TK<sup>-/-</sup>) mice to explore the mechanism of VEGF-B186 in promoting vascular growth. Ultrasound-guided adenoviral VEGF-B186, VEGF-B186R127S, and control vector gene transfers were performed into VEGFR1 TK<sup>-/-</sup> mice hearts. In vitro studies in cardiac endothelial cells and further validation in normal and ischemic pig hearts, as well as in wild-type mice, were conducted. Both VEGF-B186 forms promoted vascular growth in VEGFR1 TK<sup>-/-</sup> mouse heart and increased the expression of proangiogenic and hematopoietic factors. Unlike VEGF-A, VEGF-B186 forms induced endoplasmic reticulum (ER) stress via the upregulation of Binding immunoglobulin Protein (BiP) as well as ER stress sensors (ATF6, PERK, IRE1α) through ITGAV and ITGA5 integrins, newly identified receptors for VEGF-B, activating the unfolded protein response (UPR) through XBP1. VEGFR1 and NRP are not essential for VEGF-B186-induced vascular growth. Instead, VEGF-B186 can stimulate cardiac regeneration through RGD-binding integrins and ER stress, suggesting a novel mechanism of action for VEGF-B186.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3242-3256"},"PeriodicalIF":12.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625496","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}
{"title":"Single-dose intranasal AdC68-vectored vaccines rapidly protect Syrian hamsters against lethal Nipah virus infection.","authors":"Mingqing Lu, Yanfeng Yao, Hang Liu, Yun Peng, Xuejie Li, Ge Gao, Miaoyu Chen, Xuekai Zhang, Lingjing Mao, Peipei Yang, XiaoYu Zhang, Jing Miao, Zhiming Yuan, Jiaming Lan, Chao Shan","doi":"10.1016/j.ymthe.2025.03.032","DOIUrl":"10.1016/j.ymthe.2025.03.032","url":null,"abstract":"<p><p>Nipah virus (NiV) infection is highly lethal in humans, and the development of vaccines that provide rapid protection is critical for addressing NiV outbreaks. In this study, we demonstrate that a single intranasal immunization with the chimpanzee adenoviral-vectored NiV vaccine, AdC68-F, induced robust and sustained cellular and humoral responses in BALB/c mice, and provided complete protection against challenge with the NiV-Malaysia strain (NiV-M) in Syrian hamsters. Notably, AdC68-F, administered at a dose of 5 × 10<sup>9</sup> viral particles, offered a complete prophylactic protection window as few as 7 days before exposure to a lethal NiV-M challenge. Furthermore, passive transfer of sera from AdC68-F or AdC68-G immunized animals conferred complete protection against NiV-M infection in naive hamsters. These findings underscore the pivotal role of antigen-specific immunity in controlling NiV infection and highlight the potential of single-dose intranasal AdC68-based NiV vaccines for rapid protection during outbreaks. By providing rapid and effective protection, these vaccines could help reduce human-to-human transmission and aid in curbing NiV outbreaks.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3270-3285"},"PeriodicalIF":12.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12266052/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720565","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}
Molecular TherapyPub Date : 2025-07-02Epub Date: 2025-03-22DOI: 10.1016/j.ymthe.2025.03.028
Sara Shoeibi, Wenyu Gou, Tiffany Yeung, Kristi Helke, Erica Green, Charlie Strange, Hongjun Wang
{"title":"AAT-MSC-EVs: Novel implications for suppressing ferroptosis, fibrosis and pain associated with chronic pancreatitis.","authors":"Sara Shoeibi, Wenyu Gou, Tiffany Yeung, Kristi Helke, Erica Green, Charlie Strange, Hongjun Wang","doi":"10.1016/j.ymthe.2025.03.028","DOIUrl":"10.1016/j.ymthe.2025.03.028","url":null,"abstract":"<p><p>Chronic pancreatitis (CP) is characterized by inflammation, acinar cell death, fibrosis, and persistent pain. We investigated mesenchymal stem/stromal cell (MSC)-derived extracellular vesicles (EVs) for CP treatment. CP was modeled in male mice using bile duct TNBS infusion, and pancreatic tissues from CP patients were also analyzed. EVs from immortalized human MSCs overexpressing alpha-1 antitrypsin (iAAT-MSCs) were tested for their effects on ferroptosis, fibrosis, and pain. CP tissues showed reduced glutathione peroxidase 4 (GPx4) activity (p < 0.05) and iron accumulation, indicating ferroptosis. iMSC and iAAT-MSC-EVs alleviated CP symptoms by suppressing ferroptosis, restoring GPx4 activity, reducing MDA levels, and mitigating fibrosis markers (α-smooth muscle actin, transforming growth factor-β1, matrix metalloproteinase 2). EV treatment also alleviated pain by decreasing macrophage and mast cell infiltration into the pancreas and dorsal root ganglia while reducing pain-related gene expression (TRVP1, TacR1, Necab3). Additionally, iAAT-MSC-EVs were distinct in cytokine signaling, PI3K-Akt pathway activation, and upregulation of miRNAs like miR-9, miR-10a-5p, miR-92a, miR-200, miR-370, and miR-146a. These results suggest ferroptosis as a key mechanism in CP and highlight the therapeutic potential of iAAT-MSC-EVs in addressing ferroptosis, fibrosis, and pain, presenting a promising, cell-free therapeutic strategy for CP.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3321-3338"},"PeriodicalIF":12.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12266032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692709","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}
Molecular TherapyPub Date : 2025-07-02Epub Date: 2025-03-20DOI: 10.1016/j.ymthe.2025.03.023
Rui Hou, Xiaoxue Zhang, Zejun Zhang, Wenyin He, Huan Li, Xu Wang, Xuan Zhao, Sijin Li, Zhangchun Guan, Ying Sun, Dan Liu, Junnian Zheng, Ming Shi
{"title":"IFN-γ-mediated suppression of Caspase-7 exacerbates acute lung injury induced by CAR-T cells.","authors":"Rui Hou, Xiaoxue Zhang, Zejun Zhang, Wenyin He, Huan Li, Xu Wang, Xuan Zhao, Sijin Li, Zhangchun Guan, Ying Sun, Dan Liu, Junnian Zheng, Ming Shi","doi":"10.1016/j.ymthe.2025.03.023","DOIUrl":"10.1016/j.ymthe.2025.03.023","url":null,"abstract":"<p><p>On-target off-tumor effects precipitate severe adverse reactions in patients, significantly hindering the application of chimeric antigen receptor (CAR) T cells in both hematological and solid tumors. The underlying mechanisms remain elusive due to the absence of suitable preclinical models. To elucidate these mechanisms, a human epidermal growth factor receptor 2 (Her2) transgenic mouse model was developed to investigate CAR-T cell-induced on-target off-tumor effects. CAR-T cells initially migrated to the lungs, targeting alveolar epithelial cells and resulting in interferon-γ (IFN-γ)-dependent acute lung injury. Additionally, a regulatory mechanism involving IFN-γ-induced degradation of caspase-7 mRNA 5' untranslated regions (UTR), which amplifies acute lung injury mediated by CAR-T cells, was identified. Consequently, a strategy was validated to antagonize IFN-γ during CAR-T cell infusion, thereby mitigating acute lung injury without compromising antitumor efficacy. These findings elucidate the mechanisms of CAR-T cell-induced acute lung injury and demonstrate the viability of targeting IFN-γ to prevent this adverse reaction.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3392-3406"},"PeriodicalIF":12.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676611","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}
Molecular TherapyPub Date : 2025-07-02Epub Date: 2025-03-20DOI: 10.1016/j.ymthe.2025.03.021
Xiaoxue He, Tong Yan, Zongming Song, Lue Xiang, Jiayang Xiang, Yeqin Yang, Kaiqun Ren, Jicheng Bu, Xilin Xu, Zhuo Li, Xiaowei Guo, Bin Lin, Qinghua Zhou, Ge Lin, Feng Gu
{"title":"Correcting a patient-specific Rhodopsin mutation with adenine base editor in a mouse model.","authors":"Xiaoxue He, Tong Yan, Zongming Song, Lue Xiang, Jiayang Xiang, Yeqin Yang, Kaiqun Ren, Jicheng Bu, Xilin Xu, Zhuo Li, Xiaowei Guo, Bin Lin, Qinghua Zhou, Ge Lin, Feng Gu","doi":"10.1016/j.ymthe.2025.03.021","DOIUrl":"10.1016/j.ymthe.2025.03.021","url":null,"abstract":"<p><p>Genome editing offers a great promise to treating human genetic diseases. To assess genome-editing-mediated therapeutic effects in vivo, an animal model is indispensable. The genomic disparities between mice and humans often impede the direct clinical application of genome-editing-mediated treatments using conventional mouse models. Thus, the generation of a mouse model with a humanized genomic segment containing a patient-specific mutation is highly sought after for translational research. In this study, we successfully developed a knockin mouse model for autosomal-dominant retinitis pigmentosa (adRP), designated as hT17M knockin, which incorporates a 75-nucleotide DNA segment with the T17M mutation (Rhodopsin-c.C50T; p.T17M). This model demonstrated significant reductions in electroretinogram amplitudes and exhibited disruptions in retinal structure. Subsequently, we administered an adeno-associated virus vectors carrying an adenine base editor (ABE) and a single-guide RNA specifically targeting the T17M mutation, achieving a peak correction rate of 39.7% at the RNA level and significantly improving retinal function in ABE-injected mice. These findings underscore that the hT17M knockin mouse model recapitulates the clinical features of adRP patients and exhibits therapeutic effects with ABE-mediated treatments. It offers a promising avenue for the development of gene-editing therapies for RP.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3101-3113"},"PeriodicalIF":12.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676587","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}
Molecular TherapyPub Date : 2025-07-02Epub Date: 2024-12-12DOI: 10.1016/j.ymthe.2024.12.020
Senthil Velan Bhoopalan, Thiyagaraj Mayuranathan, Nana Liu, Kalin Mayberry, Yu Yao, Jingjing Zhang, Jean-Yves Métais, Koon-Kiu Yan, Robert E Throm, Steven R Ellis, Yan Ju, Lei Han, Shruthi Suryaprakash, Lance E Palmer, Sheng Zhou, Jiyang Yu, Yong Cheng, Jonathan S Yen, Stephen Gottschalk, Mitchell J Weiss
{"title":"Preclinical development of lentiviral vector gene therapy for Diamond-Blackfan anemia syndrome.","authors":"Senthil Velan Bhoopalan, Thiyagaraj Mayuranathan, Nana Liu, Kalin Mayberry, Yu Yao, Jingjing Zhang, Jean-Yves Métais, Koon-Kiu Yan, Robert E Throm, Steven R Ellis, Yan Ju, Lei Han, Shruthi Suryaprakash, Lance E Palmer, Sheng Zhou, Jiyang Yu, Yong Cheng, Jonathan S Yen, Stephen Gottschalk, Mitchell J Weiss","doi":"10.1016/j.ymthe.2024.12.020","DOIUrl":"10.1016/j.ymthe.2024.12.020","url":null,"abstract":"<p><p>Diamond-Blackfan anemia syndrome (DBAS) is an inherited bone marrow failure disorder caused by haploinsufficiency of ribosomal protein genes, most commonly RPS19. Limited access to patient hematopoietic stem and progenitor cells (HSPCs) is a major roadblock to developing novel therapies for DBAS. We developed a self-inactivating third-generation RPS19-encoding lentiviral vector (LV) called SJEFS-S19 for DBAS gene therapy. To facilitate LV design, optimize transduction, and assess potential therapeutic efficacy, we leveraged a human cellular model of DBAS based on heterozygous disruption of RPS19 in healthy donor CD34<sup>+</sup> HSPCs. We show that SJEFS-S19 LV can rescue DBAS-associated defects in ribosomal RNA processing, erythropoiesis, and competitive bone marrow repopulation. Transduction of RPS19<sup>+/-</sup> CD34<sup>+</sup> HSPCs with SJEFS-S19 LV followed by xenotransplantation into immunodeficient mice generated a polyclonal HSPC population with normal multilineage differentiation and a diverse integration site profile resembling that of clinically proven LVs. Overall, these preclinical studies demonstrate the safety and efficacy of SJEFS-S19, a novel LV for future DBAS gene therapy.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3086-3100"},"PeriodicalIF":12.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824157","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}
Molecular TherapyPub Date : 2025-07-02Epub Date: 2025-04-03DOI: 10.1016/j.ymthe.2025.03.051
Jie Liu, Jun Chen, Shisheng Huang, Junfan Guo, Xiangyang Li, Ying Yan, Ruijing Chen, Guanglei Li, Ming Liu, Jiao Wei, Xingxu Huang, Yunbo Qiao
{"title":"An engineered mitoCBE facilitates efficient mitochondrial DNA editing and modified mitochondrial transfer.","authors":"Jie Liu, Jun Chen, Shisheng Huang, Junfan Guo, Xiangyang Li, Ying Yan, Ruijing Chen, Guanglei Li, Ming Liu, Jiao Wei, Xingxu Huang, Yunbo Qiao","doi":"10.1016/j.ymthe.2025.03.051","DOIUrl":"10.1016/j.ymthe.2025.03.051","url":null,"abstract":"<p><p>Double-stranded DNA cytosine deaminase DddA orthologs from multiple types of bacteria have been fused with the transcription-activator-like effector system for mitochondrial DNA (mtDNA) base editing, while the efficiencies remain limited and its nuclear off-targeting activity cannot be ignored yet. Here we identified a DddA ortholog from Burkholderia gladioli (BgDddA) and generated nuclear or mtDNA cytosine base editors (mitoCBEs), exhibiting higher C⋅G-to-T⋅A editing frequencies compared with canonical DdCBE, and fusion with transactivator Rta remarkably improved editing efficiencies by up to 6.4-fold at non-TC targets. Referring to DddA11, we further introduced six substitutions into BgDddA and generated mitoCBE3.2, which efficiently induced disease-associated mtDNA mutations in mouse and human cell lines at both TC and non-TC targets with efficiency reaching up to 99.2%. Using mitoCBE3.2, single clones containing homoplasmic mtDNA mutations or premature stop codons associated with human diseases were generated, and the functions of these mutations have been evaluated upon the treatment of reactive oxygen species inducers. Importantly, mitochondria harboring these homoplasmic mutations were transplanted into wild-type cells, enabling precise base conversions, without the risk of nuclear gene off-targets. Thus, we have engineered an efficient mitoCBE using BgDddA, facilitating mitochondrial disease modeling and potential mutation correction with the aid of mitochondrial transplantation.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3114-3127"},"PeriodicalIF":12.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12266020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779713","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}
Molecular TherapyPub Date : 2025-07-02Epub Date: 2024-10-28DOI: 10.1016/j.ymthe.2024.10.019
Fabio Dell'Aquila, Roberto Di Cunto, Elena Marrocco, Eugenio Del Prete, Alfonso D'Alessio, Lucia De Stefano, Simone Notaro, Edoardo Nusco, Alberto Auricchio
{"title":"Combined intraocular and intravenous gene delivery for therapy of gyrate atrophy of the choroid and retina.","authors":"Fabio Dell'Aquila, Roberto Di Cunto, Elena Marrocco, Eugenio Del Prete, Alfonso D'Alessio, Lucia De Stefano, Simone Notaro, Edoardo Nusco, Alberto Auricchio","doi":"10.1016/j.ymthe.2024.10.019","DOIUrl":"10.1016/j.ymthe.2024.10.019","url":null,"abstract":"<p><p>Gyrate atrophy of the choroid and retina (GACR) is due to ornithine aminotransferase (OAT) deficiency, which causes hyperornithinemia, leading to retinal pigment epithelium, followed by choroidal and retinal degeneration. Adeno-associated virus serotype 8 (AAV8) vector-mediated OAT (AAV8-OAT) liver gene transfer reduces ornithinemia in the Oat<sup>-/-</sup> mouse model of GACR and improves retinal function and structure. Since OAT is expressed in various tissues including the retina, we investigated the efficacy of restoration of OAT expression in either retina or liver or both tissues on the retinal phenotype of Oat<sup>-/-</sup> mice. Intravenous and subretinal administration of AAV8-OAT resulted in intraocular and liver OAT expression with reduced ornithinemia after intravenous AAV8-OAT administration, while intraocular ornithine levels were significantly reduced only following combined gene delivery. Accordingly, only Oat<sup>-/-</sup> animals treated with combined intravenous and subretinal AAV8-OAT administrations showed significant improvements in both retinal morphology and function. This work shows the benefits of combined liver and retinal OAT supplementation for the treatment of GACR.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2997-3005"},"PeriodicalIF":12.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569254","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}
Molecular TherapyPub Date : 2025-07-02Epub Date: 2025-03-13DOI: 10.1016/j.ymthe.2025.03.018
Tyler Ellis Papp, Jianhao Zeng, Hamna Shahnawaz, Awurama Akyianu, Laura Breda, Amir Yadegari, Joseph Steward, Ruiqi Shi, Qin Li, Barbara L Mui, Ying K Tam, Drew Weissman, Stefano Rivella, Vladimir Shuvaev, Vladimir R Muzykantov, Hamideh Parhiz
{"title":"CD47 peptide-cloaked lipid nanoparticles promote cell-specific mRNA delivery.","authors":"Tyler Ellis Papp, Jianhao Zeng, Hamna Shahnawaz, Awurama Akyianu, Laura Breda, Amir Yadegari, Joseph Steward, Ruiqi Shi, Qin Li, Barbara L Mui, Ying K Tam, Drew Weissman, Stefano Rivella, Vladimir Shuvaev, Vladimir R Muzykantov, Hamideh Parhiz","doi":"10.1016/j.ymthe.2025.03.018","DOIUrl":"10.1016/j.ymthe.2025.03.018","url":null,"abstract":"<p><p>mRNA-based therapeutics delivered via lipid nanoparticles (LNP-mRNA) hold great promise for treating diverse diseases. However, further improvements are needed to refine outcomes in non-vaccine, extrahepatic applications, such as minimizing the rapid clearance and off-target uptake in undesired tissues of the mononuclear phagocyte system (MPS). We propose modifying LNP surfaces with the phagocytic cell \"don't eat me\" signal, CD47, in combination with our previously established antibody-based targeted LNP (tLNP) to create a CD47/tLNP platform with reduced phagocytic clearance and off-target effects and improved efficiency for cell-specific delivery. We showed that CD47 modification decreased macrophage and hepatic uptake both in vitro and in vivo. Combining CD47 modification with antibodies targeting endothelial cells, T cells, or hematopoietic stem cells (HSCs) increased targeting efficiency up to 3-fold compared to tLNP alone. Enhanced targeting of CD47/tLNP to HSCs with reduced off-targeting enabled the delivery of pro-apoptotic mRNA for HSC depletion as a preconditioning strategy prior to bone marrow transplant. Additionally, CD47-modified LNPs showed diminished inflammatory effects on hepatic tissue and an altered protein corona. Our CD47/tLNP-mRNA platform, with its reduced phagocytic clearance, mitigated inflammatory effects, and enhanced targeted delivery, should further facilitate the development of in vivo mRNA therapeutics.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3195-3208"},"PeriodicalIF":12.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265960/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634242","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}
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