Molecular Therapy. Methods & Clinical Development最新文献_第2页

Co-transducing B7H3 CAR-NK cells with the DNR preserves their cytolytic function against GBM in the presence of exogenous TGF-β. 在外源性TGF-β存在下，B7H3 CAR-NK细胞与DNR共转导可保留其抗GBM的细胞溶解功能。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2022-10-21 eCollection Date: 2022-12-08 DOI: 10.1016/j.omtm.2022.10.010

Kajal Chaudhry, Ashley Geiger, Ehsan Dowlati, Haili Lang, Danielle K Sohai, Eugene I Hwang, Christopher A Lazarski, Eric Yvon, Matthias Holdhoff, Richard Jones, Barbara Savoldo, Conrad Russell Y Cruz, Catherine M Bollard

{"title":"Co-transducing B7H3 CAR-NK cells with the DNR preserves their cytolytic function against GBM in the presence of exogenous TGF-β.","authors":"Kajal Chaudhry, Ashley Geiger, Ehsan Dowlati, Haili Lang, Danielle K Sohai, Eugene I Hwang, Christopher A Lazarski, Eric Yvon, Matthias Holdhoff, Richard Jones, Barbara Savoldo, Conrad Russell Y Cruz, Catherine M Bollard","doi":"10.1016/j.omtm.2022.10.010","DOIUrl":"https://doi.org/10.1016/j.omtm.2022.10.010","url":null,"abstract":"Cord blood (CB)-derived natural killer (NK) cells that are genetically engineered to express a chimeric antigen receptor (CAR) are an attractive off-the-shelf therapy for the treatment of cancer, demonstrating a robust safety profile in vivo. For poor prognosis brain tumors such as glioblastoma multiforme (GBM), novel therapies are urgently needed. Although CAR-T cells demonstrate efficacy in preclinical GBM models, an off-the-shelf product may exhibit unwanted side effects like graft-versus-host disease. Hence, we developed an off-the-shelf CAR-NK cell approach using a B7H3 CAR and showed that CAR-transduced NK cells have robust cytolytic activity against GBM cells in vitro. However, transforming growth factor (TGF)-β within the tumor microenvironment has devastating effects on the cytolytic activity of both unmodified and CAR-transduced NK cells. To overcome this potent immune suppression, we demonstrated that co-transducing NK cells with a B7H3 CAR and a TGF-β dominant negative receptor (DNR) preserves cytolytic function in the presence of exogenous TGF-β. This study demonstrates that a novel DNR and CAR co-expression strategy may be a promising therapeutic for recalcitrant CNS tumors like GBM.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"415-430"},"PeriodicalIF":4.7,"publicationDate":"2022-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b0/7a/main.PMC9661497.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40468536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 6

Analysis of thermally driven structural changes, genome release, disassembly, and aggregation of recombinant AAV by CDMS. 利用CDMS分析重组AAV的热驱动结构变化、基因组释放、拆卸和聚集。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2022-10-14 eCollection Date: 2022-12-08 DOI: 10.1016/j.omtm.2022.10.008

Lauren F Barnes, Benjamin E Draper, Martin F Jarrold

{"title":"Analysis of thermally driven structural changes, genome release, disassembly, and aggregation of recombinant AAV by CDMS.","authors":"Lauren F Barnes, Benjamin E Draper, Martin F Jarrold","doi":"10.1016/j.omtm.2022.10.008","DOIUrl":"https://doi.org/10.1016/j.omtm.2022.10.008","url":null,"abstract":"Charge detection mass spectrometry (CDMS) was used to analyze recombinant adeno-associated virus serotype 8 (rAAV8) vectors after incubation at elevated temperatures. rAAV8 vectors with a range of genomes of interest (GOIs) from 2.22 to 4.84 kb were investigated. For the shorter GOIs, GOI release occurred at surprisingly low temperatures (15 min at 45°C for cytomegalovirus [CMV]-GFP). The released DNA and intermediates with the GOI extruded from the capsid were detected. The temperature required to release the short GOIs is well below the 65°C incubation temperature required to disassemble the empty rAAV8 capsid. The temperature for GOI release increased with its GOI length. With the longer GOIs, the GOI stabilized the capsid so that it remained intact under conditions that would disassemble the empty particle. After incubation at 65°C, the main species in the CDMS mass distributions for the longer GOIs was the vector with the GOI. However, for GOIs longer than the wild-type genome (∼4.7 kb), the stability diminished, and genome release occurred at a lower temperature. Heterogeneous DNA fragments from the host cells or plasmids is released at a lower temperature than the longer GOIs, suggesting that the GOIs have a feature that resists early release.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"327-336"},"PeriodicalIF":4.7,"publicationDate":"2022-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9630626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40468535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 11

Intrabiliary infusion of naked DNA vectors targets periportal hepatocytes in mice. 胆内输注裸DNA载体靶向小鼠门静脉周围肝细胞。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2022-10-10 eCollection Date: 2022-12-08 DOI: 10.1016/j.omtm.2022.10.006

Sereina Deplazes, Andrea Schlegel, Zhuolun Song, Gabriella Allegri, Nicole Rimann, Tanja Scherer, Melanie Willimann, Lennart Opitz, Sharon C Cunningham, Ian E Alexander, Anja Kipar, Johannes Häberle, Beat Thöny, Hiu Man Grisch-Chan

{"title":"Intrabiliary infusion of naked DNA vectors targets periportal hepatocytes in mice.","authors":"Sereina Deplazes, Andrea Schlegel, Zhuolun Song, Gabriella Allegri, Nicole Rimann, Tanja Scherer, Melanie Willimann, Lennart Opitz, Sharon C Cunningham, Ian E Alexander, Anja Kipar, Johannes Häberle, Beat Thöny, Hiu Man Grisch-Chan","doi":"10.1016/j.omtm.2022.10.006","DOIUrl":"https://doi.org/10.1016/j.omtm.2022.10.006","url":null,"abstract":"Hydrodynamic tail vein injection (HTV) is the \"gold standard\" for delivering naked DNA vectors to mouse liver, thereby transfecting predominately perivenous hepatocytes. While HTV corrects metabolic liver defects such as phenylketonuria or cystathionine β-synthase deficiency, correction of spf ash mice with ornithine transcarbamylase (OTC) deficiency was not possible despite overexpression in the liver, as the OTC enzyme is primarily expressed in periportal hepatocytes. To target periportal hepatocytes, we established hydrodynamic retrograde intrabiliary injection (HRII) in mice and optimized minicircle (MC) vector delivery using luciferase as a marker gene. HRII resulted in a transfection efficiency below 1%, 100-fold lower than HTV. While HRII induced minimal liver toxicity compared with HTV, overexpression of luciferase by both methods, but not of a natural liver-specific enzyme, elicited an immune response that led to the elimination of luciferase expression. Further testing of MC vectors delivered via HRII in spf ash mice did not result in sufficient therapeutic efficacy and needs further optimization and/or selection of the corrected cells. This study reveals that luciferase expression is toxic for the liver. Furthermore, physical delivery of MC vectors via the bile duct has the potential to treat defects restricted to periportal hepatocytes, which opens new doors for non-viral liver-directed gene therapy.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"352-367"},"PeriodicalIF":4.7,"publicationDate":"2022-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6f/0f/main.PMC9630613.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40465631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

AAVrh10 vector corrects pathology in animal models of GM1 gangliosidosis and achieves widespread distribution in the CNS of nonhuman primates. AAVrh10载体纠正了GM1神经节脂质病动物模型的病理，并在非人灵长类动物的中枢神经系统中实现了广泛分布。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2022-10-07 eCollection Date: 2022-12-08 DOI: 10.1016/j.omtm.2022.10.004

Michaël Hocquemiller, Laura Giersch, Xin Mei, Amanda L Gross, Ashley N Randle, Heather L Gray-Edwards, Judith A Hudson, Sophia Todeasa, Lorelei Stoica, Douglas R Martin, Miguel Sena-Esteves, Karen Aiach, Ralph Laufer

{"title":"AAVrh10 vector corrects pathology in animal models of GM1 gangliosidosis and achieves widespread distribution in the CNS of nonhuman primates.","authors":"Michaël Hocquemiller, Laura Giersch, Xin Mei, Amanda L Gross, Ashley N Randle, Heather L Gray-Edwards, Judith A Hudson, Sophia Todeasa, Lorelei Stoica, Douglas R Martin, Miguel Sena-Esteves, Karen Aiach, Ralph Laufer","doi":"10.1016/j.omtm.2022.10.004","DOIUrl":"https://doi.org/10.1016/j.omtm.2022.10.004","url":null,"abstract":"GM1 gangliosidosis is a rare, inherited neurodegenerative disorder caused by mutations in the GLB1 gene, which encodes the lysosomal hydrolase acid β-galactosidase (β-gal). β-gal deficiency leads to toxic accumulation of GM1 ganglioside, predominantly in the central nervous system (CNS), resulting in progressive neurodegeneration. LYS-GM101 is an AAVrh.10-based gene therapy vector carrying the human GLB1 cDNA. The efficacy of intra-cerebrospinal fluid injection of LYS-GM101 analogs was demonstrated in GM1 mouse and cat models with widespread diffusion of β-gal and correction of GM1 ganglioside accumulation in the CNS without observable adverse effects. Clinical dose selection was performed, based on a good-laboratory-practice study, in nonhuman primates (NHPs) using the clinical LYS-GM101 vector. A broadly distributed increase of β-gal activity was observed in NHP brain 3 months after intra-cisterna magna injection of LYS-GM101 at 1.0 × 1012 vg/mL CSF and 4.0 × 1012 vg/mL CSF, with 20% and 60% increases compared with vehicle-treated animals, respectively. Histopathologic examination revealed asymptomatic adverse changes in the sensory pathways of the spinal cord and dorsal root ganglia in both sexes and at both doses. Taken as a whole, these pre-clinical data support the initiation of a clinical study with LYS-GM101 for the treatment of GM1 gangliosidosis.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"281-292"},"PeriodicalIF":4.7,"publicationDate":"2022-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/13/e2/main.PMC9594110.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40661461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

Gene therapy using human FMRP isoforms driven by the human FMR1 promoter rescues fragile X syndrome mouse deficits. 使用由人类FMR1启动子驱动的人类FMRP同种异构体进行基因治疗可拯救脆性X综合征小鼠缺陷。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2022-10-07 eCollection Date: 2022-12-08 DOI: 10.1016/j.omtm.2022.10.002

Yiru Jiang, Linkun Han, Jian Meng, Zijie Wang, Yunqiang Zhou, Huilong Yuan, Hui Xu, Xian Zhang, Yingjun Zhao, Jinsheng Lu, Huaxi Xu, Chen Zhang, Yun-Wu Zhang

{"title":"Gene therapy using human FMRP isoforms driven by the human FMR1 promoter rescues fragile X syndrome mouse deficits.","authors":"Yiru Jiang, Linkun Han, Jian Meng, Zijie Wang, Yunqiang Zhou, Huilong Yuan, Hui Xu, Xian Zhang, Yingjun Zhao, Jinsheng Lu, Huaxi Xu, Chen Zhang, Yun-Wu Zhang","doi":"10.1016/j.omtm.2022.10.002","DOIUrl":"https://doi.org/10.1016/j.omtm.2022.10.002","url":null,"abstract":"Fragile X syndrome (FXS) is caused by the loss of the fragile X messenger ribonucleoprotein 1 (FMRP) encoded by the FMR1 gene. Gene therapy using adeno-associated virus (AAV) to restore FMRP expression is a promising therapeutic strategy. However, so far AAV gene therapy tests for FXS only utilized rodent FMRPs driven by promoters other than the human FMR1 promoter. Restoration of human FMRP in appropriate cell types and at physiological levels, preferably driven by the human FMR1 promoter, would be more suitable for its clinical use. Herein, we generated two human FMR1 promoter subdomains that effectively drive gene expression. When AAVs expressing two different human FMRP isoforms under the control of a human FMR1 promoter subdomain were administered into bilateral ventricles of neonatal Fmr1 -/y and wild-type (WT) mice, both human FMRP isoforms were expressed throughout the brain in a pattern reminiscent to that of mouse FMRP. Importantly, human FMRP expression attenuated social behavior deficits and stereotyped and repetitive behavior, and reversed dysmorphological dendritic spines in Fmr1 -/y mice, without affecting WT mouse behaviors. Our results demonstrate that human FMR1 promoter can effectively drive human FMRP expression in the brain to attenuate Fmr1 -/y mouse deficits, strengthening the notion of using AAV gene therapy for FXS treatment.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"246-258"},"PeriodicalIF":4.7,"publicationDate":"2022-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c2/51/main.PMC9593309.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40661464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

NCS1 overexpression restored mitochondrial activity and behavioral alterations in a zebrafish model of Wolfram syndrome. NCS1过表达恢复了Wolfram综合征斑马鱼模型的线粒体活性和行为改变。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2022-10-07 eCollection Date: 2022-12-08 DOI: 10.1016/j.omtm.2022.10.003

Lucie Crouzier, Elodie M Richard, Camille Diez, Morgane Denus, Amandine Peyrel, Hala Alzaeem, Nicolas Cubedo, Thomas Delaunay, Tangui Maurice, Benjamin Delprat

{"title":"NCS1 overexpression restored mitochondrial activity and behavioral alterations in a zebrafish model of Wolfram syndrome.","authors":"Lucie Crouzier, Elodie M Richard, Camille Diez, Morgane Denus, Amandine Peyrel, Hala Alzaeem, Nicolas Cubedo, Thomas Delaunay, Tangui Maurice, Benjamin Delprat","doi":"10.1016/j.omtm.2022.10.003","DOIUrl":"https://doi.org/10.1016/j.omtm.2022.10.003","url":null,"abstract":"Wolfram syndrome (WS) is a rare neurodegenerative disease resulting in deafness, optic atrophy, diabetes, and neurological disorders. Currently, no treatment is available for patients. The mutated gene, WFS1, encodes an endoplasmic reticulum (ER) protein, Wolframin. We previously reported that Wolframin regulated the ER-mitochondria Ca2+ transfer and mitochondrial activity by protecting NCS1 from degradation in patients' fibroblasts. We relied on a zebrafish model of WS, the wfs1ab KO line, to analyze the functional and behavioral impact of NCS1 overexpression as a novel therapeutic strategy. The wfs1ab KO line showed an increased locomotion in the visual motor and touch-escape responses. The absence of wfs1 did not impair the cellular unfolded protein response, in basal or tunicamycin-induced ER stress conditions. In contrast, metabolic analysis showed an increase in mitochondrial respiration in wfs1ab KO larvae. Interestingly, overexpression of NCS1 using mRNA injection restored the alteration of mitochondrial respiration and hyperlocomotion. Taken together, these data validated the wfs1ab KO zebrafish line as a pertinent experimental model of WS and confirmed the therapeutic potential of NCS1. The wfs1ab KO line therefore appeared as an efficient model to identify novel therapeutic strategies, such as gene or pharmacological therapies targeting NCS1 that will correct or block WS symptoms.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"295-308"},"PeriodicalIF":4.7,"publicationDate":"2022-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9594121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40661462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 4

Combined PD-L1 and TIM3 blockade improves expansion of fit human CD8⁺ antigen-specific T cells for adoptive immunotherapy. PD-L1和TIM3联合阻断可改善人类CD8+抗原特异性T细胞在过继免疫治疗中的扩增。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2022-10-04 eCollection Date: 2022-12-08 DOI: 10.1016/j.omtm.2022.09.016

Shirin Lak, Valérie Janelle, Anissa Djedid, Gabrielle Boudreau, Ann Brasey, Véronique Lisi, Ali Smaani, Cédric Carli, Lambert Busque, Vincent-Philippe Lavallée, Jean-Sébastien Delisle

{"title":"Combined PD-L1 and TIM3 blockade improves expansion of fit human CD8+ antigen-specific T cells for adoptive immunotherapy.","authors":"Shirin Lak, Valérie Janelle, Anissa Djedid, Gabrielle Boudreau, Ann Brasey, Véronique Lisi, Ali Smaani, Cédric Carli, Lambert Busque, Vincent-Philippe Lavallée, Jean-Sébastien Delisle","doi":"10.1016/j.omtm.2022.09.016","DOIUrl":"https://doi.org/10.1016/j.omtm.2022.09.016","url":null,"abstract":"Antigen-specific T cell expansion ex vivo followed by adoptive transfer enables targeting of a multitude of microbial and cancer antigens. However, clinical-scale T cell expansion from rare precursors requires repeated stimulation, which may lead to T cell dysfunction and limited therapeutic potential. We used a clinically compliant protocol to expand Epstein-Barr virus (EBV) and Wilms tumor 1 (WT1) antigen-specific CD8+ T cells, and leveraged T cell exhaustion-associated inhibitory receptor blockade to improve T cell expansion. Several inhibitory receptors were expressed early by ex vivo-expanded antigen-specific CD8+ T cells, including PD-1 and TIM3, with co-expression matching evidence of T cell dysfunction as the cultures progressed. Introduction of anti-PD-L1 and anti-TIM3 blockade in combination (but not individually) to the culture led to markedly improved antigen-specific T cell expansion without inducing T cell dysfunction. Single-cell RNA sequencing (RNA-seq) and T cell receptor (TCR) repertoire profiling revealed that double blockade does not impart specific transcriptional programs in T cells or alterations in TCR repertoires. However, combined blockade may affect gene expression in a minority of clonotypes in a donor-specific fashion. We conclude that antigen-specific CD8+ T cell manufacturing can be improved by using TIM3 and PD-L1/PD-1 axis blockade in combination. This approach is readily applicable to several adoptive immunotherapy strategies.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"230-245"},"PeriodicalIF":4.7,"publicationDate":"2022-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9593254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40661463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 4

Intravenous immunoglobulin prevents peripheral liver transduction of intrathecally delivered AAV vectors. 静脉注射免疫球蛋白阻止鞘内递送的AAV载体的外周肝转导。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2022-10-04 eCollection Date: 2022-12-08 DOI: 10.1016/j.omtm.2022.09.017

Makoto Horiuchi, Christian J Hinderer, Jenny A Greig, Cecilia Dyer, Elizabeth L Buza, Peter Bell, Jessica A Chichester, Peter M Hayashi, Hanying Yan, Tamara Goode, James M Wilson

{"title":"Intravenous immunoglobulin prevents peripheral liver transduction of intrathecally delivered AAV vectors.","authors":"Makoto Horiuchi, Christian J Hinderer, Jenny A Greig, Cecilia Dyer, Elizabeth L Buza, Peter Bell, Jessica A Chichester, Peter M Hayashi, Hanying Yan, Tamara Goode, James M Wilson","doi":"10.1016/j.omtm.2022.09.017","DOIUrl":"https://doi.org/10.1016/j.omtm.2022.09.017","url":null,"abstract":"Gene therapy using neurotropic adeno-associated virus vectors represents an emerging solution for genetic disorders affecting the central nervous system. The first approved central nervous system-targeting adeno-associated virus gene therapy, Zolgensma®, for treating spinal muscular atrophy is administered intravenously at high doses that cause liver-associated adverse events in 20%-30% of patients. Intrathecal routes of vector administration, such as the intra-cisterna magna route, provide efficient gene transduction to central nervous system cells while reducing off-target liver transduction. However, significant levels of liver transduction often occur upon intra-cisterna magna vector delivery in preclinical studies. Using vectors expressing monoclonal antibody transgenes, we examined whether passive transfer of adeno-associated virus-neutralizing antibodies as intravenous immunoglobulin before intrathecal adeno-associated virus delivery improved the safety of viral gene therapy targeting the central nervous system in mice and nonhuman primates. We used intracerebroventricular and intra-cisterna magna routes for vector administration to mice and nonhuman primates, respectively, and evaluated transgene expression and vector genome distribution. Our data indicate that pretreatment with intravenous immunoglobulin significantly reduced gene transduction to the liver and other peripheral organs but not to the central nervous system in both species. With further refinement, this method may improve the safety of adeno-associated virus-based, central nervous system-targeting gene therapies in clinical settings.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"272-280"},"PeriodicalIF":4.7,"publicationDate":"2022-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9593247/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40675348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

AAV9-NGLY1 gene replacement therapy improves phenotypic and biomarker endpoints in a rat model of NGLY1 Deficiency. AAV9-NGLY1基因替代疗法改善NGLY1缺乏症大鼠模型的表型和生物标志物终点。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2022-10-03 eCollection Date: 2022-12-08 DOI: 10.1016/j.omtm.2022.09.015

Lei Zhu, Brandon Tan, Selina S Dwight, Brendan Beahm, Matt Wilsey, Brett E Crawford, Becky Schweighardt, Jennifer W Cook, Thomas Wechsler, William F Mueller

{"title":"AAV9-NGLY1 gene replacement therapy improves phenotypic and biomarker endpoints in a rat model of NGLY1 Deficiency.","authors":"Lei Zhu, Brandon Tan, Selina S Dwight, Brendan Beahm, Matt Wilsey, Brett E Crawford, Becky Schweighardt, Jennifer W Cook, Thomas Wechsler, William F Mueller","doi":"10.1016/j.omtm.2022.09.015","DOIUrl":"https://doi.org/10.1016/j.omtm.2022.09.015","url":null,"abstract":"N-glycanase 1 (NGLY1) Deficiency is a progressive, ultra-rare, autosomal recessive disorder with no approved therapy and five core clinical features: severe global developmental delay, hyperkinetic movement disorder, elevated liver transaminases, alacrima, and peripheral neuropathy. Here, we confirmed and characterized the Ngly1 -/- / rat as a relevant disease model. GS-100, a gene therapy candidate, is a recombinant, single-stranded adeno-associated virus (AAV) 9 vector designed to deliver a functional copy of the human NGLY1 gene. Using the Ngly1 -/- rat, we tested different administration routes for GS-100: intracerebroventricular (ICV), intravenous (IV), or the dual route (IV + ICV). ICV and IV + ICV administration resulted in widespread biodistribution of human NGLY1 DNA and corresponding mRNA and protein expression in CNS tissues. GS-100 delivered by ICV or IV + ICV significantly reduced levels of the substrate biomarker N-acetylglucosamine-asparagine (GlcNAc-Asn or GNA) in CSF and brain tissue compared with untreated Ngly1-/- rats. ICV and IV + ICV administration of GS-100 resulted in behavioral improvements in rotarod and rearing tests, whereas IV-only administration did not. IV + ICV did not provide additional benefit compared with ICV administration alone. These data provide evidence that GS-100 could be an effective therapy for NGLY1 Deficiency using the ICV route of administration.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"259-271"},"PeriodicalIF":4.7,"publicationDate":"2022-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/39/14/main.PMC9593239.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40675350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 4

Determination of AAV properties by single amino acids: Go(o)d is in the details. 单氨基酸测定AAV性质:Go(o)d是详细的。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2022-09-29 eCollection Date: 2022-12-08 DOI: 10.1016/j.omtm.2022.09.006

Olena Maiakovska, Conradin Baumgartl, Dirk Grimm

引用次数: 0