Molecular Therapy-Methods & Clinical Development最新文献

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Bioengineering extracellular vesicle cargo for optimal therapeutic efficiency 生物工程细胞外囊泡货物,实现最佳治疗效果
IF 4.7 2区 医学
Molecular Therapy-Methods & Clinical Development Pub Date : 2024-04-26 DOI: 10.1016/j.omtm.2024.101259
Charlotte A. René, Robin J. Parks
{"title":"Bioengineering extracellular vesicle cargo for optimal therapeutic efficiency","authors":"Charlotte A. René, Robin J. Parks","doi":"10.1016/j.omtm.2024.101259","DOIUrl":"https://doi.org/10.1016/j.omtm.2024.101259","url":null,"abstract":"Extracellular vesicles (EVs) have the innate ability to carry proteins, lipids, and nucleic acids between cells, and thus these vesicles have gained much attention as potential therapeutic delivery vehicles. Many strategies have been explored to enhance the loading of specific cargoes of interest into EVs, which could result in the delivery of more therapeutic to recipient cells, thus enhancing therapeutic efficacy. In this review, we discuss the natural biogenesis of EVs, the mechanism by which proteins and nucleic acids are selected for inclusion in EVs, and novel methods that have been employed to enhance loading of specific cargoes into EVs. As well, we discuss biodistribution of administered EVs and summarize clinical trials that have attempted to harness the therapeutic potential of EVs.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"24 1","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140883186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Nanodysferlins support membrane repair and binding to TRIM72/MG53 but do not localize to t-tubules or stabilize Ca2+ signaling 纳米铁蛋白支持膜修复并与 TRIM72/MG53 结合,但不会定位到 t 型微管或稳定 Ca2+ 信号传导
IF 4.7 2区 医学
Molecular Therapy-Methods & Clinical Development Pub Date : 2024-04-26 DOI: 10.1016/j.omtm.2024.101257
Joaquin Muriel, Valeriy Lukyanenko, Thomas A. Kwiatkowski, Yi Li, Sayak Bhattacharya, Kassidy K. Banford, Daniel Garman, Hannah R. Bulgart, Roger B. Sutton, Noah Weisleder, Robert J. Bloch
{"title":"Nanodysferlins support membrane repair and binding to TRIM72/MG53 but do not localize to t-tubules or stabilize Ca2+ signaling","authors":"Joaquin Muriel, Valeriy Lukyanenko, Thomas A. Kwiatkowski, Yi Li, Sayak Bhattacharya, Kassidy K. Banford, Daniel Garman, Hannah R. Bulgart, Roger B. Sutton, Noah Weisleder, Robert J. Bloch","doi":"10.1016/j.omtm.2024.101257","DOIUrl":"https://doi.org/10.1016/j.omtm.2024.101257","url":null,"abstract":"Mutations in the gene, encoding the protein dysferlin, lead to several forms of muscular dystrophy. In healthy skeletal muscle, dysferlin concentrates in the transverse tubules and is involved in repairing the sarcolemma and stabilizing Ca signaling after membrane disruption. The gene encodes 7–8 C2 domains, several Fer and Dysf domains, and a C-terminal transmembrane sequence. Because its coding sequence is too large to package in adeno-associated virus, the full-length sequence is not amendable to current gene delivery methods. Thus, we have examined smaller versions of dysferlin, termed “nanodysferlins,” designed to eliminate several C2 domains, specifically C2 domains D, E, and F; B, D, and E; and B, D, E, and F. We also generated a variant by replacing eight amino acids in C2G in the nanodysferlin missing domains D through F. We electroporated dysferlin-null A/J mouse myofibers with Venus fusion constructs of these variants, or as untagged nanodysferlins together with GFP, to mark transfected fibers We found that, although these nanodysferlins failed to concentrate in transverse tubules, three of them supported membrane repair after laser wounding while all four bound the membrane repair protein, TRIM72/MG53, similar to WT dysferlin. By contrast, they failed to suppress Ca waves after myofibers were injured by mild hypoosmotic shock. Our results suggest that the internal C2 domains of dysferlin are required for normal t-tubule localization and Ca signaling and that membrane repair does not require these C2 domains.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"25 1","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140889716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Epigenetic control of multiple genes with a single lentiviral vector encoding transcriptional repressors fused to compact zinc finger arrays 用编码与紧凑型锌指阵列融合的转录抑制因子的单个慢病毒载体对多个基因进行表观遗传控制
IF 4.7 2区 医学
Molecular Therapy-Methods & Clinical Development Pub Date : 2024-04-24 DOI: 10.1016/j.omtm.2024.101255
Davide Monteferrario, Marion David, Satish K. Tadi, Yuanyue Zhou, Irène Marchetti, Caroline Jeanneau, Gaëlle Saviane, Coralie F. Dupont, Angélique E. Martelli, Lynn N. Truong, Jason A. Eshleman, Colman C. Ng, Marshall W. Huston, Gregory D. Davis, Jason D. Fontenot, Andreas Reik, Maurus de la Rosa, David Fenard
{"title":"Epigenetic control of multiple genes with a single lentiviral vector encoding transcriptional repressors fused to compact zinc finger arrays","authors":"Davide Monteferrario, Marion David, Satish K. Tadi, Yuanyue Zhou, Irène Marchetti, Caroline Jeanneau, Gaëlle Saviane, Coralie F. Dupont, Angélique E. Martelli, Lynn N. Truong, Jason A. Eshleman, Colman C. Ng, Marshall W. Huston, Gregory D. Davis, Jason D. Fontenot, Andreas Reik, Maurus de la Rosa, David Fenard","doi":"10.1016/j.omtm.2024.101255","DOIUrl":"https://doi.org/10.1016/j.omtm.2024.101255","url":null,"abstract":"Gene silencing without gene editing holds great potential for the development of safe therapeutic applications. Here, we describe a novel strategy to concomitantly repress multiple genes using zinc finger proteins fused to Krüppel-Associated Box repression domains (ZF-Rs). This was achieved via the optimization of a lentiviral system tailored for the delivery of ZF-Rs in hematopoietic cells. We showed that an optimal design of the lentiviral backbone is crucial to multiplex up to three ZF-Rs or two ZF-Rs and a chimeric antigen receptor. ZF-R expression had no impact on the integrity and functionality of transduced cells. Furthermore, gene repression in ZF-R-expressing T cells was highly efficient and during the entire monitoring period (up to 10 weeks), and it was accompanied by epigenetic remodeling events. Finally, we described an approach to improve ZF-R specificity to illustrate the path toward the generation of ZF-Rs with a safe clinical profile. In conclusion, we successfully developed an epigenetic-based cell engineering approach for concomitant modulation of multiple gene expressions that bypass the risks associated with DNA editing.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"17 1","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140841572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Metabolic priming of GD2 TRAC-CAR T cells during manufacturing promotes memory phenotypes while enhancing persistence 在制造过程中对 GD2 TRAC-CAR T 细胞进行代谢引物处理可促进记忆表型,同时增强持久性
IF 4.7 2区 医学
Molecular Therapy-Methods & Clinical Development Pub Date : 2024-04-10 DOI: 10.1016/j.omtm.2024.101249
Dan Cappabianca, Dan Pham, Matthew H. Forsberg, Madison Bugel, Anna Tommasi, Anthony Lauer, Jolanta Vidugiriene, Brookelyn Hrdlicka, Alexandria McHale, Quaovi Sodji, Melissa C. Skala, Christian M. Capitini, Krishanu Saha
{"title":"Metabolic priming of GD2 TRAC-CAR T cells during manufacturing promotes memory phenotypes while enhancing persistence","authors":"Dan Cappabianca, Dan Pham, Matthew H. Forsberg, Madison Bugel, Anna Tommasi, Anthony Lauer, Jolanta Vidugiriene, Brookelyn Hrdlicka, Alexandria McHale, Quaovi Sodji, Melissa C. Skala, Christian M. Capitini, Krishanu Saha","doi":"10.1016/j.omtm.2024.101249","DOIUrl":"https://doi.org/10.1016/j.omtm.2024.101249","url":null,"abstract":"Manufacturing chimeric antigen receptor (CAR) T cell therapies is complex, with limited understanding of how medium composition impacts T cell phenotypes. CRISPR-Cas9 ribonucleoproteins can precisely insert a CAR sequence while disrupting the endogenous T cell receptor alpha constant () gene resulting in -CAR T cells with an enriched stem cell memory T cell population, a process that could be further optimized through modifications to the medium composition. In this study we generated anti-GD2 -CAR T cells using \"metabolic priming\" (MP), where the cells were activated in glucose/glutamine-low medium and then expanded in glucose/glutamine-high medium. T cell products were evaluated using spectral flow cytometry, metabolic assays, cytokine production, cytotoxicity assays , and potency against human GD2+ xenograft neuroblastoma models . Compared with standard -CAR T cells, MP -CAR T cells showed less glycolysis, higher CCR7/CD62L expression, more bound NAD(P)H activity, and reduced IFN-γ, IL-2, IP-10, IL-1β, IL-17, and TGF-β production at the end of manufacturing , with increased central memory CAR T cells and better persistence observed . MP with medium during CAR T cell biomanufacturing can minimize glycolysis and enrich memory phenotypes , which could lead to better responses against solid tumors .","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"140 1","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140636895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Dose-response evaluation of intravenous gene therapy in a symptomatic mouse model of metachromatic leukodystrophy 变色性白质营养不良症无症状小鼠模型中静脉注射基因疗法的剂量-反应评估
IF 4.7 2区 医学
Molecular Therapy-Methods & Clinical Development Pub Date : 2024-04-06 DOI: 10.1016/j.omtm.2024.101248
Emilie Audouard, Nicolas Khefif, Charlotte Mansat, Océane Nelcha, Elena-Gaia Banchi, Camille Lupiet, Dominique Farabos, Antonin Lamaziere, Caroline Sevin, Françoise Piguet
{"title":"Dose-response evaluation of intravenous gene therapy in a symptomatic mouse model of metachromatic leukodystrophy","authors":"Emilie Audouard, Nicolas Khefif, Charlotte Mansat, Océane Nelcha, Elena-Gaia Banchi, Camille Lupiet, Dominique Farabos, Antonin Lamaziere, Caroline Sevin, Françoise Piguet","doi":"10.1016/j.omtm.2024.101248","DOIUrl":"https://doi.org/10.1016/j.omtm.2024.101248","url":null,"abstract":"Metachromatic leukodystrophy (MLD) is a rare, autosomal recessive neurodegenerative disease caused by deficient activity of the lysosomal enzyme arylsulfatase A (ARSA), resulting in sulfatide accumulation and subsequent demyelination and neuronal damage within the central and peripheral nervous systems. Three clinical forms of MLD have been described, based on age at symptom onset. The most frequent and severe forms have an early onset, with the disease progressing rapidly toward severe motor and cognitive regression and ultimately premature death. There are currently no approved therapies for most of these early-onset patients once symptoms are present. Thus, it is crucial to develop new approaches to treat symptomatic patients. Here, we proposed a gene therapy approach based on the intravenous delivery of AAVPHP.eB encoding ARSA. MLD mice were treated at 6 months for a dose-response study and at 9 months to assess late-treatment efficacy. Therapeutic efficacy was evaluated 3 or 6 months after injection. We demonstrated a broad transduction in the central nervous system, a complete correction of sulfatide storage, and a significant improvement in neuroinflammation at low dose and late treatment. Taken together, this work establishes a strong rationale for proposing a phase I/II clinical trial in MLD patients.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"79 1","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140569379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
An investigation of the immune epitope properties of adeno-associated virus capsid-derived peptides among hemophilia patients 对血友病患者腺相关病毒壳衍生肽免疫表位特性的调查
IF 4.7 2区 医学
Molecular Therapy-Methods & Clinical Development Pub Date : 2024-04-02 DOI: 10.1016/j.omtm.2024.101245
Li Liu, Bingqi Xu, Lingling Chen, Jia Liu, Wei Liu, Feng Xue, Sizhou Feng, Erlie Jiang, Mingzhe Han, Wenwei Shao, Lei Zhang, Xiaolei Pei
{"title":"An investigation of the immune epitope properties of adeno-associated virus capsid-derived peptides among hemophilia patients","authors":"Li Liu, Bingqi Xu, Lingling Chen, Jia Liu, Wei Liu, Feng Xue, Sizhou Feng, Erlie Jiang, Mingzhe Han, Wenwei Shao, Lei Zhang, Xiaolei Pei","doi":"10.1016/j.omtm.2024.101245","DOIUrl":"https://doi.org/10.1016/j.omtm.2024.101245","url":null,"abstract":"Adeno-associated virus (AAV) is an optimal gene vector for monogenic disorders. However, neutralizing antibodies (Nabs) against AAV hinder its widespread application in gene therapy. In this study, we biosynthesized peptides recognized by the binding antibodies (Babs) from the sera containing high Nab titers against AAV2. We established four immunological methods to detect immune epitopes of the AAV2-derived peptides, including a Bab assay, Nab assay, B cell receptor (BCR) detecting assay, and immunoglobin-producing B cell enzyme-linked immunosorbent spot (B cell ELISpot) assay. Correlations among the epitopes determined by these four methods were analyzed using the serum samples and peripheral blood mononuclear cells from 89 patients with hemophilia A/B. As decoys, the peptides’ ability to block the Nab of AAV2 particles was assessed using AAV transduction models both and . Overall, we provide insights into AAV2-capsid-derived peptide immune epitopes, involving the Nab, Bab, BCR, and B cell ELISpot assays, offering alternative immunological evaluation approaches and strategies to overcome Nab barriers in AAV-mediated gene therapy.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"13 1","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140569378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Subretinal AAV delivery of RNAi-therapeutics targeting VEGFA reduces choroidal neovascularization in a large animal model 在大型动物模型中,视网膜下 AAV 释放靶向 VEGFA 的 RNAi- 治疗药物可减少脉络膜新生血管的形成
IF 4.7 2区 医学
Molecular Therapy-Methods & Clinical Development Pub Date : 2024-03-22 DOI: 10.1016/j.omtm.2024.101242
Silja Hansen Haldrup, Bjørn K. Fabian-Jessing, Thomas Stax Jakobsen, Anna Bøgh Lindholm, Rikke L. Adsersen, Lars Aagaard, Toke Bek, Anne Louise Askou, Thomas J. Corydon
{"title":"Subretinal AAV delivery of RNAi-therapeutics targeting VEGFA reduces choroidal neovascularization in a large animal model","authors":"Silja Hansen Haldrup, Bjørn K. Fabian-Jessing, Thomas Stax Jakobsen, Anna Bøgh Lindholm, Rikke L. Adsersen, Lars Aagaard, Toke Bek, Anne Louise Askou, Thomas J. Corydon","doi":"10.1016/j.omtm.2024.101242","DOIUrl":"https://doi.org/10.1016/j.omtm.2024.101242","url":null,"abstract":"Neovascular age-related macular degeneration (nAMD) is a frequent cause of vision loss among the elderly in the Western world. Current disease management with repeated injections of anti-VEGF agents accumulates the risk for adverse events and constitutes a burden for society and the individual patient. Sustained suppression of VEGF using gene therapy is an attractive alternative, which we explored using adeno-associated virus (AAV)-based delivery of novel RNA interference (RNAi) effectors in a porcine model of choroidal neovascularization (CNV). The potency of -targeting, Ago2-dependent short hairpin RNAs placed in pri-microRNA scaffolds (miR-agshRNA) was established and in mice. Subsequently, AAV serotype 8 (AAV2.8) vectors encoding -targeting or irrelevant miR-agshRNAs under the control of a tissue-specific promotor were delivered to the porcine retina via subretinal injection before CNV induction by laser. Notably, -targeting miR-agshRNAs resulted in a significant and sizable reduction of CNV compared with the non-targeting control. We also demonstrated that single-stranded and self-complementary AAV2.8 vectors efficiently transduce porcine retinal pigment epithelium cells but differ in their transduction characteristics and retinal safety. Collectively, our data demonstrated a robust anti-angiogenic effect of -targeting miR-aghsRNAs in a large translational animal model, thereby suggesting AAV-based delivery of anti-VEGFA RNAi therapeutics as a valuable tool for the management of nAMD.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"115 1","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140569733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Combining CRISPR/Cas mediated terminal resolution with a novel genetic workflow to achieve high-diversity adenoviral libraries 将 CRISPR/Cas 介导的末端解析与新型遗传学工作流程相结合,实现高多样性腺病毒文库
IF 4.7 2区 医学
Molecular Therapy-Methods & Clinical Development Pub Date : 2024-03-18 DOI: 10.1016/j.omtm.2024.101241
Julian Fischer, Ariana Fedotova, Lena Jaki, Erwan Sallard, Anja Erhardt, Jonas Fuchs, Zsolt Ruzsics
{"title":"Combining CRISPR/Cas mediated terminal resolution with a novel genetic workflow to achieve high-diversity adenoviral libraries","authors":"Julian Fischer, Ariana Fedotova, Lena Jaki, Erwan Sallard, Anja Erhardt, Jonas Fuchs, Zsolt Ruzsics","doi":"10.1016/j.omtm.2024.101241","DOIUrl":"https://doi.org/10.1016/j.omtm.2024.101241","url":null,"abstract":"While recombinant Adenoviruses are widely used in both laboratory and medical gene transfer, library-based applications using this vector platform are not readily available. Recently, we developed a new method, the CRISPR/Cas9 mediated terminal resolution aiding high-efficiency rescue of recombinant Adenoviruses from recombinant DNA. Here we report on a genetic workflow that allows construction of BAC-based recombinant Adenoviruses libraries reconstituted using highly efficient terminal resolution. We utilized frequent, pre-existing genomic sequences to allow the insertion of a selection marker, complementing two selected target sites into novel endonuclease recognition sites. In the second step, this selection marker is replaced with a transgene or mutation of interest via Gibson assembly. Our approach does not cause unwanted genomic off-target mutations while providing substantial flexibility for the site and nature of the genetic modification. This new genetic workflow, which we termed half-site directed fragment replacement allows the introduction of >10ˆ6 unique modifications into rAd encoding BACs using laboratory scale methodology. To demonstrate the power of HFR, we rescued barcoded viral vector libraries yielding a diversity of ∼2.5x10ˆ4 unique recombinant Adenoviruses per cmˆ2 of transfected cell culture.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"126 1","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140150515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Strengthening health systems for access to gene therapy in rare genetic disorders 加强卫生系统,促进罕见遗传疾病的基因治疗
IF 4.7 2区 医学
Molecular Therapy-Methods & Clinical Development Pub Date : 2024-03-13 DOI: 10.1016/j.omtm.2024.101220
Sonal Bhatia, Yann Le Cam, Juan Carrion, Lauren Diamond, Paul Fennessy, Safiyya Gassman, Felix Gutzwiller, Stephen Kagan, Diana Pankevich, Jennifer Young Maloney, Nitin Mahadev, Martin Schulz, Durhane Wong-Rieger, Paolo Morgese
{"title":"Strengthening health systems for access to gene therapy in rare genetic disorders","authors":"Sonal Bhatia, Yann Le Cam, Juan Carrion, Lauren Diamond, Paul Fennessy, Safiyya Gassman, Felix Gutzwiller, Stephen Kagan, Diana Pankevich, Jennifer Young Maloney, Nitin Mahadev, Martin Schulz, Durhane Wong-Rieger, Paolo Morgese","doi":"10.1016/j.omtm.2024.101220","DOIUrl":"https://doi.org/10.1016/j.omtm.2024.101220","url":null,"abstract":"","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"2013 1","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140156559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
AAV-delivered hepato-adrenal cooperativity in steroidogenesis: implications for gene therapy for congenital adrenal hyperplasia 类固醇生成过程中的肝-肾协同作用:先天性肾上腺皮质增生症基因疗法的意义
IF 4.7 2区 医学
Molecular Therapy-Methods & Clinical Development Pub Date : 2024-03-12 DOI: 10.1016/j.omtm.2024.101232
Lara E. Graves, Eva B. van Dijk, Erhua Zhu, Sundar Koyyalamudi, Tiffany Wotton, Dinah Sung, Shubha Srinivasan, Samantha L. Ginn, Ian E. Alexander
{"title":"AAV-delivered hepato-adrenal cooperativity in steroidogenesis: implications for gene therapy for congenital adrenal hyperplasia","authors":"Lara E. Graves, Eva B. van Dijk, Erhua Zhu, Sundar Koyyalamudi, Tiffany Wotton, Dinah Sung, Shubha Srinivasan, Samantha L. Ginn, Ian E. Alexander","doi":"10.1016/j.omtm.2024.101232","DOIUrl":"https://doi.org/10.1016/j.omtm.2024.101232","url":null,"abstract":"Despite the availability of life-saving corticosteroids for 70 years, treatment for adrenal insufficiency is not able to recapitulate physiological diurnal cortisol secretion and results in numerous complications. Gene therapy is an attractive possibility for monogenic adrenocortical disorders such as congenital adrenal hyperplasia, however, requires further development of gene transfer/editing technologies and knowledge of the target progenitor cell populations. Vectors based on adeno-associated virus are the leading system for direct gene delivery but have limitations in targeting replicating cell populations such as in the adrenal cortex. One strategy to overcome this technological limitation is to deliver the relevant adrenocortical gene to a currently targetable organ outside of the adrenal cortex. To explore this possibility, we developed a vector encoding human 21-hydroxylase and directed expression to the liver in a mouse model of congenital adrenal hyperplasia. This extra-adrenal expression resulted in reconstitution of the steroidogenic pathway. Aldosterone and renin levels normalised, and corticosterone levels improved sufficiently to reduce adrenal hyperplasia. This strategy could provide an alternative treatment option for monogenic adrenal disorders, particularly for mineralocorticoid defects. These findings also demonstrate, when targeting the adrenal gland, that inadvertent liver transduction should be precluded as it may confound data interpretation.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"49 1","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140156554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
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