Molecular TherapyPub Date : 2025-05-14DOI: 10.1016/j.ymthe.2025.04.040
Carolyn Riley Chapman,Timothy P Cripe,Alison S Bateman-House
{"title":"Patient-centered long-term follow-up for gene therapies aligns with ethics and science.","authors":"Carolyn Riley Chapman,Timothy P Cripe,Alison S Bateman-House","doi":"10.1016/j.ymthe.2025.04.040","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.04.040","url":null,"abstract":"","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"10 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065790","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}
Molecular TherapyPub Date : 2025-05-14DOI: 10.1016/j.ymthe.2025.05.015
Haibin Zhou, Jiajing Dai, Dong Li, Luyao Wang, Meng Ye, Xiaoling Hu, Joseph LoTurco, Ji Hu, Wenzhi Sun
{"title":"Efficient gene delivery admitted by small metabolites specifically targeting astrocytes in the mouse brain.","authors":"Haibin Zhou, Jiajing Dai, Dong Li, Luyao Wang, Meng Ye, Xiaoling Hu, Joseph LoTurco, Ji Hu, Wenzhi Sun","doi":"10.1016/j.ymthe.2025.05.015","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.05.015","url":null,"abstract":"","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079154","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}
Molecular TherapyPub Date : 2025-05-09DOI: 10.1016/j.ymthe.2025.05.009
Won-Kyu Ju, Keun-Young Kim, Tonking Bastola, Ziyao Shen, Seunghwan Choi, Guy A Perkins, Sinwoo Hwang, Jungsu Kim, Jin-Woo Kwon, Muna Poudel, Sébastien Phan, Fan Xia, Shuizhen Shi, Hyunkyung Cho, Hua Liu, Wenbo Zhang, Robert N Weinreb, Mark H Ellisman, Yury I Miller, Soo-Ho Choi
{"title":"Restoring AIBP expression in the retina provides neuroprotection in glaucoma.","authors":"Won-Kyu Ju, Keun-Young Kim, Tonking Bastola, Ziyao Shen, Seunghwan Choi, Guy A Perkins, Sinwoo Hwang, Jungsu Kim, Jin-Woo Kwon, Muna Poudel, Sébastien Phan, Fan Xia, Shuizhen Shi, Hyunkyung Cho, Hua Liu, Wenbo Zhang, Robert N Weinreb, Mark H Ellisman, Yury I Miller, Soo-Ho Choi","doi":"10.1016/j.ymthe.2025.05.009","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.05.009","url":null,"abstract":"<p><p>Glaucoma is a neurodegenerative disease manifested by retinal ganglion cell (RGC) death and irreversible blindness. We have identified apolipoprotein A-I binding protein (AIBP) that controls excessive cholesterol accumulation and neuroinflammation in the retina by upregulating the cholesterol transporter ABCA1 and reducing TLR4 signaling and mitochondrial dysfunction. Here, we demonstrated that AIBP and ABCA1 expression were decreased, while TLR4, IL-1β, and the cholesterol content increased in the retina of patients with glaucoma and mouse models of glaucoma. Restoring AIBP deficiency by a single intravitreal injection of AAV protected RGCs and ameliorated visual dysfunction in experimental glaucoma. Conversely, AAV-mediated RGC-specific AIBP knockdown exacerbated RGC loss and visual dysfunction in a mouse model of glaucoma. Mechanistically, AAV-AIBP attenuated TLR4 and IL-1β expression and localization of TLR4 to lipid rafts, reduced cholesterol accumulation, and ameliorated visual dysfunction. Additionally, AAV-AIBP promoted mitochondrial complexity and function in Müller glia in vivo. Recombinant AIBP protein inhibited TLR4 and IL-1β activation and alleviated mitochondrial dysfunction in Müller glia in response to elevated pressure in vitro. These studies indicate that restoring AIBP expression in the glaucomatous retina reduces neuroinflammation and protects RGCs and Müller glia, suggesting the therapeutic potential of AAV-AIBP in human glaucoma.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019478","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}
Molecular TherapyPub Date : 2025-05-09DOI: 10.1016/j.ymthe.2025.05.010
Alexandra Weiss, James W Gilbert, Iris Valeria Rivera Flores, Jillian Belgrad, Chantal Ferguson, Elif O Dogan, Nicholas Wightman, Kit Mocarski, Dimas Echeverria, Ashley L Harkins, Ashley Summers, Brianna Bramoto, Nicholas McHugh, Raymond Furgal, Nozomi Yamada, David Cooper, Kathryn Monopoli, Bruno M D C Godinho, Matthew R Hassler, Ken Yamada, Paul Greer, Nils Henninger, Robert H Brown, Anastasia Khvorova
{"title":"RNAi-mediated silencing of SOD1 profoundly extends survival and functional outcomes in ALS mice.","authors":"Alexandra Weiss, James W Gilbert, Iris Valeria Rivera Flores, Jillian Belgrad, Chantal Ferguson, Elif O Dogan, Nicholas Wightman, Kit Mocarski, Dimas Echeverria, Ashley L Harkins, Ashley Summers, Brianna Bramoto, Nicholas McHugh, Raymond Furgal, Nozomi Yamada, David Cooper, Kathryn Monopoli, Bruno M D C Godinho, Matthew R Hassler, Ken Yamada, Paul Greer, Nils Henninger, Robert H Brown, Anastasia Khvorova","doi":"10.1016/j.ymthe.2025.05.010","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.05.010","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition, with 20% of familial and 2-3% of sporadic cases linked to mutations in the cytosolic superoxide dismutase (SOD1) gene. Mutant SOD1 protein is toxic to motor neurons, making SOD1 gene suppression a promising approach, supported by preclinical data and the 2023 FDA approval of the GapmeR ASO targeting SOD1, tofersen. Despite the approval of an ASO and the optimism it brings to the field, the pharmacodynamics and pharmacokinetics of therapeutic SOD1 modulation can be improved. Here, we developed a chemically stabilized divalent siRNA scaffold (di-siRNA) that effectively suppresses SOD1 expression in vitro and in vivo. With optimized chemical modification, it achieves remarkable CNS tissue permeation and SOD1 silencing in vivo. Administered intraventricularly, di-siRNA<sup>SOD1</sup> extended survival in SOD1-G93A ALS mice, increasing survival beyond that previously seen in these mice by ASO modalities, slowed disease progression according to the standard ALS preclinical endpoints, and attenuated ALS neuropathology. These properties offer an improved therapeutic strategy for SOD1-mediated ALS and may extend to other dominantly inherited neurological disorders.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144014165","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}
{"title":"CD38hi macrophages promote fibrotic transition following acute kidney injury by modulating NAD+ metabolism.","authors":"Weijian Yao,Menghan Liu,Zehua Li,Lei Qu,Shuang Sui,Chengang Xiang,Lei Jiang,Suxia Wang,Gang Liu,Ying Chen,Li Yang","doi":"10.1016/j.ymthe.2025.04.039","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.04.039","url":null,"abstract":"Acute kidney injury (AKI) encompasses a spectrum of conditions, varying from mild and self-limiting to severe cases that can lead to chronic kidney disease (CKD). Macrophages are crucial in the progression from AKI to CKD, yet the diversity of macrophage subsets complicates the identification of key functional types. We established a detailed single-cell atlas of mononuclear macrophages from the onset of AKI through its progression to CKD. Our results indicate that a macrophage subset with high CD38 expression is closely linked to renal fibrosis following AKI in both mouse model and AKI patients. These CD38hi macrophages, derived from resident macrophages via Csf1 signaling, secrete the NAD-depleting enzyme CD38, inducing senescence in renal tubular cells and promoting chronic inflammation and renal fibrosis. Knocking out Cd38 in macrophages elevated renal NAD levels, reducing senescence and fibrotic responses. Furthermore, we initiated a dosing regimen for a Cd38 inhibitor, demonstrating its potential to reduce fibrosis post-AKI, suggesting that targeting CD38hi macrophages mediated NAD+ metabolism could be a promising therapy to halt AKI to CKD progression.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"37 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143932770","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}
Molecular TherapyPub Date : 2025-05-09DOI: 10.1016/j.ymthe.2025.05.011
Rangoli Aeran,Annie Tanenhaus,Sheila M S Sears,Nathan Moerke,Adam Miller,Camille Artur,Yosr Bouhlal,Peter F Bove,Alexander Diaz de Arce,Saki Shimizu,Jason Le,Keith Place,Dixon Hoffelt,Tselmeg Amarlkhagva,Jennifer Su,Ming Chen,Brooke Babineau,John McLaughlin,Myat Soe,Warren Macdonald,I Winnie Lin,Dhruv Bole,Kristen Valentine,Elizabeth Hallam,Puja Dhanota,Serena Liu,Steven A Tan,Ben Zhao,Raghavendra Hosur,Maria Candida Vila,Suresh Poda,Archana Belle,Stephanie Tagliatela
{"title":"Neuronal-targeted gene replacement rescues multiple phenotypes of STXBP1-related disorders in mice and is well-tolerated in nonhuman primates.","authors":"Rangoli Aeran,Annie Tanenhaus,Sheila M S Sears,Nathan Moerke,Adam Miller,Camille Artur,Yosr Bouhlal,Peter F Bove,Alexander Diaz de Arce,Saki Shimizu,Jason Le,Keith Place,Dixon Hoffelt,Tselmeg Amarlkhagva,Jennifer Su,Ming Chen,Brooke Babineau,John McLaughlin,Myat Soe,Warren Macdonald,I Winnie Lin,Dhruv Bole,Kristen Valentine,Elizabeth Hallam,Puja Dhanota,Serena Liu,Steven A Tan,Ben Zhao,Raghavendra Hosur,Maria Candida Vila,Suresh Poda,Archana Belle,Stephanie Tagliatela","doi":"10.1016/j.ymthe.2025.05.011","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.05.011","url":null,"abstract":"De novo heterozygous variants in the neuronal STXBP1 gene cause severe, early-onset developmental and epileptic encephalopathy. Adeno-associated virus (AAV)-based gene replacement therapy offers the potential for a one-time, disease-modifying approach for STXBP1-related disorders. However, off-target overexpression in the liver and dorsal root ganglion (DRG) are known potential toxicities of AAV vectors. In addition, while loss of STXBP1 in GABAergic interneurons contributes to disease pathogenesis, typical gene therapy promoters do not express well in these cell populations. We engineered novel promoter cassettes to drive potent, selective STXBP1 expression across both excitatory and inhibitory neurons, and a 3'UTR regulatory element to detarget expression in DRG. Bilateral intracerebroventricular (ICV) injection of these promoter candidates achieved robust neuronal expression of STXBP1 and rescued key behavioral phenotypes in Stxbp1+/- haploinsufficient mice. In nonhuman primates, widespread vector biodistribution and transgene expression were observed in the central nervous system after unilateral ICV administration of AAV9-STXBP1 vectors. The vectors were well-tolerated, and addition of the detargeting regulatory element significantly reduced expression in DRG while ameliorating histopathologic effects and functional nerve conduction alterations. Taken together, these data support the feasibility of a one-time AAV-based therapeutic approach for STXBP1-related disorders.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"57 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143932771","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}
{"title":"Renal tubular epithelial IGFBP7 interacts with PKM2 to drive renal lipid accumulation and fibrosis.","authors":"Ju-Tao Yu,Shuai-Shuai Xie,Xiao-Yu Shen,Zeng Li,Xiao-Wei Hu,Yao Zhang,Ze-Hui Dong,Jia-Nan Wang,Xiang-Yu Li,Yu-Hang Dong,Chao Li,Ming-Lu Ji,Xiao-Guo Suo,Chen Yang,Juan Jin,Wei Wang,Jia-Gen Wen,Ming-Ming Liu,Li Li,Qin Yang,Xiao-Ming Meng","doi":"10.1016/j.ymthe.2025.05.013","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.05.013","url":null,"abstract":"Renal fibrosis serves as a critical pathological mechanism driving the progression of chronic kidney disease (CKD). However, the pathogenesis and therapeutic targets involved in this process remain unclear. Interestingly, we currently found that IGFBP7 is highly expressed in tubular epithelial cells (TECs) from the fibrotic kidneys of human patients and animal models. However, their functional roles in abnormal kidney repair and renal fibrosis remain unclear. Here, we report that IGFBP7 knockout (KO) or TEC conditional KO (cKO) attenuated renal fibrosis in multiple mouse models, whereas IGFBP7 knock-in or restoration in IGFBP7-KO mice enhanced renal fibrosis. These in vivo findings were verified using cultured TECs and organoids generated from IGFBP7-cKO mice. Mechanistically, we found that IGFBP7 bound to pyruvate kinase M2 (PKM2) to promote the acetylation of PKM2 at the K433 site, thereby enhancing PKM2 dimerization and nuclear translocation, and subsequently accelerating lipid production and renal fibrosis via SREBP1-dependent mechanisms. Notably, through drug screening, we identified salmeterol (an asthma medication) as an IGFBP7 antagonist that effectively reduced fibrosis. Our findings reveal the IGFBP7/PKM2/SREBP1 axis as a central regulator of lipogenic fibrosis, offering genetic and pharmacological inhibition of IGFBP7 as promising therapeutic strategies for CKD.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"2 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143932588","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}
Molecular TherapyPub Date : 2025-05-08DOI: 10.1016/j.ymthe.2025.05.008
Jorge Mansilla-Soto,Michael C Milone
{"title":"Concept CARs are picking up speed.","authors":"Jorge Mansilla-Soto,Michael C Milone","doi":"10.1016/j.ymthe.2025.05.008","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.05.008","url":null,"abstract":"The field of adoptive T cell immunotherapy has been dominated by a CAR design that combines antigen recognition through antibody-derived domains and signaling into a single polypeptide. This conventional design redirects the immense cytotoxic potential of T cells towards tumors, and it is the core of several commercially marketed CAR T cell products. Recent research in the field has been focused on developing more effective CAR designs especially for solid tumors. Although most approaches have layered on top of the conventional CAR design, recent studies have taken a step back and redesigned the basic CAR to retain more of the natural structure of immunoreceptors such as the TCR or killer immunoglobulin-like receptors. These redesigned CARs promote enhanced function in preclinical models compared with conventional CAR designs, including in the more challenging solid tumor setting, and several have entered the clinic with emerging data on their activity. These observations highlight the importance of considering CAR design and looking beyond conventional CARs when developing new T cell immunotherapy approaches.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"24 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926386","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}
Molecular TherapyPub Date : 2025-05-07Epub Date: 2025-03-10DOI: 10.1016/j.ymthe.2025.03.005
Kisha K Patel, Mito Tariveranmoshabad, Siddhant Kadu, Nour Shobaki, Carl June
{"title":"From concept to cure: The evolution of CAR-T cell therapy.","authors":"Kisha K Patel, Mito Tariveranmoshabad, Siddhant Kadu, Nour Shobaki, Carl June","doi":"10.1016/j.ymthe.2025.03.005","DOIUrl":"10.1016/j.ymthe.2025.03.005","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-T cell therapy has revolutionized cancer immunotherapy in the 21st century, providing innovative solutions and life-saving therapies for previously untreatable diseases. This approach has shown remarkable success in treating various hematological malignancies and is now expanding into clinical trials for solid tumors, such as prostate cancer and glioblastoma, as well as infectious and autoimmune diseases. CAR-T cell therapy involves harvesting a patient's T cells, genetically engineering them with viral vectors to express CARs targeting specific antigens and reinfusing the modified cells into the patient. These CAR-T cells function independently of major histocompatibility complex (MHC) antigen presentation, selectively identifying and eliminating target cells. This review highlights the key milestones in CAR-T cell evolution, from its invention to its clinical applications. It outlines the historical timeline leading to the invention of CAR-T cells, discusses the major achievements that have transformed them into a breakthrough therapy, and addresses remaining challenges, including high manufacturing costs, limited accessibility, and toxicity issues such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. Additionally, the review explores future directions and advances in the field, such as developing next-generation CAR-T cells aiming to maximize efficacy, minimize toxicity, and broaden therapeutic applications.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2123-2140"},"PeriodicalIF":12.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605920","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}
Molecular TherapyPub Date : 2025-05-07DOI: 10.1016/j.ymthe.2025.04.046
Tyler C Moyer, Brett A Hoffman, Weitong Chen, Ishan Shah, Xiao-Qin Ren, Tatiana Knox, Jiachen Liu, Wei Wang, Jiangyu Li, Hamza Khalid, Anupriya S Kulkarni, Munachiso Egbuchulam, Joseph Clement, Alexis Bloedel, Matthew Child, Rupinderjit Kaur, Emily Rouse, Kristin Graham, Damien Maura, Zachary Thorpe, Ambreen Sayed-Zahid, Charlotte Hiu-Yan Chung, Alexander Kutchin, Amy Johnson, Johnny Yao, Jeffrey Thompson, Nilesh Pande, Mathieu E Nonnenmacher
{"title":"Highly conserved brain vascular receptor ALPL mediates transport of engineered AAV vectors across the blood-brain barrier.","authors":"Tyler C Moyer, Brett A Hoffman, Weitong Chen, Ishan Shah, Xiao-Qin Ren, Tatiana Knox, Jiachen Liu, Wei Wang, Jiangyu Li, Hamza Khalid, Anupriya S Kulkarni, Munachiso Egbuchulam, Joseph Clement, Alexis Bloedel, Matthew Child, Rupinderjit Kaur, Emily Rouse, Kristin Graham, Damien Maura, Zachary Thorpe, Ambreen Sayed-Zahid, Charlotte Hiu-Yan Chung, Alexander Kutchin, Amy Johnson, Johnny Yao, Jeffrey Thompson, Nilesh Pande, Mathieu E Nonnenmacher","doi":"10.1016/j.ymthe.2025.04.046","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.04.046","url":null,"abstract":"<p><p>Delivery of systemically administered therapeutics to the central nervous system (CNS) is restricted by the blood-brain barrier (BBB). Bioengineered Adeno-Associated Virus (AAV) capsids have been shown to penetrate the BBB with great efficacy in mouse and non-human primate models, but their translational potential is often limited by species selectivity and undefined mechanisms of action. Here, we apply our RNA-guided TRACER AAV capsid evolution platform to generate VCAP-102, an AAV9 variant with markedly increased brain tropism following intravenous delivery in both rodents and primates. Relative to AAV9, VCAP-102 demonstrates 20- to 400-fold increased gene transfer across multiple brain regions. We identify alkaline phosphatase (ALPL) as the primary receptor used by VCAP-102 to cross the BBB and demonstrate that direct binding of VCAP-102 to human ALPL can initiate receptor-mediated transcytosis in a cell barrier model. Our work identifies VCAP-102 as a cross-species CNS gene delivery vector with a strong potential for clinical translation and establishes ALPL as a brain delivery shuttle capable of efficient BBB transport to maximize CNS delivery of biotherapeutics.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010275","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}
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
