Molecular and cellular therapies最新文献

{"title":"Extended blood circulation and joint accumulation of a p(HPMA-co-AzMA)-based nanoconjugate in a murine model of rheumatoid arthritis.","authors":"Morten F Ebbesen, Konrad Bienk, Bent W Deleuran, Kenneth A Howard","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Background: </strong>We recently synthesized a hydrophilic polymer, poly(N-(2-hydroxypropyl)methacrylamide-co-N-(3-azidopropyl)methacrylamide), p(HPMA-co-AzMA), by RAFT polymerization using a novel azide-containing methacrylamide monomer that through a post modification strategy using click chemistry enabled facile preparation of a panel of versatile and well-defined bioconjugates. In this work we screen a panel of different molecular weight (Mw) fluorescently tagged p(HPMA-co-AzMA) in healthy mice, by live bioimaging, to select an extended circulatory half-life material for investigating joint accumulation in a murine collagen antibody-induced arthritis model.</p><p><strong>Findings: </strong>Fluorescence image analysis revealed half-lifes of <20 min, 2.8 h and 6.4 h for p(HPMA-co-AzMA) of 15, 36 and 54 kDa, respectively, with ~10% polymer retained in the blood after 24 h for the highest Mw. p(HPMA-co-AzMA) of 54 kDa showed enhanced accumulation in the joints of the arthritic mouse model with a bioavailability (AUC = 1783% · h) ~12 times higher (P = 0.01) than healthy control (AUC = 148% · h).</p><p><strong>Conclusions: </strong>p(HPMA-co-AzMA) of 54 kDa exhibited extended circulatory half-life and preferential accumulation in inflamed joints of a murine model of rheumatoid arthritis (RA). This combined with well-defined polymer size and versatility for conjugation of a range of biomolecules promotes p(HPMA-co-AzMA) for potential applications in the delivery of drugs for treatment of RA.</p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 ","pages":"29"},"PeriodicalIF":0.0,"publicationDate":"2014-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33252366","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}

{"title":"Gene therapy for cancer: present status and future perspective.","authors":"Magid H Amer","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Advancements in human genomics over the last two decades have shown that cancer is mediated by somatic aberration in the host genome. This discovery has incited enthusiasm among cancer researchers; many now use therapeutic approaches in genetic manipulation to improve cancer regression and find a potential cure for the disease. Such gene therapy includes transferring genetic material into a host cell through viral (or bacterial) and non-viral vectors, immunomodulation of tumor cells or the host immune system, and manipulation of the tumor microenvironment, to reduce tumor vasculature or to increase tumor antigenicity for better recognition by the host immune system. Overall, modest success has been achieved with relatively minimal side effects. Previous approaches to cancer treatment, such as retrovirus integration into the host genome with the risk of mutagenesis and second malignancies, immunogenicity against the virus and/or tumor, and resistance to treatment with disease relapse, have markedly decreased with the new generation of viral and non-viral vectors. Several tumor-specific antibodies and genetically modified immune cells and vaccines have been developed, yet few are presently commercially available, while many others are still ongoing in clinical trials. It is anticipated that gene therapy will play an important role in future cancer therapy as part of a multimodality treatment, in combination with, or following other forms of cancer therapy, such as surgery, radiation and chemotherapy. The type and mode of gene therapy will be determined based on an individual's genomic constituents, as well as his or her tumor specifics, genetics, and host immune status, to design a multimodality treatment that is unique to each individual's specific needs. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 ","pages":"27"},"PeriodicalIF":0.0,"publicationDate":"2014-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33252365","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}

{"title":"Selective vulnerability of motoneuron and perturbed mitochondrial calcium homeostasis in amyotrophic lateral sclerosis: implications for motoneurons specific calcium dysregulation.","authors":"Manoj Kumar Jaiswal","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disorder characterized by the selective degeneration of defined subgroups of motoneuron in the brainstem, spinal cord and motor cortex with signature hallmarks of mitochondrial Ca(2+) overload, free radical damage, excitotoxicity and impaired axonal transport. Although intracellular disruptions of cytosolic and mitochondrial calcium, and in particular low cytosolic calcium ([Ca(2+)]c) buffering and a strong interaction between metabolic mechanisms and [Ca(2+)]i have been identified predominantly in motoneuron impairment, the causes of these disruptions are unknown. The existing evidence suggests that the mutant superoxide dismutase1 (mtSOD1)-mediated toxicity in ALS acts through mitochondria, and that alteration in cytosolic and mitochondria-ER microdomain calcium accumulation are critical to the neurodegenerative process. Furthermore, chronic excitotoxcity mediated by Ca(2+)-permeable AMPA and NMDA receptors seems to initiate vicious cycle of intracellular calcium dysregulation which leads to toxic Ca(2+) overload and thereby selective neurodegeneration. Recent advancement in the experimental analysis of calcium signals with high spatiotemporal precision has allowed investigations of calcium regulation in-vivo and in-vitro in different cell types, in particular selectively vulnerable/resistant cell types in different animal models of this motoneuron disease. This review provides an overview of latest advances in this field, and focuses on details of what has been learned about disrupted Ca(2+) homeostasis and mitochondrial degeneration. It further emphasizes the critical role of mitochondria in preventing apoptosis by acting as a Ca(2+) buffers, especially in motoneurons, in pathophysiological conditions such as ALS. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 ","pages":"26"},"PeriodicalIF":0.0,"publicationDate":"2014-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33252364","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}

{"title":"Adoptive T-cell therapy for Leukemia.","authors":"Haven R Garber, Asma Mirza, Elizabeth A Mittendorf, Gheath Alatrash","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Allogeneic stem cell transplantation (alloSCT) is the most robust form of adoptive cellular therapy (ACT) and has been tremendously effective in the treatment of leukemia. It is one of the original forms of cancer immunotherapy and illustrates that lymphocytes can specifically recognize and eliminate aberrant, malignant cells. However, because of the high morbidity and mortality that is associated with alloSCT including graft-versus-host disease (GvHD), refining the anti-leukemia immunity of alloSCT to target distinct antigens that mediate the graft-versus-leukemia (GvL) effect could transform our approach to treating leukemia, and possibly other hematologic malignancies. Over the past few decades, many leukemia antigens have been discovered that can separate malignant cells from normal host cells and render them vulnerable targets. In concert, the field of T-cell engineering has matured to enable transfer of ectopic high-affinity antigen receptors into host or donor cells with greater efficiency and potency. Many preclinical studies have demonstrated that engineered and conventional T-cells can mediate lysis and eradication of leukemia via one or more leukemia antigen targets. This evidence now serves as a foundation for clinical trials that aim to cure leukemia using T-cells. The recent clinical success of anti-CD19 chimeric antigen receptor (CAR) cells for treating patients with acute lymphoblastic leukemia and chronic lymphocytic leukemia displays the potential of this new therapeutic modality. In this review, we discuss some of the most promising leukemia antigens and the novel strategies that have been implemented for adoptive cellular immunotherapy of lymphoid and myeloid leukemias. It is important to summarize the data for ACT of leukemia for physicians in-training and in practice and for investigators who work in this and related fields as there are recent discoveries already being translated to the patient setting and numerous accruing clinical trials. We primarily focus on ACT that has been used in the clinical setting or that is currently undergoing preclinical testing with a foreseeable clinical endpoint. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 ","pages":"25"},"PeriodicalIF":0.0,"publicationDate":"2014-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33247340","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}

{"title":"Stem cell in alternative treatments for brain tumors: potential for gene delivery.","authors":"Veronica Mariotti, Steven J Greco, Ryan D Mohan, George R Nahas, Pranela Rameshwar","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Despite ongoing research efforts and attempts to bring new drugs into trial, the prognosis for brain tumors remains poor. Patients with the most common and lethal intracranial neoplasia, glioblastoma multiforme (GBM), have an average survival of one year with combination of surgical resection, radiotherapy and temozolomide. One of the main problems in the treatment of GBM is getting drugs across the blood brain barrier (BBB) efficiently. In an attempt to solve this problem, there are ongoing experimental and clinical trials to deliver drugs within stem cells. The purpose for this method is the ease by which stem cells home to the brain. This review discusses the experimental and clinical applications of stem cells for GBM. We also discuss the different properties of stem cells. This information is important to understand why one stem cell would be advantageous over another in cell therapy. We provide an overview of the different drug delivery methods, gene-based treatments and cancer vaccines for GBM, including the stem cell subset. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 ","pages":"24"},"PeriodicalIF":0.0,"publicationDate":"2014-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33247339","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}

{"title":"Magnetic nanoparticles for oligodendrocyte precursor cell transplantation therapies: progress and challenges.","authors":"Stuart I Jenkins, Humphrey H P Yiu, Matthew J Rosseinsky, Divya M Chari","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Oligodendrocyte precursor cells (OPCs) have shown high promise as a transplant population to promote regeneration in the central nervous system, specifically, for the production of myelin - the protective sheath around nerve fibers. While clinical trials for these cells have commenced in some areas, there are currently key barriers to the translation of neural cell therapies. These include the ability to (a) image transplant populations in vivo; (b) genetically engineer transplant cells to augment their repair potential; and (c) safely target cells to sites of pathology. Here, we review the evidence that magnetic nanoparticles (MNPs) are a 'multifunctional nanoplatform' that can aid in safely addressing these translational challenges in neural cell/OPC therapy: by facilitating real-time and post-mortem assessment of transplant cell biodistribution, and biomolecule delivery to transplant cells, as well as non-invasive 'magnetic cell targeting' to injury sites by application of high gradient fields. We identify key issues relating to the standardization and reporting of physicochemical and biological data in the field; we consider that it will be essential to systematically address these issues in order to fully evaluate the utility of the MNP platform for neural cell transplantation, and to develop efficacious neurocompatible particles for translational applications. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 ","pages":"23"},"PeriodicalIF":0.0,"publicationDate":"2014-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33247338","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}

{"title":"Relevance of Wnt signaling for osteoanabolic therapy.","authors":"Timur A Yorgan, Thorsten Schinke","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The Wnt signaling pathway is long known to play fundamental roles in various aspects of embryonic development, but also in several homeostatic processes controlling tissue functions in adults. The complexity of this system is best underscored by the fact that the mammalian genome encodes for 19 different Wnt ligands, most but not all of them acting through an intracellular stabilization of β-catenin, representing the key molecule within the so-called canonical Wnt signaling pathway. Wnt ligands primarily bind to 10 different serpentine receptors of the Fzd family, and this binding can be positively or negatively regulated by additional molecules present at the surface of the respective target cells. One of these molecules is the transmembrane protein Lrp5, which has been shown to act as a Wnt co-receptor. In 2001, Lrp5, and thereby Wnt signaling, entered center stage in the research area of bone remodeling, a homeostatic process controlling bone mass, whose disturbance causes osteoporosis, one of the most prevalent disorders worldwide. More specifically, it was found that inactivating mutations of the human LRP5 gene cause osteoporosis-pseudoglioma syndrome, a rare genetic disorder characterized by impaired bone formation and persistence of hyaloid vessels in the eyeballs. In addition, activating LRP5 mutations were identified in individuals with osteosclerosis, a high bone mass condition characterized by excessive bone formation. Especially explained by the lack of cost-effective osteoanabolic treatment options, these findings had an immediate impact on the research regarding the bone-forming cell type, i.e. the osteoblast, whose differentiation and function is apparently controlled by Wnt signaling. This review summarizes the most important results obtained in a large number of studies, involving tissue culture experiments, mouse models and human patients. While there are still many open questions regarding the precise molecular interactions controlling Wnt signaling in osteoblasts, it is obvious that understanding this pathway is a key to optimize the therapeutic strategies for treating various skeletal disorders, including osteoporosis. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 ","pages":"22"},"PeriodicalIF":0.0,"publicationDate":"2014-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33247336","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}

{"title":"Gene therapy for malignant glioma.","authors":"Hidehiro Okura, Christian A Smith, James T Rutka","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Glioblastoma multiforme (GBM) is the most frequent and devastating primary brain tumor in adults. Despite current treatment modalities, such as surgical resection followed by chemotherapy and radiotherapy, only modest improvements in median survival have been achieved. Frequent recurrence and invasiveness of GBM are likely due to the resistance of glioma stem cells to conventional treatments; therefore, novel alternative treatment strategies are desperately needed. Recent advancements in molecular biology and gene technology have provided attractive novel treatment possibilities for patients with GBM. Gene therapy is defined as a technology that aims to modify the genetic complement of cells to obtain therapeutic benefit. To date, gene therapy for the treatment of GBM has demonstrated anti-tumor efficacy in pre-clinical studies and promising safety profiles in clinical studies. However, while this approach is obviously promising, concerns still exist regarding issues associated with transduction efficiency, viral delivery, the pathologic response of the brain, and treatment efficacy. Tumor development and progression involve alterations in a wide spectrum of genes, therefore a variety of gene therapy approaches for GBM have been proposed. Improved viral vectors are being evaluated, and the potential use of gene therapy alone or in synergy with other treatments against GBM are being studied. In this review, we will discuss the most commonly studied gene therapy approaches for the treatment of GBM in preclinical and clinical studies including: prodrug/suicide gene therapy; oncolytic gene therapy; cytokine mediated gene therapy; and tumor suppressor gene therapy. In addition, we review the principles and mechanisms of current gene therapy strategies as well as advantages and disadvantages of each. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 ","pages":"21"},"PeriodicalIF":0.0,"publicationDate":"2014-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33247337","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}

{"title":"Making sense of how HIV kills infected CD4 T cells: implications for HIV cure.","authors":"Nathan W Cummins, Andrew D Badley","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Defining how HIV does, and does not, kill the host CD4 T cell that it infects is of paramount importance in an era when research is approaching a cure for infection. Three mutually exclusive pathways can lead to the death of HIV-infected cells during the HIV life cycle, before, coincident and after HIV integration and consequently may affect viral replication. We discuss the molecular mechanism underlying these pathways, the evidence supporting their roles in vivo, and contemplate how understanding these pathways might inform novel approaches to promote viral cure of HIV. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 ","pages":"20"},"PeriodicalIF":0.0,"publicationDate":"2014-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33247334","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}

{"title":"Improvements in biomaterial matrices for neural precursor cell transplantation.","authors":"Nolan B Skop, Frances Calderon, Cheul H Cho, Chirag D Gandhi, Steven W Levison","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Progress is being made in developing neuroprotective strategies for traumatic brain injuries; however, there will never be a therapy that will fully preserve neurons that are injured from moderate to severe head injuries. Therefore, to restore neurological function, regenerative strategies will be required. Given the limited regenerative capacity of the resident neural precursors of the CNS, many investigators have evaluated the regenerative potential of transplanted precursors. Unfortunately, these precursors do not thrive when engrafted without a biomaterial scaffold. In this article we review the types of natural and synthetic materials that are being used in brain tissue engineering applications for traumatic brain injury and stroke. We also analyze modifications of the scaffolds including immobilizing drugs, growth factors and extracellular matrix molecules to improve CNS regeneration and functional recovery. We conclude with a discussion of some of the challenges that remain to be solved towards repairing and regenerating the brain. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 ","pages":"19"},"PeriodicalIF":0.0,"publicationDate":"2014-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33247335","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}