Molecular Therapy. Methods & Clinical Development最新文献_第3页

Safety study supports clinical development of immunotherapeutic oncolytic measles vaccine. 安全性研究支持免疫治疗溶瘤麻疹疫苗的临床开发。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2022-09-24 eCollection Date: 2022-12-08 DOI: 10.1016/j.omtm.2022.09.003

Christine E Engeland

引用次数: 1

Erratum: Hematopoietic stem cell gene therapy ameliorates CNS involvement in murine model of GM1-gangliosidosis. 更正:造血干细胞基因治疗可改善小鼠gm1神经节脂质病模型中中枢神经系统的参与。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2022-09-21 eCollection Date: 2022-12-08 DOI: 10.1016/j.omtm.2022.09.004

Toshiki Tsunogai, Toya Ohashi, Yohta Shimada, Takashi Higuchi, Ayaka Kimura, Ayako M Watabe, Fusao Kato, Hiroyuki Ida, Hiroshi Kobayashi

引用次数: 0

Vaccination of cats with Sad23L-nCoV-S vaccine candidate against major variants of SARS-CoV-2. 猫接种抗SARS-CoV-2主要变体的Sad23L-nCoV-S候选疫苗

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2022-09-08 Epub Date: 2022-06-22 DOI: 10.1016/j.omtm.2022.06.011

Panli Zhang, Shengxue Luo, Peng Zou, Chaolan Liang, Cong Wang, Jinfeng Li, Yongyin Li, Gang Wang, Ling Zhang, Tingting Li, Chengyao Li

{"title":"Vaccination of cats with Sad23L-nCoV-S vaccine candidate against major variants of SARS-CoV-2.","authors":"Panli Zhang, Shengxue Luo, Peng Zou, Chaolan Liang, Cong Wang, Jinfeng Li, Yongyin Li, Gang Wang, Ling Zhang, Tingting Li, Chengyao Li","doi":"10.1016/j.omtm.2022.06.011","DOIUrl":"https://doi.org/10.1016/j.omtm.2022.06.011","url":null,"abstract":"Cats are susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and risk transmitting viruses to naive cats or humans. Here, based on our novel adenovirus-vectored COVID-19 vaccine, the immunogenicity of Sad23L-nCoV-S vaccine was evaluated in cats by prime-boost vaccinations. Five cats were primed with a dose of 108 plaque-forming units (PFUs) Sad23L-nCoV-S vaccine and then boosted with an equal dose of same vaccine at a 4-week interval. Cat serum neutralizing antibody (NAb) titers (the sample dilution at which 50% inhibitory concentration [IC50]) were measured as IC50 15,849 to wild-type strain, IC50 6,591 to Alpha, IC50 2,315 to Beta, IC50 2,744 to Gamma, IC50 1,848 to Delta, and IC50 318 to Omicron variants of pseudotyped SARS-CoV-2 viruses at week 6 post-prime vaccination. All NAb levels to these five variants were ≥IC50 49 from vaccinated cats at week 10, while 48.8% to Delta and 100% to Omicron variants were <IC50 10 from human vaccinees at week 2 or 4 after receiving two injections of the inactivated SARS-CoV-2 vaccines. Robust T cell response of interferon (IFN)-γ to S peptides were detected in vaccinated cats. It was concluded that Sad23L-nCoV-S vaccine could be a promising vaccine candidate against SARS-CoV-2 infection in cats by prime or plus boost vaccinations.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"181-190"},"PeriodicalIF":4.7,"publicationDate":"2022-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e5/77/main.PMC9217069.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40401018","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: 0

Selection of rAAV vectors that cross the human blood-brain barrier and target the central nervous system using a transwell model. 利用transwell模型选择跨越人血脑屏障靶向中枢神经系统的rAAV载体。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2022-09-07 eCollection Date: 2022-12-08 DOI: 10.1016/j.omtm.2022.09.002

Ren Song, Katja Pekrun, Themasap A Khan, Feijie Zhang, Sergiu P Paşca, Mark A Kay

{"title":"Selection of rAAV vectors that cross the human blood-brain barrier and target the central nervous system using a transwell model.","authors":"Ren Song, Katja Pekrun, Themasap A Khan, Feijie Zhang, Sergiu P Paşca, Mark A Kay","doi":"10.1016/j.omtm.2022.09.002","DOIUrl":"https://doi.org/10.1016/j.omtm.2022.09.002","url":null,"abstract":"A limitation for recombinant adeno-associated virus (rAAV)-mediated gene transfer into the central nervous system (CNS) is the low penetration of vectors across the human blood-brain barrier (BBB). High doses of intravenously delivered vector are required to reach the CNS, which has resulted in varying adverse effects. Moreover, selective transduction of various cell types might be important depending on the disorder being treated. To enhance BBB penetration and improve CNS cell selectivity, we screened an AAV capsid-shuffled library using an in vitro transwell BBB system with separate layers of human endothelial cells, primary astrocytes and/or human induced pluripotent stem cell-derived cortical neurons. After multiple passages through the transwell, we identified chimeric AAV capsids with enhanced penetration and improved transduction of astrocytes and/or neurons compared with wild-type capsids. We identified the amino acids (aa) from regions 451-470 of AAV2 associated with the capsids selected for neurons, and a combination of aa from regions 413-496 of AAV-rh10 and 538-598 of AAV3B/LK03 associated with capsids selected for astrocytes. A small interfering RNA screen identified several genes that affect transcytosis of AAV across the BBB. Our work supports the use of a human transwell system for selecting enhanced AAV capsids targeting the CNS and may allow for unraveling the underlying molecular mechanisms of BBB penetration.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"73-88"},"PeriodicalIF":4.7,"publicationDate":"2022-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/fb/b6/main.PMC9494039.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40391707","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

Applying a clinical lens to animal models of CAR-T cell therapies. 应用临床镜头到CAR-T细胞治疗的动物模型。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2022-08-30 eCollection Date: 2022-12-08 DOI: 10.1016/j.omtm.2022.08.008

Brynn B Duncan, Cynthia E Dunbar, Kazusa Ishii

{"title":"Applying a clinical lens to animal models of CAR-T cell therapies.","authors":"Brynn B Duncan, Cynthia E Dunbar, Kazusa Ishii","doi":"10.1016/j.omtm.2022.08.008","DOIUrl":"https://doi.org/10.1016/j.omtm.2022.08.008","url":null,"abstract":"Chimeric antigen receptor (CAR)-T cells have emerged as a promising treatment modality for various hematologic and solid malignancies over the past decade. Animal models remain the cornerstone of pre-clinical evaluation of human CAR-T cell products and are generally required by regulatory agencies prior to clinical translation. However, pharmacokinetics and pharmacodynamics of adoptively transferred T cells are dependent on various recipient factors, posing challenges for accurately predicting human engineered T cell behavior in non-human animal models. For example, murine xenograft models did not forecast now well-established cytokine-driven systemic toxicities of CAR-T cells seen in humans, highlighting the limitations of animal models that do not perfectly recapitulate complex human immune systems. Understanding the concordance as well as discrepancies between existing pre-clinical animal data and human clinical experiences, along with established advantages and limitations of each model, will facilitate investigators' ability to appropriately select and design animal models for optimal evaluation of future CAR-T cell products. We summarize the current state of animal models in this field, and the advantages and disadvantages of each approach depending on the pre-clinical questions being asked.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"17-31"},"PeriodicalIF":4.7,"publicationDate":"2022-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/38/8e/main.PMC9478925.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33482551","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

AAV2/9-mediated gene transfer into murine lacrimal gland leads to a long-term targeted tear film modification. aav2 /9介导的基因转移到小鼠泪腺导致长期靶向泪膜修饰。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2022-08-24 eCollection Date: 2022-12-08 DOI: 10.1016/j.omtm.2022.08.006

Benoit Gautier, Léna Meneux, Nadège Feret, Christine Audrain, Laetitia Hudecek, Alison Kuony, Audrey Bourdon, Caroline Le Guiner, Véronique Blouin, Cécile Delettre, Frédéric Michon

{"title":"AAV2/9-mediated gene transfer into murine lacrimal gland leads to a long-term targeted tear film modification.","authors":"Benoit Gautier, Léna Meneux, Nadège Feret, Christine Audrain, Laetitia Hudecek, Alison Kuony, Audrey Bourdon, Caroline Le Guiner, Véronique Blouin, Cécile Delettre, Frédéric Michon","doi":"10.1016/j.omtm.2022.08.006","DOIUrl":"https://doi.org/10.1016/j.omtm.2022.08.006","url":null,"abstract":"Corneal blindness is the fourth leading cause of blindness worldwide. Since corneal epithelium is constantly renewed, non-integrative gene transfer cannot be used to treat corneal diseases. In many of these diseases, the tear film is defective. Tears are a complex biological fluid secreted by the lacrimal apparatus. Their composition is modulated according to the context. After a corneal wound, the lacrimal gland secretes reflex tears, which contain growth factors supporting the wound healing process. In various pathological contexts, the tear composition can support neither corneal homeostasis nor wound healing. Here, we propose to use the lacrimal gland as bioreactor to produce and secrete specific factors supporting corneal physiology. In this study, we use an AAV2/9-mediated gene transfer to supplement the tear film. First, we demonstrate that a single injection of AAV2/9 is sufficient to transduce all epithelial cell types of the lacrimal gland efficiently and widely. Second, we detect no adverse effect after AAV2/9-mediated nerve growth factor expression in the lacrimal gland. Only a transitory increase in tear flow is measured. Remarkably, AAV2/9 induces an important and long-lasting secretion of this growth factor in the tear film. Altogether, our findings provide a new clinically applicable approach to tackle corneal blindness.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"1-16"},"PeriodicalIF":4.7,"publicationDate":"2022-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/40/3d/main.PMC9463184.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33483591","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: 0

PAM-altering SNP-based allele-specific CRISPR-Cas9 therapeutic strategies for Huntington's disease. 基于pam改变snp的等位基因特异性CRISPR-Cas9治疗亨廷顿舞蹈病的策略

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2022-08-14 eCollection Date: 2022-09-08 DOI: 10.1016/j.omtm.2022.08.005

Jun Wan Shin, Eun Pyo Hong, Seri S Park, Doo Eun Choi, Sophia Zeng, Richard Z Chen, Jong-Min Lee

{"title":"PAM-altering SNP-based allele-specific CRISPR-Cas9 therapeutic strategies for Huntington's disease.","authors":"Jun Wan Shin, Eun Pyo Hong, Seri S Park, Doo Eun Choi, Sophia Zeng, Richard Z Chen, Jong-Min Lee","doi":"10.1016/j.omtm.2022.08.005","DOIUrl":"https://doi.org/10.1016/j.omtm.2022.08.005","url":null,"abstract":"Huntington's disease (HD) is caused by an expanded CAG repeat in huntingtin (HTT). Since HD is dominant and loss of HTT leads to neurological abnormalities, safe therapeutic strategies require selective inactivation of mutant HTT. Previously, we proposed a concept of CRISPR-Cas9 using mutant-specific PAM sites generated by SNPs to selectively inactivate mutant HTT. Aiming at revealing suitable targets for clinical development, we analyzed the largest HD genotype dataset to identify target PAM-altering SNPs (PAS) and subsequently evaluated their allele specificities. The gRNAs based on the PAM sites generated by rs2857935, rs16843804, and rs16843836 showed high levels of allele specificity in patient-derived cells. Simultaneous use of two gRNAs based on rs2857935-rs16843804 or rs2857935-rs16843836 produced selective genomic deletions in mutant HTT and prevented the transcription of mutant HTT mRNA without impacting the expression of normal counterpart or re-integration of the excised fragment elsewhere in the genome. RNA-seq and off-target analysis confirmed high levels of allele specificity and the lack of recurrent off-targeting. Approximately 60% of HD subjects are eligible for mutant-specific CRISPR-Cas9 strategies of targeting one of these three PAS in conjunction with one non-allele-specific site, supporting high applicability of PAS-based allele-specific CRISPR approaches in the HD patient population.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"547-561"},"PeriodicalIF":4.7,"publicationDate":"2022-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/08/e3/main.PMC9450073.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33460694","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

Full-length ATP7B reconstituted through protein trans-splicing corrects Wilson disease in mice. 通过蛋白质反式剪接重组全长ATP7B纠正小鼠威尔逊病。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2022-08-13 eCollection Date: 2022-09-08 DOI: 10.1016/j.omtm.2022.08.004

Agnese Padula, Raffaella Petruzzelli, Sasha A Philbert, Stephanie J Church, Federica Esposito, Severo Campione, Marcello Monti, Filomena Capolongo, Claudia Perna, Edoardo Nusco, Hartmut H Schmidt, Alberto Auricchio, Garth J S Cooper, Roman Polishchuk, Pasquale Piccolo

{"title":"Full-length ATP7B reconstituted through protein trans-splicing corrects Wilson disease in mice.","authors":"Agnese Padula, Raffaella Petruzzelli, Sasha A Philbert, Stephanie J Church, Federica Esposito, Severo Campione, Marcello Monti, Filomena Capolongo, Claudia Perna, Edoardo Nusco, Hartmut H Schmidt, Alberto Auricchio, Garth J S Cooper, Roman Polishchuk, Pasquale Piccolo","doi":"10.1016/j.omtm.2022.08.004","DOIUrl":"https://doi.org/10.1016/j.omtm.2022.08.004","url":null,"abstract":"Wilson disease (WD) is a genetic disorder of copper homeostasis, caused by deficiency of the copper transporter ATP7B. Gene therapy with recombinant adeno-associated vectors (AAV) holds promises for WD treatment. However, the full-length human ATP7B gene exceeds the limited AAV cargo capacity, hampering the applicability of AAV in this disease context. To overcome this limitation, we designed a dual AAV vector approach using split intein technology. Split inteins catalyze seamless ligation of two separate polypeptides in a highly specific manner. We selected a DnaE intein from Nostoc punctiforme (Npu) that recognizes a specific tripeptide in the human ATP7B coding sequence. We generated two AAVs expressing either the 5'-half of a codon-optimized human ATP7B cDNA followed by the N-terminal Npu DnaE intein or the C-terminal Npu DnaE intein followed by the 3'-half of ATP7B cDNA, under the control of a liver-specific promoter. Intravenous co-injection of the two vectors in wild-type and Atp7b -/- mice resulted in efficient reconstitution of full-length ATP7B protein in the liver. Moreover, Atp7b -/- mice treated with intein-ATP7B vectors were protected from liver damage and showed improvements in copper homeostasis. Taken together, these data demonstrate the efficacy of split intein technology to drive the reconstitution of full-length human ATP7B and to rescue copper-mediated liver damage in Atp7b -/- mice, paving the way to the development of a new gene therapy approach for WD.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"495-504"},"PeriodicalIF":4.7,"publicationDate":"2022-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9436707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33460697","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: 7

Young mice administered adult doses of AAV5-hFVIII-SQ achieve therapeutic factor VIII expression into adulthood. 给予成年剂量AAV5-hFVIII-SQ的幼鼠在成年期获得治疗因子VIII的表达。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2022-08-13 eCollection Date: 2022-09-08 DOI: 10.1016/j.omtm.2022.08.002

Lening Zhang, Bridget Yates, Ryan Murphy, Su Liu, Lin Xie, Britta Handyside, Choong-Ryoul Sihn, Taren Bouwman, Nicole Galicia, Danielle Tan, Carlos Fonck, Jeremy Arens, Annie Clark, Weiming Zhang, Sundeep Chandra, Jaydeep Srimani, Jennifer Holcomb, Andrea Van Tuyl, Joshua Henshaw, Christian Vettermann, Silvia Siso, Cheng Su, Sherry Bullens, Stuart Bunting, Charles O'Neill, Sylvia Fong

{"title":"Young mice administered adult doses of AAV5-hFVIII-SQ achieve therapeutic factor VIII expression into adulthood.","authors":"Lening Zhang, Bridget Yates, Ryan Murphy, Su Liu, Lin Xie, Britta Handyside, Choong-Ryoul Sihn, Taren Bouwman, Nicole Galicia, Danielle Tan, Carlos Fonck, Jeremy Arens, Annie Clark, Weiming Zhang, Sundeep Chandra, Jaydeep Srimani, Jennifer Holcomb, Andrea Van Tuyl, Joshua Henshaw, Christian Vettermann, Silvia Siso, Cheng Su, Sherry Bullens, Stuart Bunting, Charles O'Neill, Sylvia Fong","doi":"10.1016/j.omtm.2022.08.002","DOIUrl":"https://doi.org/10.1016/j.omtm.2022.08.002","url":null,"abstract":"Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) gene transfer provided reduced bleeding for adult clinical trial participants with severe hemophilia A. However, pediatric outcomes are unknown. Using a mouse model of hemophilia A, we investigated the effect of vector dose and age at treatment on transgene production and persistence. We dosed AAV5-hFVIII-SQ to neonatal and adult mice based on body weight or at a fixed dose and assessed human factor VIII-SQ variant (hFVIII-SQ) expression through 16 weeks. AAV5-hFVIII-SQ dosed per body weight in neonatal mice did not result in meaningful plasma hFVIII-SQ protein levels in adulthood. When treated with the same total vector genomes per mouse as adult mice, neonates maintained hFVIII-SQ expression into adulthood, although plasma levels were 3- to 4-fold lower versus mice dosed as adults. Mice <1 week old initially exhibited high hFVIII-SQ plasma levels and maintained meaningful levels into adulthood, despite a partial decline potentially due to age-related body mass and blood volume increases. Spatial transduction patterns differed between mice dosed as neonates versus adults. No features of hepatotoxicity or endoplasmic reticulum stress were observed with dosing at any age. These data suggest that young mice require the same total vector genomes as adult mice to sustain hFVIII-SQ plasma levels.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"519-531"},"PeriodicalIF":4.7,"publicationDate":"2022-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d3/2a/main.PMC9440360.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33460695","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

AAV-monoclonal antibody expression protects mice from Ebola virus without impeding the endogenous antibody response to heterologous challenge. aav -单克隆抗体表达保护小鼠免受埃博拉病毒感染，而不阻碍内源抗体对异源攻击的反应。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2022-08-12 eCollection Date: 2022-09-08 DOI: 10.1016/j.omtm.2022.08.003

Laura P van Lieshout, Amira D Rghei, Wenguang Cao, Shihua He, Geoff Soule, Wenjun Zhu, Sylvia P Thomas, Debra Sorensen, Kathy Frost, Kevin Tierney, Brad Thompson, Stephanie Booth, David Safronetz, Raveendra R Kulkarni, Byram W Bridle, Xiangguo Qiu, Logan Banadyga, Sarah K Wootton

{"title":"AAV-monoclonal antibody expression protects mice from Ebola virus without impeding the endogenous antibody response to heterologous challenge.","authors":"Laura P van Lieshout, Amira D Rghei, Wenguang Cao, Shihua He, Geoff Soule, Wenjun Zhu, Sylvia P Thomas, Debra Sorensen, Kathy Frost, Kevin Tierney, Brad Thompson, Stephanie Booth, David Safronetz, Raveendra R Kulkarni, Byram W Bridle, Xiangguo Qiu, Logan Banadyga, Sarah K Wootton","doi":"10.1016/j.omtm.2022.08.003","DOIUrl":"https://doi.org/10.1016/j.omtm.2022.08.003","url":null,"abstract":"Filoviruses cause severe hemorrhagic fever with case fatality rates as high as 90%. Filovirus-specific monoclonal antibodies (mAbs) confer protection in nonhuman primates as late as 5 days after challenge, and FDA-approved mAbs REGN-EB3 and mAb114 have demonstrated efficacy against Ebola virus (EBOV) infection in humans. Vectorized antibody expression mediated by adeno-associated virus (AAV) can generate protective and sustained concentrations of therapeutic mAbs in animal models for a variety of infectious diseases, including EBOV. Here we demonstrate that AAV6.2FF-mediated expression of murine IgG2a EBOV mAbs, 2G4 and 5D2, protects from mouse-adapted (MA)-EBOV infection with none of the surviving mice developing anti-VP40 antibodies above background. Protective serum concentrations of AAV6.2FF-2G4/AAV6.2FF-5D2 did not alter endogenous antibody responses to heterologous virus infection. AAV-mediated expression of EBOV mAbs 100 and 114, and pan-ebolavirus mAbs, FVM04, ADI-15878, and CA45, as human IgG1 antibodies conferred protection against MA-EBOV at low serum concentrations, with minimum protective serum levels as low as 2 μg/mL. Vectorized expression of murine IgG2a or human IgG1 mAbs led to sustained expression in the serum of mice for >400 days or for the lifetime of the animal, respectively. AAV6.2FF-mediated mAb expression offers an alternative to recombinant antibody administration in scenarios where long-term protection is preferable to passive immunization.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"505-518"},"PeriodicalIF":4.7,"publicationDate":"2022-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/77/5e/main.PMC9436706.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33460698","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