A novel approach to Mesenchymal Stem Cell Transduction
间充质干细胞转导的新方法
基本信息
- 批准号:10325618
- 负责人:
- 金额:$ 24.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-20 至 2024-03-19
- 项目状态:已结题
- 来源:
- 关键词:AddressAdipose tissueAnimal ModelBiological AssayCD34 geneCanis familiarisCardiovascular systemCartilageCell SurvivalCell TherapyCellsChildChronic Granulomatous DiseaseClinicClinicalClinical TrialsClonal ExpansionClone CellsDataDevelopmentDiseaseEnsureFaceFlow CytometryFrequenciesGTP-Binding Protein alpha Subunits, GsGammaretrovirusGene TransferGene-ModifiedGenesGeneticGreen Fluorescent ProteinsHIV-1HematopoieticHematopoietic stem cellsHigh-Throughput Nucleotide SequencingHumanImmunologicsInsertional MutagenesisLentivirus VectorLeukemic CellLinkMalignant NeoplasmsMature T-LymphocyteMesenchymal Stem CellsModificationMusNeurologicOrthopedicsPatientsPatternPhasePhenotypePlayPrimary carcinoma of the liver cellsPropertyPublishingReportingResearch PersonnelRiskRisk EstimateRoleSafetySiteSourceSurfaceT-LymphocyteThalassemiaTherapeuticTransplantationVertebral BoneVesicular stomatitis Indiana virusViralWiskott-Aldrich SyndromeWorkbasebonebone marrow mesenchymal stem cellcell bankcell immortalizationcell typecellular transductionchimeric antigen receptorclinical developmentclinical implementationcostdetection assayefficacy studygene therapy clinical trialgene transfer vectorgenetically modified cellsgenotoxicityhematopoietic stem cell expansionimprovedinnovative technologiesintegration sitelentiviral integrationlentivirally transducedleukemianovelnovel strategiesparticlepre-clinicalpreferenceprematuresafety studysenescencestem cell genesstem cell modelstem cellstherapeutic effectivenessvectorvertebra body
项目摘要
PROJECT SUMMARY
Mesenchymal stem cells (MSC) are in clinical development for cardiovascular, neurologic, orthopedic, and
other indications. Ossium is developing a novel source of MSC from vertebral bodies (vbMSC). Genetic
modification of vbMSC using lentiviral vector (LV) has the potential to improve the therapeutic potential.
Understanding how genetic modification might alter the vbMSC phenotype will be critical to ensuring LV do
not initiate premature senescence or diminish their therapeutic properties. Moreover, an important safety and
regulatory barrier to clinical implementation of gene modified vbMSC will be estimating the risk of insertional
mutagenesis. Gammaretroviral vectors used to modify hematopoietic stem cells (HSC) led to leukemia in at
least 4 clinical trials. While lentiviral vectors appear safer, clonal expansion of HSC and mature T cells have
now been reported. Ossium seeks to address important safety and efficacy issues in this Phase I proposal.
We hypothesize that (1) A HIV-1 based LV pseudotyped with a novel foamy viral envelope (LV-FV) will
efficiently transduce vbMSC with less change in cell phenotype compared to LV pseudotyped with VSV-G;
(2), the LV integration pattern, distribution among cancer associated genes and ability to induce cell
immortalization, will be similar to that seen in other cell types. To study this, we propose: Specific Aim 1:
Assess the Effect of LV Gene Transfer and Vector Pseudotype on vbMSC phenotype. LV expressing green
fluorescent protein (GFP) pseudotyped with VSVG and FV will be used to transduce vbMSC. Cells will be
assessed for gene transfer (vector copy number) and expression (GFP by flow cytometry), viability,
expansion capacity, MSC-associated surface markers, secretome, and ability to differentiate into three
lineages (bone, adipose and cartilage). Specific Aim 2: Evaluate Insertional Mutagenesis Risk in LV
transduced vbMSC. This aim seeks to investigate the genotoxicity of LV vectors in MSC. Specific Aim 2A.
Evaluating LV-transduced vbMSC for Integration Pattern and Cancer-Associated Gene Preferences.
Comparisons between LV and gammaretroviral vectors in low and high passage vbMSC will be compared
to published data on HSC integrations. Specific Aim 2B. Evaluating LV-transduced vbMSC for
Immortalization. In this sub-aim we will seek to develop an assay for assessing IM risk by evaluating vbMSC
after gene transfer. The findings will have broad applicability given the number of disease states in which
MSC may play a therapeutic role. This proposal also uses a variety of innovative technologies, including a
novel LV-FV, a novel stem cell source (vertebral body MSC), and will be the first study aimed at assessing
the risk of immortalization in MSC.
项目摘要
间充质干细胞(MSC)正在临床开发中,用于心血管、神经、骨科和
其他迹象。Ossium正在开发一种新的来源于椎体的MSC(vbMSC)。遗传
使用慢病毒载体(LV)修饰vbMSC具有改善治疗潜力的潜力。
了解遗传修饰如何改变vbMSC表型对于确保LV在体外发育过程中发挥作用至关重要。
不会引发过早衰老或降低其治疗特性。此外,重要的安全和
基因修饰的vbMSC的临床实施的监管障碍将是估计插入的风险,
诱变用于修饰造血干细胞(HSC)的γ逆转录病毒载体导致白血病,
4临床试验虽然慢病毒载体看起来更安全,但HSC和成熟T细胞的克隆扩增具有更高的安全性。
现在被报道了。Ossium寻求解决I期提案中的重要安全性和有效性问题。
我们假设:(1)一种具有新型泡沫病毒包膜的HIV-1假型LV(LV-FV),
与用VSV-G假型化的LV相比,有效地转染vbMSC,细胞表型变化较小;
(2)LV整合模式、癌症相关基因的分布以及诱导细胞凋亡的能力
永生化,将类似于在其他细胞类型中看到的。为了研究这个问题,我们提出:具体目标1:
评估LV基因转移和载体假型对vbMSC表型的影响。LV表达绿色
用VSVG和FV假型化的荧光蛋白(GFP)将用于转染vbMSC。细胞将被
评估基因转移(载体拷贝数)和表达(GFP,通过流式细胞术),活力,
扩增能力、MSC相关表面标志物、分泌组和分化成三种细胞的能力
谱系(骨、脂肪和软骨)。特定目的2:评价LV中的插入突变风险
转导的vbMSC。该目的旨在研究LV载体在MSC中的遗传毒性。具体目标2A.
评估LV转导的vbMSC的整合模式和癌症相关基因偏好。
将比较LV和γ逆转录病毒载体在低代和高代vbMSC中的作用
发表的HSC整合数据。具体目标2B。评价LV转导的vbMSC用于
不朽。在这个子目标中,我们将寻求开发一种通过评估vbMSC来评估IM风险的测定法。
基因转移后。考虑到疾病状态的数量,
MSC可能发挥治疗作用。该提案还使用了各种创新技术,包括
新的LV-FV,一种新的干细胞来源(椎体MSC),将是第一项旨在评估
MSC中永生化的风险。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Gene therapy access: Global challenges, opportunities, and views from Brazil, South Africa, and India.
- DOI:10.1016/j.ymthe.2022.04.002
- 发表时间:2022-06-01
- 期刊:
- 影响因子:12.4
- 作者:Cornetta, Kenneth;Bonamino, Martin;Mahlangu, Johnny;Mingozzi, Federico;Rangarajan, Savita;Rao, Jayandharan
- 通讯作者:Rao, Jayandharan
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
KENNETH CORNETTA其他文献
KENNETH CORNETTA的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('KENNETH CORNETTA', 18)}}的其他基金
NATIONAL GENE VECTOR BIOREPOSITORY AND COORDINATING CENTER (NGVB): TASK AREA B, CORE SCIENTIFIC ACTIVITIES FOR NCI
国家基因载体生物保藏和协调中心 (NGVB):任务领域 B,NCI 的核心科学活动
- 批准号:
10291046 - 财政年份:2020
- 资助金额:
$ 24.85万 - 项目类别:
NATIONAL GENE VECTOR BIOREPOSITORY AND COORDINATING CENTER (NGVB): TASK AREA B, CORE SCIENTIFIC ACTIVITIES FOR NCI
国家基因载体生物保藏和协调中心 (NGVB):任务领域 B,NCI 的核心科学活动
- 批准号:
10593034 - 财政年份:2020
- 资助金额:
$ 24.85万 - 项目类别:
PURPOSE OF THE NGVB CONTRACT IS TO CONTINUE SUPPORTING GENE THERAPY RESEARCH.
NGVB 合同的目的是继续支持基因治疗研究。
- 批准号:
10046193 - 财政年份:2019
- 资助金额:
$ 24.85万 - 项目类别:
IGF::OT::IGF - Gene Therapy Resource Program (GTRP) Lentivirus Vector Production
IGF::OT::IGF - 基因治疗资源计划 (GTRP) 慢病毒载体生产
- 批准号:
9300816 - 财政年份:2012
- 资助金额:
$ 24.85万 - 项目类别:
IGF::OT::IGF - Gene Therapy Resource Program (GTRP) Lentivirus Vector Production
IGF::OT::IGF - 基因治疗资源计划 (GTRP) 慢病毒载体生产
- 批准号:
8862323 - 财政年份:2012
- 资助金额:
$ 24.85万 - 项目类别:
Packaging Cell Lines for Lentiviral Vector Products
慢病毒载体产品的包装细胞系
- 批准号:
7909260 - 财政年份:2010
- 资助金额:
$ 24.85万 - 项目类别:
Automated Nucleic Acid Extractor System:AutoGenFlex Star/AutoGen Quick-Gene 810
自动化核酸提取系统:AutoGenFlex Star/AutoGen Quick-Gene 810
- 批准号:
7793989 - 财政年份:2010
- 资助金额:
$ 24.85万 - 项目类别:
American Society of Gene Therapy Annual Meeting (2009-2013)
美国基因治疗学会年会(2009-2013)
- 批准号:
7749863 - 财政年份:2010
- 资助金额:
$ 24.85万 - 项目类别:
New Faculty Recruitment to the Indiana University Gene Therapy Program
印第安纳大学基因治疗项目新教师招聘
- 批准号:
7861187 - 财政年份:2009
- 资助金额:
$ 24.85万 - 项目类别:
New Faculty Recruitment to the Indiana University Gene Therapy Program
印第安纳大学基因治疗项目新教师招聘
- 批准号:
7935348 - 财政年份:2009
- 资助金额:
$ 24.85万 - 项目类别:
相似海外基金
Deciphering the role of adipose tissue in common metabolic disease via adipose tissue proteomics
通过脂肪组织蛋白质组学解读脂肪组织在常见代谢疾病中的作用
- 批准号:
MR/Y013891/1 - 财政年份:2024
- 资助金额:
$ 24.85万 - 项目类别:
Research Grant
ESTABLISHING THE ROLE OF ADIPOSE TISSUE INFLAMMATION IN THE REGULATION OF MUSCLE MASS IN OLDER PEOPLE
确定脂肪组织炎症在老年人肌肉质量调节中的作用
- 批准号:
BB/Y006542/1 - 财政年份:2024
- 资助金额:
$ 24.85万 - 项目类别:
Research Grant
Canadian Alliance of Healthy Hearts and Minds: Dissecting the Pathways Linking Ectopic Adipose Tissue to Cognitive Dysfunction
加拿大健康心灵联盟:剖析异位脂肪组织与认知功能障碍之间的联系途径
- 批准号:
479570 - 财政年份:2023
- 资助金额:
$ 24.85万 - 项目类别:
Operating Grants
Determinants of Longitudinal Progression of Adipose Tissue Inflammation in Individuals at High-Risk for Type 2 Diabetes: Novel Insights from Metabolomic Profiling
2 型糖尿病高危个体脂肪组织炎症纵向进展的决定因素:代谢组学分析的新见解
- 批准号:
488898 - 财政年份:2023
- 资助金额:
$ 24.85万 - 项目类别:
Operating Grants
Activation of human brown adipose tissue using food ingredients that enhance the bioavailability of nitric oxide
使用增强一氧化氮生物利用度的食品成分激活人体棕色脂肪组织
- 批准号:
23H03323 - 财政年份:2023
- 资助金额:
$ 24.85万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Development of new lung regeneration therapies by elucidating the lung regeneration mechanism of adipose tissue-derived stem cells
通过阐明脂肪组织干细胞的肺再生机制开发新的肺再生疗法
- 批准号:
23K08293 - 财政年份:2023
- 资助金额:
$ 24.85万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
A study on the role of brown adipose tissue in the development and maintenance of skeletal muscles
棕色脂肪组织在骨骼肌发育和维持中作用的研究
- 批准号:
23K19922 - 财政年份:2023
- 资助金额:
$ 24.85万 - 项目类别:
Grant-in-Aid for Research Activity Start-up
Adipose Tissue T Cell Polarization and Metabolic Health in Persons Living with HIV
HIV 感染者的脂肪组织 T 细胞极化和代谢健康
- 批准号:
10619176 - 财政年份:2023
- 资助金额:
$ 24.85万 - 项目类别:
Estrogen Signaling in the Ventromedial Hypothalamus Modulates Adipose Tissue Metabolic Adaptation
下丘脑腹内侧区的雌激素信号调节脂肪组织代谢适应
- 批准号:
10604611 - 财政年份:2023
- 资助金额:
$ 24.85万 - 项目类别:
Obesity and Childhood Asthma: The Role of Adipose Tissue
肥胖和儿童哮喘:脂肪组织的作用
- 批准号:
10813753 - 财政年份:2023
- 资助金额:
$ 24.85万 - 项目类别: