Molecular Therapy最新文献_第2页

A fantastically encapsulated idea. 一个奇妙的想法。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-04-18 DOI: 10.1016/j.ymthe.2025.04.013

Matthew Campbell, Thomas Ritter

引用次数: 0

Gene therapy for hemophilia - From basic science to first approvals of "one-and-done" therapies. 血友病的基因治疗-从基础科学到“一次性”疗法的首次批准。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-03-27 DOI: 10.1016/j.ymthe.2025.03.043

Roland W Herzog, Radoslaw Kaczmarek, Katherine A High

{"title":"Gene therapy for hemophilia - From basic science to first approvals of \"one-and-done\" therapies.","authors":"Roland W Herzog, Radoslaw Kaczmarek, Katherine A High","doi":"10.1016/j.ymthe.2025.03.043","DOIUrl":"10.1016/j.ymthe.2025.03.043","url":null,"abstract":"Realistic paths to gene therapy for the X-linked bleeding disorder hemophilia started to materialize in the mid 1990s, resulting in disease correction in small and large animal models. Out of a diversity of approaches, in vivo adeno-associated viral (AAV) gene transfer to hepatocytes emerged as the most promising strategy, eventually forming the basis for multiple advanced clinical trials and regulatory approval of two products for the treatment of hemophilia B (coagulation factor IX deficiency) and one for hemophilia A (factor VIII deficiency). Ideally, gene therapy is effective with a single administration, thus providing therapeutic factor levels over a period of years, without the need for frequent injections. Overcoming multiple obstacles, some not predicted by preclinical studies, sustained partial to complete correction of coagulation for several years to an entire decade has now been documented in patients, with observation ongoing. A hyperactive form of FIX improved efficacy in hemophilia B, and superior engineered variants of FVIII are emerging. Nonetheless, challenges remain, including pre-existing immunity to AAV capsids, toxicities, inter-patient variability in response to treatment, and difficulty in obtaining durable therapeutic expression of FVIII. In alternative approaches, in vivo gene editing and ex vivo gene therapies targeting hemopoietic cells are in development.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2015-2034"},"PeriodicalIF":12.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743070","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}

引用次数: 0

FLT201, a novel liver-directed AAV gene therapy candidate for Gaucher disease Type 1. FLT201，一种新的肝靶向AAV基因治疗戈谢病1型的候选药物。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-05-07 DOI: 10.1016/j.ymthe.2025.05.003

Fabrizio Comper,Carlos J Miranda,Benjamin Liou,Tihomir Dodev,Jey M Jeyakumar,Miriam Canavese,Clement Cocita,Khashayar Khoshrou,Gustavo Tiscornia,Elisa Chisari,Emmaline Stotter,Erald Shehu,Sudharsan Sridharan,I-Mei Yu,Jalpa Pandya,Jaminder Khinder,Natalie Northcott,Petya Kalcheva,Samantha Correia,Ying Sun,Allison Dane,Rose Sheridan,Amit C Nathwani,Romuald Corbau

{"title":"FLT201, a novel liver-directed AAV gene therapy candidate for Gaucher disease Type 1.","authors":"Fabrizio Comper,Carlos J Miranda,Benjamin Liou,Tihomir Dodev,Jey M Jeyakumar,Miriam Canavese,Clement Cocita,Khashayar Khoshrou,Gustavo Tiscornia,Elisa Chisari,Emmaline Stotter,Erald Shehu,Sudharsan Sridharan,I-Mei Yu,Jalpa Pandya,Jaminder Khinder,Natalie Northcott,Petya Kalcheva,Samantha Correia,Ying Sun,Allison Dane,Rose Sheridan,Amit C Nathwani,Romuald Corbau","doi":"10.1016/j.ymthe.2025.05.003","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.05.003","url":null,"abstract":"Gaucher disease Type 1 (GD1) is caused by mutations in the GBA1 gene, which result in deficient enzyme β-glucocerebrosidase (GCase) activity and production with the harmful accumulation of the lipid substrate glucocerebroside. Replacement of GCase is current standard-of-care for GD1; however, GCase has a relatively short active half-life at both physiological and lysosomal pH and biweekly intravenous administration does not provide a consistent exposure to active enzyme. FLT201 is the first AAV gene therapy in clinical trials for treatment of GD1. FLT201 consists of a rationally designed AAV capsid (AAVS3) containing an expression cassette with an engineered GBA1 transgene that encodes a unique glucocerebrosidase variant (GCase85). GCase-85 includes an engineered disulfide, which results in a >6-fold increase in active half-life in human serum and a >21-fold increase in active half-life at lysosomal pH conditions, with similar catalytic properties to those of wild-type and exogenous GCase. Preclinical data indicates that FLT201 could offer a durable treatment for Gaucher disease Type 1, addressing unmet needs related to substrate accumulation in tissues poorly treated by current enzyme replacement therapy. The improved stability of the engineered GCase85 variant is predicted to be crucial for FLT201's therapeutic effectiveness.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"120 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926389","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}

引用次数: 0

Progress in skin gene therapy: From the inside and out. 皮肤基因治疗的进展：从内到外。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-03-12 DOI: 10.1016/j.ymthe.2025.03.017

Mark J Osborn, Sidharth Panda, Theresa M Reineke, Jakub Tolar, Alexander Nyström

{"title":"Progress in skin gene therapy: From the inside and out.","authors":"Mark J Osborn, Sidharth Panda, Theresa M Reineke, Jakub Tolar, Alexander Nyström","doi":"10.1016/j.ymthe.2025.03.017","DOIUrl":"10.1016/j.ymthe.2025.03.017","url":null,"abstract":"The skin is the largest organ of the body and forms and serves as the barrier for preventing external material from accessing and damaging internal organs. As the outward interface to the environment, it is accessible for the application of therapeutic agents and cellular and gene therapy represent attractive and promising options to treat severe genetic conditions for which palliation has long been the main stay. However, because of its barrier function, transit across and to the subdermal compartment can be challenging. This commentary examines the current approaches of cell and gene therapies for genetic skin disorders. We write this from a local and systemic \"outside and inside.\" perspective. Delivery from the outside encompasses topical, intradermal, and transdermal strategies for cell and vector delivery and ex vivo cell expansion and grafting. The inside approach details systemic delivery via infusion of cells or agents toward providing benefit to the skin. We use recessive dystrophic epidermolysis bullosa (RDEB) as a representative and paradigmatic disease to showcase these approaches as a means to highlight potential broader applicability to other conditions.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2065-2081"},"PeriodicalIF":12.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143616154","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}

引用次数: 0

Recent developments in gene therapy for Parkinson's disease. 帕金森病基因疗法的最新进展。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-03-22 DOI: 10.1016/j.ymthe.2025.03.030

Sandor Szunyogh, Emily Carroll, Richard Wade-Martins

{"title":"Recent developments in gene therapy for Parkinson's disease.","authors":"Sandor Szunyogh, Emily Carroll, Richard Wade-Martins","doi":"10.1016/j.ymthe.2025.03.030","DOIUrl":"10.1016/j.ymthe.2025.03.030","url":null,"abstract":"Parkinson's disease (PD) is a progressive, neurodegenerative disorder for which there is currently no cure. Gene therapy has emerged as a novel approach offering renewed hope for the development of treatments that meaningfully alter the course of the disease. In this review, we explore various gene therapy strategies currently being developed targeting key aspects of PD pathogenesis: the restoration of the dopamine system by delivering genes involved in dopamine biosynthesis, reinforcing the inhibitory signaling pathways through glutamic acid decarboxylase (GAD) delivery to increase GABA production, enhancing neuronal survival and development by introducing various neurotrophic factors, delivery of genes to complement recessive familial PD mutations to correct mitochondrial dysfunction, restoring lysosomal function through delivery of GBA1 to increase glucocerebrosidase (GCase) activity, and reducing α-synuclein levels by reducing or silencing SNCA expression. Despite promising early work, challenges remain in developing safe, effective, and long-lasting gene therapies. Key considerations include optimizing viral vectors for targeted delivery, achieving controlled and sustained gene expression using different promoters, minimizing immune responses, and increasing transgene delivery capacity. Future prospects may involve combinatory strategies targeting multiple pathways, such as multi-gene constructs delivered via high-capacity viral systems.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2052-2064"},"PeriodicalIF":12.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692719","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}

引用次数: 0

Machine learning approaches enable the discovery of therapeutics across domains. 机器学习方法可以跨领域发现治疗方法。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-04-03 DOI: 10.1016/j.ymthe.2025.04.001

Prabal Chhibbar, Jishnu Das

引用次数: 0

How to democratize cell and gene therapy: A global approach. 如何使细胞和基因治疗民主化：全球方法。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-04-02 DOI: 10.1016/j.ymthe.2025.03.061

Rayne H Rouce, Bambi J Grilley

{"title":"How to democratize cell and gene therapy: A global approach.","authors":"Rayne H Rouce, Bambi J Grilley","doi":"10.1016/j.ymthe.2025.03.061","DOIUrl":"10.1016/j.ymthe.2025.03.061","url":null,"abstract":"Over the past 25 years, the field of cell and gene therapy has grown substantially, with almost 50 therapies approved in the United States to treat severe, often life-threatening diseases. Despite clinical successes, the high costs and complex manufacturing and delivery requirements of cell and gene therapies (CGTs) present significant challenges to their broad use and equitable access. Disparities in access to CGTs range from financial constraints to infrastructure limitations and regulatory hurdles. As CGT trials expand globally, innovative strategies are needed to address these inequities, including alternative manufacturing models, harmonizing regulatory requirements, and innovative payment structures to replace the high up-front cost of current treatments. Addressing barriers like lack of infrastructure-stem cell processing and specialized personnel, for example-will be necessary to increase global CGT access and requires a multi-stakeholder approach. Academic, pharmaceutical, government, and nonprofit entities must cooperate to develop a more sustainable model for CGTs. Additionally, new university-led and public-private partnerships aim to facilitate access in underserved populations. To achieve equitable global access, a comprehensive strategy must involve innovative manufacturing, education, regulatory alignment, and stakeholder engagement, while ensuring that CGTs are both accessible and affordable to those who would benefit most from them.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2082-2090"},"PeriodicalIF":12.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780232","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}

引用次数: 0

Current and future treatments for sickle cell disease: From hematopoietic stem cell transplantation to in vivo gene therapy. 镰状细胞病目前和未来的治疗方法——从造血干细胞移植到体内基因治疗。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-03-12 DOI: 10.1016/j.ymthe.2025.03.016

Julia Ball, Avery Bradley, Anh Le, John F Tisdale, Naoya Uchida

{"title":"Current and future treatments for sickle cell disease: From hematopoietic stem cell transplantation to in vivo gene therapy.","authors":"Julia Ball, Avery Bradley, Anh Le, John F Tisdale, Naoya Uchida","doi":"10.1016/j.ymthe.2025.03.016","DOIUrl":"10.1016/j.ymthe.2025.03.016","url":null,"abstract":"Sickle cell disease (SCD) is a single-gene disorder caused by a point mutation of the β-globin gene, resulting in hemolytic anemia, acute pain, multiorgan damage, and early mortality. Hydroxyurea is a first-line drug therapy that switches sickle-globin to non-pathogenic γ-globin; however, it requires lifelong oral administration. Allogeneic hematopoietic stem cell (HSC) transplantation allows for a one-time cure for SCD, albeit with histocompatibility limitations. Therefore, autologous HSC gene therapy was developed to cure SCD in a single treatment, without HSC donors. Current HSC gene therapy is based on the ex vivo culture of patients' HSCs with lentiviral gene addition and gene editing, followed by autologous transplantation back to the patient. However, the complexity of the treatment process and high costs hinder the universal application of ex vivo gene therapy. Therefore, the development of in vivo HSC gene therapy, where gene therapy tools are directly administered to patients, is desirable to provide a more accessible, cost-effective solution that can cure SCD worldwide. In this review, we discuss current treatments, including drug therapies, HSC transplantation, and ex vivo gene therapy; the development of gene therapy tools; and progress toward curative in vivo gene therapy in SCD.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2172-2191"},"PeriodicalIF":12.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625483","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}

引用次数: 0

Advances in AAV capsid engineering: Integrating rational design, directed evolution and machine learning. AAV 胶囊工程的进展：整合合理设计、定向进化和机器学习。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-04-01 DOI: 10.1016/j.ymthe.2025.03.056

Alan M Nisanov, Julio A Rivera de Jesús, David V Schaffer

引用次数: 0

Genome editing strategies for targeted correction of β-globin mutation in sickle cell disease: From bench to bedside. 镰状细胞病β-珠蛋白突变靶向校正的基因组编辑策略：从实验室到床边。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-03-30 DOI: 10.1016/j.ymthe.2025.03.047

Henna Butt, Shruti Sathish, Evan London, Taylor Lee Johnson, Khaled Essawi, Alexis Leonard, John F Tisdale, Selami Demirci

{"title":"Genome editing strategies for targeted correction of β-globin mutation in sickle cell disease: From bench to bedside.","authors":"Henna Butt, Shruti Sathish, Evan London, Taylor Lee Johnson, Khaled Essawi, Alexis Leonard, John F Tisdale, Selami Demirci","doi":"10.1016/j.ymthe.2025.03.047","DOIUrl":"10.1016/j.ymthe.2025.03.047","url":null,"abstract":"Sickle cell disease (SCD) includes a range of genotypes that result in a clinical syndrome, where abnormal red blood cell (RBC) physiology leads to widespread complications affecting nearly every organ system. Treatment strategies for SCD can be broadly categorized into disease-modifying therapies and those aimed toward a cure. Although several disease-modifying drugs have been approved, they do not fully address the complexity and severity of SCD. Recent advances in allogeneic transplantation and autologous gene therapy show promising outcomes in terms of efficacy and safety. While these approaches have improved the lives of many patients, achieving a durable and comprehensive cure for all remains challenging. To address this, gene-editing technologies, including zinc-finger nucleases, TALENs, CRISPR-Cas, base editing, and prime editing, have been explored both ex vivo and in vivo for targeted correction of the β-globin gene (HBB) in SCD. However, direct correction of HBB and its translation from the laboratory to the clinic presents ongoing limitations, with challenges involved in achieving robust mutation-correction efficiency, off-target effects, and high costs of therapies. The optimal strategy for curing SCD remains uncertain, but several promising approaches are emerging. This review touches on past, present, and future developments in HBB correction.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2154-2171"},"PeriodicalIF":12.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753680","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}

引用次数: 0