Gene Therapy最新文献_第10页

Implications of maternal-fetal health on perinatal stem cell banking 母婴健康对围产期干细胞库的影响。

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-10-26 DOI: 10.1038/s41434-023-00426-w

Dandan Zhu, Mehri Barabadi, Courtney McDonald, Gina Kusuma, Ishmael Miguel Inocencio, Rebecca Lim

引用次数: 0

Prednisolone and rapamycin reduce the plasma cell gene signature and may improve AAV gene therapy in cynomolgus macaques 泼尼松龙和雷帕霉素降低了食蟹猴的浆细胞基因特征，并可能改善AAV基因治疗。

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-10-13 DOI: 10.1038/s41434-023-00423-z

Alexander Kistner, Jessica A. Chichester, Lili Wang, Roberto Calcedo, Jenny A. Greig, Leah N. Cardwell, Margaret C. Wright, Julien Couthouis, Sunjay Sethi, Brian E. McIntosh, Kathleen McKeever, Samuel Wadsworth, James M. Wilson, Emil Kakkis, Barbara A. Sullivan

{"title":"Prednisolone and rapamycin reduce the plasma cell gene signature and may improve AAV gene therapy in cynomolgus macaques","authors":"Alexander Kistner, Jessica A. Chichester, Lili Wang, Roberto Calcedo, Jenny A. Greig, Leah N. Cardwell, Margaret C. Wright, Julien Couthouis, Sunjay Sethi, Brian E. McIntosh, Kathleen McKeever, Samuel Wadsworth, James M. Wilson, Emil Kakkis, Barbara A. Sullivan","doi":"10.1038/s41434-023-00423-z","DOIUrl":"10.1038/s41434-023-00423-z","url":null,"abstract":"Adeno-associated virus (AAV) vector gene therapy is a promising approach to treat rare genetic diseases; however, an ongoing challenge is how to best modulate host immunity to improve transduction efficiency and therapeutic outcomes. This report presents two studies characterizing multiple prophylactic immunosuppression regimens in male cynomolgus macaques receiving an AAVrh10 gene therapy vector expressing human coagulation factor VIII (hFVIII). In study 1, no immunosuppression was compared with prednisolone, rapamycin (or sirolimus), rapamycin and cyclosporin A in combination, and cyclosporin A and azathioprine in combination. Prednisolone alone demonstrated higher mean peripheral blood hFVIII expression; however, this was not sustained upon taper. Anti-capsid and anti-hFVIII antibody responses were robust, and vector genomes and transgene mRNA levels were similar to no immunosuppression at necropsy. Study 2 compared no immunosuppression with prednisolone alone or in combination with rapamycin or methotrexate. The prednisolone/rapamycin group demonstrated an increase in mean hFVIII expression and a mean delay in anti-capsid IgG development until after rapamycin taper. Additionally, a significant reduction in the plasma cell gene signature was observed with prednisolone/rapamycin, suggesting that rapamycin’s tolerogenic effects may include plasma cell differentiation blockade. Immunosuppression with prednisolone and rapamycin in combination could improve therapeutic outcomes in AAV vector gene therapy.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 3-4","pages":"128-143"},"PeriodicalIF":5.1,"publicationDate":"2023-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-023-00423-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41198902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

p53 dry gene powder enhances anti-cancer effects of chemotherapy against malignant pleural mesothelioma p53干基因粉增强化疗对恶性胸膜间皮瘤的抗癌作用。

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-10-13 DOI: 10.1038/s41434-023-00424-y

Naomi Muramatsu, Misa Ichikawa, Tomoko Katagiri, Yumi Taguchi, Takashi Hatanaka, Tomoyuki Okuda, Hirokazu Okamoto

引用次数: 0

Artificial microRNA suppresses C9ORF72 variants and decreases toxic dipeptide repeat proteins in vivo 人工微小RNA在体内抑制C9ORF72变体并降低毒性二肽重复蛋白。

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-09-26 DOI: 10.1038/s41434-023-00418-w

Gabriela Toro Cabrera, Katharina E. Meijboom, Abbas Abdallah, Helene Tran, Zachariah Foster, Alexandra Weiss, Nicholas Wightman, Rachel Stock, Tania Gendron, Alisha Gruntman, Anthony Giampetruzzi, Leonard Petrucelli, Robert H. Brown Jr, Christian Mueller

引用次数: 0

Long-term effects of a fat-directed FGF21 gene therapy in aged female mice 脂肪导向的FGF21基因治疗对老年雌性小鼠的长期影响。

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-09-12 DOI: 10.1038/s41434-023-00422-0

Jacqueline M. Anderson, W. David Arnold, Wei Huang, Alissa Ray, Gregory Owendoff, Lei Cao

{"title":"Long-term effects of a fat-directed FGF21 gene therapy in aged female mice","authors":"Jacqueline M. Anderson, W. David Arnold, Wei Huang, Alissa Ray, Gregory Owendoff, Lei Cao","doi":"10.1038/s41434-023-00422-0","DOIUrl":"10.1038/s41434-023-00422-0","url":null,"abstract":"Fibroblast growth factor 21 (FGF21) has been developed as a potential therapeutic agent for metabolic syndromes. Moreover, FGF21 is considered a pro-longevity hormone because transgenic mice overexpressing FGF21 display extended lifespan, raising the possibility of using FGF21 to promote healthy aging. We recently showed that visceral fat directed FGF21 gene therapy improves metabolic and immune health in insulin resistant BTBR mice. Here, we used a fat directed rAAV-FGF21 vector in 17-month-old female mice to investigate whether long-term FGF21 gene transfer could mitigate aging-related functional decline. Animals with FGF21 treatment displayed a steady, significant lower body weight over 7-month of the study compared to age-matched control mice. FGF21 treatment reduced adiposity and increased relative lean mass and energy expenditure associated with almost 100 folds higher serum level of FGF21. However, those changes were not translated into benefits on muscle function and did not affect metabolic function of liver. Overall, we have demonstrated that a single dose of fat-directed AAV-FGF21 treatment can provide a sustainable, high serum level of FGF21 over long period of time, and mostly influences adipose tissue homeostasis and energy expenditure. High levels of FGF21 alone in aged mice is not sufficient to improve liver or muscle functions.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 3-4","pages":"95-104"},"PeriodicalIF":5.1,"publicationDate":"2023-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10224682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Acoustically targeted noninvasive gene therapy in large brain volumes 大容量脑声学靶向非侵入性基因治疗。

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-09-12 DOI: 10.1038/s41434-023-00421-1

Shirin Nouraein, Sangsin Lee, Vidal A. Saenz, Huckie C. Del Mundo, Joycelyn Yiu, Jerzy O. Szablowski

{"title":"Acoustically targeted noninvasive gene therapy in large brain volumes","authors":"Shirin Nouraein, Sangsin Lee, Vidal A. Saenz, Huckie C. Del Mundo, Joycelyn Yiu, Jerzy O. Szablowski","doi":"10.1038/s41434-023-00421-1","DOIUrl":"10.1038/s41434-023-00421-1","url":null,"abstract":"Focused Ultrasound Blood-Brain Barrier Opening (FUS-BBBO) can deliver adeno-associated viral vectors (AAVs) to treat genetic disorders of the brain. However, such disorders often affect large brain regions. Moreover, the applicability of FUS-BBBO in the treatment of brain-wide genetic disorders has not yet been evaluated. Herein, we evaluated the transduction efficiency and safety of opening up to 105 sites simultaneously. Increasing the number of targeted sites increased gene delivery efficiency at each site. We achieved transduction of up to 60% of brain cells with comparable efficiency in the majority of the brain regions. Furthermore, gene delivery with FUS-BBBO was safe even when all 105 sites were targeted simultaneously without negative effects on animal weight or neuronal loss. To evaluate the application of multi-site FUS-BBBO for gene therapy, we used it for gene editing using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system and found effective gene editing, but also a loss of neurons at the targeted sites. Overall, this study provides a brain-wide map of transduction efficiency, shows the synergistic effect of multi-site targeting on transduction efficiency, and is the first example of large brain volume gene editing after noninvasive gene delivery with FUS-BBBO.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 3-4","pages":"85-94"},"PeriodicalIF":5.1,"publicationDate":"2023-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10216070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

A pilot study to determine the optimal dose of scAAVIL-1ra in a large animal model of post-traumatic osteoarthritis 在创伤后骨关节炎大型动物模型中确定 scAAVIL-1ra 最佳剂量的试验研究。

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-09-11 DOI: 10.1038/s41434-023-00420-2

P. Thampi, K. A. Seabaugh, L. M. Pezzanite, C. R. Chu, J. N. Phillips, J. C. Grieger, C. W. McIlwraith, R. J. Samulski, L. R. Goodrich

{"title":"A pilot study to determine the optimal dose of scAAVIL-1ra in a large animal model of post-traumatic osteoarthritis","authors":"P. Thampi, K. A. Seabaugh, L. M. Pezzanite, C. R. Chu, J. N. Phillips, J. C. Grieger, C. W. McIlwraith, R. J. Samulski, L. R. Goodrich","doi":"10.1038/s41434-023-00420-2","DOIUrl":"10.1038/s41434-023-00420-2","url":null,"abstract":"Gene therapy approaches using adeno-associated viral vectors have been successfully tested in the equine post-traumatic osteoarthritis (PTOA) model. Owing to differences in the levels of transgene expression and adverse tissue reactions observed in published studies, we sought to identify a safe therapeutic dose of scAAVIL-1ra in an inflamed and injured joint that would result in improved functional outcomes without any adverse events. scAAVIL-1ra was delivered intra-articularly over a 100-fold range, and horses were evaluated throughout and at the end of the 10-week study. A dose-related increase in IL-1ra levels with a decrease in PGE2 levels was observed, with the peak IL-1ra concentration being observed 7 days post-treatment in all groups. Perivascular infiltration with mononuclear cells was observed within the synovial membrane of the joint treated with the highest viral dose of 5 × 1012 vg, but this was absent in the lower-dosed joints. The second-highest dose of scAAVeqIL-1ra 5 × 1011 vg demonstrated elevated IL-1ra levels without any cellular response in the synovium. Taken together, the data suggest that the 10-fold lower dose of 5 × 1011vg scAAVIL-1ra would be a safe therapeutic dose in an equine model of PTOA.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"30 12","pages":"792-800"},"PeriodicalIF":5.1,"publicationDate":"2023-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10727982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10216073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Selection of appropriate non-clinical animal models to ensure translatability of novel AAV-gene therapies to the clinic 选择适当的非临床动物模型，以确保新型 AAV 基因疗法可转化为临床疗法。

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-08-23 DOI: 10.1038/s41434-023-00417-x

Mark Singh, Andrew Brooks, Parto Toofan, Keith McLuckie

引用次数: 0

Safety and biodistribution of XC001 (encoberminogene rezmadenovec) gene therapy in rats: a potential therapy for cardiovascular diseases XC001（encoberminogene rezmadenovec）基因疗法在大鼠体内的安全性和生物分布：心血管疾病的一种潜在疗法。

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-08-18 DOI: 10.1038/s41434-023-00416-y

Duncan J. Stewart, Albert Gianchetti, Dawn Byrnes, Howard C. Dittrich, Barb Thorne, Linda L. Manza, Rickey R. Reinhardt

{"title":"Safety and biodistribution of XC001 (encoberminogene rezmadenovec) gene therapy in rats: a potential therapy for cardiovascular diseases","authors":"Duncan J. Stewart, Albert Gianchetti, Dawn Byrnes, Howard C. Dittrich, Barb Thorne, Linda L. Manza, Rickey R. Reinhardt","doi":"10.1038/s41434-023-00416-y","DOIUrl":"10.1038/s41434-023-00416-y","url":null,"abstract":"Adenovirus-mediated gene therapy holds promise for the treatment of cardiovascular diseases such as refractory angina. However, potential concerns around immunogenicity and vector dissemination from the target injected tissue require evaluation. This study was undertaken to evaluate the safety and biodistribution of XC001, a replication-deficient adenovirus serotype 5 vector expressing multiple isoforms of human vascular endothelial growth factor (VEGF), following direct administration into normal rat myocardium. Animals received the buffer formulation or increasing doses of XC001 (1 × 107, 2.5 × 108 or 2.5 × 109 viral particles). Based on in-life parameters (general health, body weights, clinical pathology, serum cardiac troponin I, plasma VEGF, and gross necropsy), there were no findings of clinical concern. On Day 8, intramyocardial administration of XC001 was associated with dose-related, left ventricular myocardial inflammation at injection sites, resolving by Day 30. XC001 DNA was not detected in blood at any time but was present at Day 8 around the site of injection and to a much lesser extent in the spleen, liver, and lungs, persisting at low levels in the heart and spleen until at least Day 91. These findings demonstrate that intramyocardial injection of XC001 is supported for use in human studies.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 1-2","pages":"45-55"},"PeriodicalIF":5.1,"publicationDate":"2023-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-023-00416-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10012194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Preclinical safety and biodistribution of CRISPR targeting SIV in non-human primates 以 SIV 为靶标的 CRISPR 在非人灵长类动物中的临床前安全性和生物分布。

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-08-17 DOI: 10.1038/s41434-023-00410-4

Tricia H. Burdo, Chen Chen, Rafal Kaminski, Ilker K. Sariyer, Pietro Mancuso, Martina Donadoni, Mandy D. Smith, Rahsan Sariyer, Maurizio Caocci, Shuren Liao, Hong Liu, Wenwen Huo, Huaqing Zhao, John Misamore, Mark G. Lewis, Vahan Simonyan, Elaine E. Thompson, Ethan Y. Xu, Thomas J. Cradick, Jennifer Gordon, Kamel Khalili

{"title":"Preclinical safety and biodistribution of CRISPR targeting SIV in non-human primates","authors":"Tricia H. Burdo, Chen Chen, Rafal Kaminski, Ilker K. Sariyer, Pietro Mancuso, Martina Donadoni, Mandy D. Smith, Rahsan Sariyer, Maurizio Caocci, Shuren Liao, Hong Liu, Wenwen Huo, Huaqing Zhao, John Misamore, Mark G. Lewis, Vahan Simonyan, Elaine E. Thompson, Ethan Y. Xu, Thomas J. Cradick, Jennifer Gordon, Kamel Khalili","doi":"10.1038/s41434-023-00410-4","DOIUrl":"10.1038/s41434-023-00410-4","url":null,"abstract":"In this study, we demonstrate the safety and utility of CRISPR-Cas9 gene editing technology for in vivo editing of proviral DNA in ART-treated, virally controlled simian immunodeficiency virus (SIV) infected rhesus macaques, an established model for HIV infection. EBT-001 is an AAV9-based vector delivering SaCas9 and dual guide RNAs designed to target multiple regions of the SIV genome: the viral LTRs, and the Gag gene. The results presented here demonstrate that a single IV inoculation of EBT-001 at each of 3 dose levels (1.4 × 1012, 1.4 × 1013 and 1.4 × 1014 genome copies/kg) resulted in broad and functional biodistribution of AAV9-EBT-001 to known tissue reservoirs of SIV. No off-target effects or abnormal pathology were observed, and animals returned to their normal body weight after receiving EBT-001. Importantly, the macaques that received the 2 highest doses of EBT-001 showed improved absolute lymphocyte counts as compared to antiretroviral-treated controls. Taken together, these results demonstrate safety, biodistribution, and in vivo proviral DNA editing following IV administration of EBT-001, supporting the further development of CRISPR-based gene editing as a potential therapeutic approach for HIV in humans.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 5-6","pages":"224-233"},"PeriodicalIF":5.1,"publicationDate":"2023-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-023-00410-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10014588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0