Current Opinion in Molecular Therapeutics最新文献_第3页

The ethics of gene therapy: balancing the risks. 基因治疗的伦理:平衡风险。

Current Opinion in Molecular Therapeutics Pub Date : 2010-10-01

Claire T Deakin, Ian E Alexander, Ian Kerridge

{"title":"The ethics of gene therapy: balancing the risks.","authors":"Claire T Deakin, Ian E Alexander, Ian Kerridge","doi":"","DOIUrl":"","url":null,"abstract":"Gene therapy research is characterized by heightened uncertainty about the risks associated with the complex products involved, particularly the risk of genotoxicity. Recognizing that uncertainty concerning risks is inescapable in first-in-human clinical trials of gene therapy, decisions on how to balance the risks nevertheless must be made. Ethics can facilitate translational progress by, first, evaluating decision-making processes during risk assessment; and second, focusing on questions that require a degree of subjective judgement. Such assessments include determining the level of risk that is acceptable in trials, the category of patients that should be exposed to the risks, and the level of certainty with respect to risk that is required for both researchers and participants to make decisions. Analysis of these issues is affected by the burden of illness, existing treatment alternatives and the possible benefits of gene therapy. Patients' attitudes and experiences in this regard can reasonably inform the decision-making of researchers. Reflecting upon the approaches used to balance risks and possible benefits in gene therapy trials may improve decision-making processes across the spectrum of decisions that are made from the initial conception of a study up to decisions by research participants about consent. This manner of reflection facilitates the advancement of science, while protecting the welfare of research participants.","PeriodicalId":50605,"journal":{"name":"Current Opinion in Molecular Therapeutics","volume":"12 5","pages":"578-85"},"PeriodicalIF":0.0,"publicationDate":"2010-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29315521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The use of neural stem cells in cancer gene therapy: predicting the path to the clinic. 神经干细胞在癌症基因治疗中的应用:预测其临床应用路径。

Current Opinion in Molecular Therapeutics Pub Date : 2010-10-01

Atique U Ahmed, Nikita G Alexiades, Maciej S Lesniak

{"title":"The use of neural stem cells in cancer gene therapy: predicting the path to the clinic.","authors":"Atique U Ahmed, Nikita G Alexiades, Maciej S Lesniak","doi":"","DOIUrl":"","url":null,"abstract":"Gene therapy is a novel means of anticancer treatment that has led to preliminary positive results in the preclinical setting, as well as in clinical trials; however, successful clinical application of this approach has been hampered by the inability of gene delivery systems to target tumors and to deliver a therapeutic payload to disseminated tumor foci efficiently. Along with viral vector systems, various mammalian cells with tropism for tumor cells have been considered as vehicles for delivery of anticancer therapeutics. The discovery of the inherent tumor-tropic properties of neural stem cells (NSCs) has provided a unique opportunity to develop targeted therapies that use NSCs as a vehicle to track invasive tumor cells and deliver anticancer agents selectively to diseased areas. Many in vivo and in vitro studies have demonstrated that the targeted migration of NSCs to infiltrative brain tumors, including malignant glioma, provides a potential therapeutic approach. In this review, the development of NSCs as targeted carriers for anticancer gene therapy is discussed, and barriers in the path to the clinic, as well as approaches to overcoming such barriers are presented.","PeriodicalId":50605,"journal":{"name":"Current Opinion in Molecular Therapeutics","volume":"12 5","pages":"546-52"},"PeriodicalIF":0.0,"publicationDate":"2010-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2958255/pdf/nihms-244582.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29315519","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

BC-819, a plasmid comprising the H19 gene regulatory sequences and diphtheria toxin A, for the potential targeted therapy of cancers. BC-819，一种包含H19基因调控序列和白喉毒素a的质粒，用于癌症的潜在靶向治疗。

Current Opinion in Molecular Therapeutics Pub Date : 2010-10-01

Marc C Smaldone, Benjamin J Davies

{"title":"BC-819, a plasmid comprising the H19 gene regulatory sequences and diphtheria toxin A, for the potential targeted therapy of cancers.","authors":"Marc C Smaldone, Benjamin J Davies","doi":"","DOIUrl":"","url":null,"abstract":"BC-819 (DTA-H19), in development by BioCancell Therapeutics Inc, under license from the Hebrew University of Jerusalem, is a double-stranded DNA plasmid carrying the gene for the A subunit of diphtheria toxin under the regulation of the H19 gene promoter. H19, a paternally imprinted, oncofetal gene, encodes an RNA that acts as a riboregulator. Expressed at substantial levels in embryonic and malignant tissues, but minimally or not expressed in adult tissues, elevated H19 RNA expression has been observed in over 30 malignancies prompting investigation into its utility as a targeted therapeutic agent. While most in vivo studies have investigated BC-819 for the treatment of bladder cancer, recent studies have also yielded encouraging results in NSCLC,colon, pancreatic and ovarian cancers. A phase I/IIa clinical trial in patients with non-muscle invasive bladder cancer receiving intravesical BC-819 reported mild local toxicity and complete and partial response rates of 22 and 44%, respectively. At the time of publication, a phase IIb trial was ongoing in patients with bladder cancer, while phase I/II clinical trials in patients with ovarian and pancreatic cancer were accruing participants. This review provides a focused summary of the existing experimental evidence demonstrating the effectiveness of the plasmid construct, early clinical outcomes and a discussion of the potential role of BC-819 as a targeted cancer therapy.","PeriodicalId":50605,"journal":{"name":"Current Opinion in Molecular Therapeutics","volume":"12 5","pages":"607-16"},"PeriodicalIF":0.0,"publicationDate":"2010-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29318247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Oncolytic adenoviruses for the treatment of brain tumors. 溶瘤腺病毒治疗脑肿瘤。

Current Opinion in Molecular Therapeutics Pub Date : 2010-10-01

Candelaria Gomez-Manzano, Juan Fueyo

{"title":"Oncolytic adenoviruses for the treatment of brain tumors.","authors":"Candelaria Gomez-Manzano, Juan Fueyo","doi":"","DOIUrl":"","url":null,"abstract":"In recent years, oncolytic viruses have been genetically engineered to target cancer cells selectively. Adenovirus is one such oncolytic virus that is being tested in clinical trials for the treatment of cancer. The observation that cells infected with replication-competent adenoviruses undergo autophagy has provided new options for investigating the mechanism of adenovirus-induced cell death. It has been suggested that the use of autophagy inducers, such as rapamycin, can enhance the oncolytic potency of recombinant adenoviruses. Additionally, several research groups have established that inserting microRNA (miRNA)-targeted sequences into the adenoviral genome can modulate adenoviral protein expression to confer tissue and tumor selectivity. Furthermore, the capability of adenoviruses to inhibit the expression of the DNA repair enzyme MGMT and to chemosensitize glioma cells to temozolomide has been demonstrated. This review discusses three aspects of the use of oncolytic adenoviruses to treat cancer: (i) the induction of autophagy and autophagic cell death during adenoviral replication; (ii) the opportunities and strategies involved in the exploitation of miRNA specificity to generate tissue- and tumor-selective oncolytic viruses; and (iii) the rationale for combining oncolytic adenoviruses with chemotherapeutic agents.","PeriodicalId":50605,"journal":{"name":"Current Opinion in Molecular Therapeutics","volume":"12 5","pages":"530-7"},"PeriodicalIF":0.0,"publicationDate":"2010-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29315516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gene therapy for Parkinson's disease: from non-human primates to humans. 帕金森病的基因治疗:从非人类灵长类动物到人类。

Current Opinion in Molecular Therapeutics Pub Date : 2010-10-01

Massimo S Fiandaca, Krystof S Bankiewicz

{"title":"Gene therapy for Parkinson's disease: from non-human primates to humans.","authors":"Massimo S Fiandaca, Krystof S Bankiewicz","doi":"","DOIUrl":"","url":null,"abstract":"Gene therapy strategies in non-human primate models of Parkinson's disease (PD) are beginning to produce results consistently, and have been successfully translated to clinical trials. Although not all of the therapeutic efforts based on gene therapy have demonstrated clinical efficacy, the stereotactic techniques and at least three different beneficial genes that have been delivered to patients have been proven to be safe. The adeno-associated virus has been used as an effective and safe delivery vehicle for the first three, single therapeutic transgenes (ie, glutamic acid decarboxylase, aromatic l-amino acid decarboxylase, and neurturin) to be tested in trials. In addition, the larger lentivirus, which has been used for the codelivery of up to three therapeutic genes in parkinsonian non-human primates, has also being used in a trial in humans. Additional preclinical and clinical research is required to advance the understanding of PD and its potential treatments. Gene therapy, however, has the potential to be a safe and effective therapeutic option for an increasing number of patients with PD in the near future. In this review, the pertinent scientific research related to the use of gene therapy for the treatment of PD is summarized, with a particular focus on the accomplishments and challenges during the past 2 years.","PeriodicalId":50605,"journal":{"name":"Current Opinion in Molecular Therapeutics","volume":"12 5","pages":"519-29"},"PeriodicalIF":0.0,"publicationDate":"2010-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29315515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The long and winding road to clinical success in gene therapy. 通往基因治疗临床成功的漫长而曲折的道路。

Current Opinion in Molecular Therapeutics Pub Date : 2010-10-01

Josef Rosenecker

引用次数: 0

TA-CIN, a vaccine incorporating a recombinant HPV fusion protein (HPV16 L2E6E7) for the potential treatment of HPV16-associated genital diseases. TA-CIN是一种含有重组HPV融合蛋白(HPV16 L2E6E7)的疫苗，可用于治疗HPV16相关生殖器疾病。

Current Opinion in Molecular Therapeutics Pub Date : 2010-10-01

Sam Hibbitts

{"title":"TA-CIN, a vaccine incorporating a recombinant HPV fusion protein (HPV16 L2E6E7) for the potential treatment of HPV16-associated genital diseases.","authors":"Sam Hibbitts","doi":"","DOIUrl":"","url":null,"abstract":"Commercially available prophylactic HPV vaccines for cervical cancer prevention have limited use in women with previous viral exposure. Therefore, a therapeutic HPV vaccine would benefit patients with HPV-associated genital diseases. Being developed by Cancer Research Technology Ltd, under license from Xenova Group plc, TA-CIN (Tissue Antigen - Cervical Intraepithelial Neoplasia) is a fusion protein vaccine comprising the HPV16 viral proteins L2, E6 and E7 for the treatment of HPV16-associated genital diseases. In mouse models, TA-CIN induced dose-dependent HPV16-specific CD4 and CD8 T-cell responses, which were enhanced when boosted with the vaccinia-based vector vaccine TA-HPV (Therapeutic Antigen - HPV). A phase I clinical trial of TA-CIN in healthy volunteers reported no serious adverse events and HPV16-specific cellular immune responses. Phase II trials in patients with anogenital and vulval intraepithelial neoplasia investigated heterologous prime/boost strategies with TA-CIN/TA-HPV and TA-HPV/TA-CIN, but neither of the regimens offered advantages over single-agent TA-HPV. A recent phase II trial investigating imiquimod/TA-CIN in patients with vulval intraepithelial neoplasia demonstrated significant infiltration of CD4 and CD8 T-cells in lesion responders and complete lesion regression in 63% of patients. More comprehensive case-controlled trials are needed to define responders to immunotherapy with TA-CIN and verify its prophylactic and therapeutic properties.","PeriodicalId":50605,"journal":{"name":"Current Opinion in Molecular Therapeutics","volume":"12 5","pages":"598-606"},"PeriodicalIF":0.0,"publicationDate":"2010-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29318246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gene therapy for tolerance and vice versa: a case for hemophilia. 基因疗法治疗耐受性，反之亦然:一例血友病。

Current Opinion in Molecular Therapeutics Pub Date : 2010-10-01

Jonathan Skupsky, Mark Saltis, Chang Song, Robert Rossi, Diane Nelson, David W Scott

{"title":"Gene therapy for tolerance and vice versa: a case for hemophilia.","authors":"Jonathan Skupsky, Mark Saltis, Chang Song, Robert Rossi, Diane Nelson, David W Scott","doi":"","DOIUrl":"","url":null,"abstract":"Hemophilia is a bleeding disorder that affects approximately 1 in 4000 males across populations worldwide. First-line therapy for the treatment of hemophilia is the intravenous administration of protein therapeutics to replace the deficient coagulation factor. However, in a significant number of patients, the immune system recognizes the therapeutic protein as 'dangerous' and mounts a humoral response that rejects the treatment and significantly increases the morbidity associated with this disease. Recent advances have been made in gene therapy in the field of hemophilia. Gene therapy provides the possibility of a cure for this disease; however, managing immunological tolerance to therapy is a challenge for this treatment modality. This review describes an approach in which gene therapy is used to deliver a tolerogenic construct to B-cells that can induce tolerance to protein therapy or to replacement gene therapy. Several other novel techniques to modulate immunity in patients with hemophilia, such as non-specific agents, mAbs and protein modifications, are at various stages of translation to the clinic and are also highlighted. The successful modulation of the immune system to accept treatment will significantly improve the quality of life for patients with hemophilia.","PeriodicalId":50605,"journal":{"name":"Current Opinion in Molecular Therapeutics","volume":"12 5","pages":"509-18"},"PeriodicalIF":0.0,"publicationDate":"2010-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29315514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sotatercept, a soluble activin receptor type 2A IgG-Fc fusion protein for the treatment of anemia and bone loss. Sotatercept是一种可溶性活化素受体2A型IgG-Fc融合蛋白，用于治疗贫血和骨质流失。

Current Opinion in Molecular Therapeutics Pub Date : 2010-10-01

Noopur Raje, Sonia Vallet

{"title":"Sotatercept, a soluble activin receptor type 2A IgG-Fc fusion protein for the treatment of anemia and bone loss.","authors":"Noopur Raje, Sonia Vallet","doi":"","DOIUrl":"","url":null,"abstract":"Sotatercept (ACE-011), under development by Acceleron Pharma Inc in collaboration with Celgene Corp, is a chimeric protein containing the extracellular domain of the activin receptor 2A (ACVR2A) fused to the Fc domain of human IgG1. Sotatercept contains the binding site of ACVR2A and interferes with downstream signaling cascades, in particular the SMAD pathway, by sequestering activin. The murine counterpart of sotatercept, referred to as RAP-011, has been extensively evaluated in preclinical studies, in particular in models of cancer- and osteoporosis-related bone loss, and the developing companies envisage that sotatercept may also have potential for the treatment of cancer and cancer-related bone loss. In a phase I clinical trial in postmenopausal females, sotatercept increased hematocrit levels, and, in a phase II trial in patients with multiple myeloma, a trend toward improvement in osteolytic lesions as well as antitumor activity was observed. At the time of publication, phase II trials in patients with anemia were ongoing. Future clinical development will rely on an evaluation of the benefits and complications of sotatercept administration, focusing in particular on suppression of ovarian function and increases in hematocrit levels without a consequent risk of hypertension and thrombosis.","PeriodicalId":50605,"journal":{"name":"Current Opinion in Molecular Therapeutics","volume":"12 5","pages":"586-97"},"PeriodicalIF":0.0,"publicationDate":"2010-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29318245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gene therapy from the perspective of systems biology. 从系统生物学的角度看基因治疗。

Current Opinion in Molecular Therapeutics Pub Date : 2010-10-01

Feilim Mac Gabhann, Brian H Annex, Aleksander S Popel

{"title":"Gene therapy from the perspective of systems biology.","authors":"Feilim Mac Gabhann, Brian H Annex, Aleksander S Popel","doi":"","DOIUrl":"","url":null,"abstract":"Gene therapy research has expanded from its original concept of replacing absent or defective DNA with functional DNA to include the manipulation (increase or decrease) of gene expression by the delivery of modified genes, siRNA or other genetic material via multiple vectors, including naked plasmid DNA, viruses and even cells. Specific tissues or cell types are targeted in order to decrease the risks of systemic or side effects. As with the development of any drug, there is an amount of empiricism in the choice of gene target, route of administration, dosing and, in particular, the scaling-up from preclinical models to clinical trials. High-throughput experimental and computational systems biology studies that account for the complexities of host-disease-therapy interactions hold significant promise in assisting in the development and optimization of gene therapies, including personalized therapies and the identification of biomarkers to evaluate the success of such strategies. This review describes some of the obstacles and successes in gene therapy, using the specific example of growth factor gene delivery to promote angiogenesis and blood vessel remodeling in ischemic diseases; anti-angiogenic gene therapy in cancer is also discussed. In addition, the opportunities for systems biology and in silico modeling to improve on current outcomes are highlighted.","PeriodicalId":50605,"journal":{"name":"Current Opinion in Molecular Therapeutics","volume":"12 5","pages":"570-7"},"PeriodicalIF":0.0,"publicationDate":"2010-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021921/pdf/nihms251650.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29318244","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