Translational Development of Replication-Competent Retrovirus Vectors

具有复制能力的逆转录病毒载体的转化开发

• 批准号: 8548414
• 负责人: NORIYUKI KASAHARA
• 金额: --
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8548414
• 关键词: Accounting; Adult; Adverse effects; Basic Science; Biodistribution; Biological Assay; Blood Tests; Bolus Infusion; Bone Marrow; Brain; Cells; Chemistry; Childhood Intracranial Neoplasm; Clinical; Clinical Protocols; Clinical Trials; Clinical trial protocol document; Collaborations; Consensus; Convection; Critical Pathways; Cryopreservation; Detection; Development; Disease; Documentation; Dose; Event; Flow Cytometry; Flucytosine; Fluorouracil; Gene Transfer; Genes; Glioblastoma; Glioma; Goals; Guidelines; Harvest; Histopathology; Human; Image; Immune response; Immunocompetent; Immunohistochemistry; Injection of therapeutic agent; Institutional Review Boards; Instruction; Intracranial Neoplasms; Intravenous; Laboratories; Magnetic Resonance Imaging; Malignant Glioma; Malignant neoplasm of brain; Measurement; Mediating; Methodology; Methods; Modeling; Molecular Analysis; Monitor; Murine leukemia virus; NMR Spectroscopy; Nori; Normal tissue morphology; Nude Mice; Patients; Phase III Clinical Trials; Plasmid Cloning Vector; Plasmids; Preparation; Primary Brain Neoplasms; Principal Investigator; Procedures; Prodrugs; Production; Protocols documentation; Publishing; Radiation therapy; Radiosurgery; Rattus; Reagent; Recovery; Recurrence; Research; Research Personnel; Retroviral Vector; Retroviridae; Risk; Rodent; Safety; Serum; Signal Transduction; Site; Spleen; Sterility; Supportive care; Testing; The Sun; Therapeutic; Time; Tissue Sample; Toxic effect; Toxicology; Transfection; Treatment Efficacy; Validation; Vial device; Virus; Wolves; Xenograft procedure; base; biobank; calcium phosphate precipitation; cell bank; chemotherapy; design; effective therapy; follow-up; gene therapy; gene transfer vector; genotoxicity; improved; in vivo; killings; neoplastic cell; neuroimaging; neurosurgery; novel strategies; organizational structure; outcome forecast; pre-clinical; process optimization; programs; reagent standard; scale up; subcutaneous; suicide gene; translational study; tumor; vector

Glioblastoma multiforme (GBM), the most common primary brain tumor in adults, is associated with a dismal prognosis of only 12-15 months despite aggressive surgery, radiation, and chemotherapy. The lack of effective treatment options has made this disease a target for new strategies such as gene therapy. However, the only major Phase III clinical trial of gene therapy, involving the use of conventional replication-defective retrovirus vectors in GBM patients, resulted in disappointingly low and therapeutically inadequate transduction levels on the order of only 0.02%. The inability of standard replication-defective retroviral vectors to achieve effective transduction of tumors in vivo is therefore a major obstacle to gene therapy for gliomas. The use of replication-competent vectors for gene transfer would be more efficient, as each tumor cell that is successfully transduced would itself become a virus- producing cell, sustaining further transduction events even after initial administration. We have previously demonstrated that direct intratumoral injection of murine leukemia virus (MLV)- based replication-competent retrovirus (RCR) vector preparations can achieve tremendously efficient suicide gene transfer in gliomas, with transduction stringently restricted to the actively dividing tumor cells without evidence of significant spread to extratumoral sites, and resulting in significantly prolonged survival upon prodrug administration, without detectable systemic side effects. Therefore, in collaboration with neurosurgery groups at UCLA, USC, and UCSF, and the National Gene Vector Biorepository (NGVB), here we propose to optimize and implement clinical grade RCR vector production and release testing (Aim 1), to re-validate these clinical grade vectors by confirmatory testing of therapeutic efficacy in at least 2 intracranial glioma models from different species per FDA stipulations, as well as re-validation of preclinical toxicology and follow-up monitoring assays as mandated by FDA guidelines (Aim 2), and to evaluate convection-enhanced delivery and non-invasive NMR imaging methodologies and develop clinical trial protocols (Aim 3). We propose to perform these necessary preclinical translational studies through this U01 mechanism, with the final goal of filing an IND and obtaining approval from the FDA to initiate clinical trials. RELEVANCE (See instructions): Glioblastoma multiforme (GBM; WHO Grade IV malignant glioma), is the most common form of malignant brain tumor in adults, accounting for 50-60% of primary brain tumors, and 7-10% of childhood intracranial neoplasms. Despite major improvements in neuroimaging, neurosurgery, radiotherapy, and supportive care, the overall prognosis for GBMs is still only 12-15 months, and current treatments only delay recurrence. Hence, there is an unmet need to develop effective new approaches against this devastating disease.

多形性胶质母细胞瘤（GBM）是成人中最常见的原发性脑肿瘤，与a

项目成果

Convection-enhanced delivery improves distribution and efficacy of tumor-selective retroviral replicating vectors in a rodent brain tumor model.

• DOI: 10.1038/cgt.2013.25
• 发表时间: 2013-06
• 期刊: Cancer gene therapy
• 影响因子: 6.4

Maintaining therapeutic activity in the operating room: compatibility of a gamma-retroviral replicating vector with clinical materials and biofluids.

在手术室中维持治疗活性：γ-逆转录病毒复制载体与临床材料和生物液体的相容性。

• DOI: 10.1038/mtm.2014.24
• 发表时间: 2014
• 期刊: Molecular therapy. Methods & clinical development
• 作者: Burnett,Ryan;Ibañez,CarlosE;Pettersson,PärL;Chen,Ching-I;Parab,Shraddha;Huang,Tiffany;Robbins,Joan;Bankiewicz,Krystof;Aghi,Manish;Logg,Christopher;Kasahara,Noriyuki;Pertschuk,Dan;Gruber,HarryE;Jolly,DouglasJ
• 通讯作者: Jolly,DouglasJ

Brain tumor eradication and prolonged survival from intratumoral conversion of 5-fluorocytosine to 5-fluorouracil using a nonlytic retroviral replicating vector.

消除脑肿瘤和从5-氟中胞菌素到5-氟尿嘧啶的肿瘤内转化延长的生存期，使用非延柳逆转录病毒复制载体。

• DOI: 10.1093/neuonc/nor199
• 发表时间: 2012-02
• 期刊: Neuro-oncology
• 影响因子: 15.9
• 作者: Ostertag D;Amundson KK;Lopez Espinoza F;Martin B;Buckley T;Galvão da Silva AP;Lin AH;Valenta DT;Perez OD;Ibañez CE;Chen CI;Pettersson PL;Burnett R;Daublebsky V;Hlavaty J;Gunzburg W;Kasahara N;Gruber HE;Jolly DJ;Robbins JM
• 通讯作者: Robbins JM