Prospects of RNA interference therapy for cancer

RNA interference (RNAi) is a powerful gene-silencing process that holds great promise in the field of cancer therapy. The discovery of RNAi has generated enthusiasm within the scientific community, not only because it has been used to rapidly identify key molecules involved in many disease processes including cancer, but also because RNAi has the potential to be translated into a technology with major therapeutic applications. Our evolving understanding of the molecular pathways important for carcinogenesis has created opportunities for cancer therapy employing RNAi technology to target the key molecules within these pathways. Many gene products involved in carcinogenesis have already been explored as targets for RNAi intervention, and RNAi targeting of molecules crucial for tumor-host interactions and tumor resistance to chemo- or radiotherapy has also been investigated. In most of these studies, the silencing of critical gene products by RNAi technology has generated significant antiproliferative and/or proapoptotic effects in cell-culture systems or in preclinical animal models. Nevertheless, significant obstacles, such as in vivo delivery, incomplete suppression of target genes, nonspecific immune responses and the so-called off-target effects, need to be overcome before this technology can be successfully translated into the clinical arena. Significant progress has already been made in addressing some of these issues, and it is foreseen that early phase clinical trials will be initiated in the very near future.     

RNA interference therapy for glioblastoma

Importance of the field: Despite numerous advances made during the last decade in brain tumor therapy, the prognosis of glioblastoma has not improved and these tumors inevitably recur with no effective treatment. Thus, any new therapeutic strategy to target this most malignant tumor will be of significant benefit. RNAi is a powful gene silencing method that might be used in combination with other agents to improve the efficacy of glioblastoma treatment.

Areas covered in this review: Recent progress and challenges of pre-clinical and clinical research of RNAi therapy for glioblastoma. The review covers literature from 2003 to 2009.

What the reader will gain: The principle of RNA interference therapy, three categories of RNAi triggers, different RNAi delivery system and pre-clinical and clinical studies that are currently underway to evaluate the validity of RNAi as a potential therapeutic strategy against glioblastoma are discussed.

Take home message: RNA inference therapy combined with other therapeutics may offer therapeutic potential for glioblastoma multiforme. Further studies are required to develop more efficient and specific delivery systems, select suitable gene targets, optimize treatment dose and administration schedule, evaluate the efficacy of combination treatment strategies, establish a validated clinical response measure system etc.     

Oncolytic-adenovirus-expressed RNA interference for cancer therapy

Importance of the field: RNA interference (RNAi) has generated considerable excitement for its potential cancer therapeutic applications. Because of the difficulties in delivering a large amount of siRNA to cancer cells and the short half-life of siRNA, it is important to choose an efficient delivery system for transduction of siRNA into target cells. Oncolytic adenovirus offers a better platform by virtue of its high transfection efficiency and selective replication in cancer cells.

Areas covered in this review: This review focuses on the synergism between oncolytic adenovirus and siRNA antitumor responses, and discusses recent progresses in oncolytic-adenovirus-expressed siRNA.

What the reader will gain: siRNA-expressing oncolytic adenovirus can generate a significantly enhanced antitumor effect through gene knockdown and viral oncolysis.

Take home message: Due to its potency and target specificity, using siRNA delivery by oncolytic adenovirus has generated much excitement and will open new avenues for treatment of human cancer.     

Photodynamic therapy for esophageal diseases: a clinical update

Photodynamic therapy (PDT) is a "drug and device" therapy that combines the use of a photosensitizing agent and a photosensitizer (a drug that selectively accumulates and is preferentially retained in dysplastic or neoplastic cells). When activated by light of a specific wavelength in the presence of oxygen, the photoactive compound produces rapid cell death in the target tissue. While studied in nearly every area of medicine, PDT has been applied most extensively in the treatment of Barrett's mucosa, dysplasia, and early and advanced cancer of the esophagus. This article represents an extensive survey of literature to review the experience gained with PDT and to assess its clinical value in the management of esophageal diseases.     

RNA interference for treating cancers caused by viral infection

The newly discovered phenomenon of RNA interference (RNAi) offers the dual facility of selective viral gene silencing coupled with ease of tailoring to meet genetic variation within the viral genome. Such promise identifies RNAi as an exciting new approach to treat viral-induced diseases, including viral-induced cancers (e.g. cervical carcinoma, hepatocellular carcinomas and haematopoietic and lymphoid malignancies). Cervical cancer is the second most common cancer in women worldwide and is caused by human papilloma virus (HPV). Silencing of HPV gene expression by RNAi induces apoptosis of cervical carcinoma cells in culture, and the effect is apparent within 3 days. The RNAi process is triggered by double-stranded RNA (dsRNA), and a single dose is sufficient to maintain RNAi for several days in vitro (cell culture) and in vivo (experimental animal models). Thus, the stage is set for the development of novel antiviral and anticancer therapies based upon selective gene silencing by RNA interference.     

Mechanisms of cellular therapy in respiratory diseases

Purpose  

Stem cells present a variety of clinical implications in the lungs. According to their origin, these cells can be divided into embryonic and adult stem cells; however, due to the important ethical and safety limitations that are involved in the embryonic stem cell use, most studies have chosen to focus on adult stem cell therapy. This article aims to present and clarify the recent advances in the field of stem cell biology, as well as to highlight the effects of mesenchymal stem cell (MSC) therapy in the context of acute lung injury/acute respiratory distress syndrome and chronic disorders such as lung fibrosis and chronic obstructive pulmonary disease.     

Therapeutic RNA interference for neurodegenerative diseases: From promise to progress

RNA interference (RNAi) has emerged as a powerful tool to manipulate gene expression in the laboratory. Due to its remarkable discriminating properties, individual genes, or even alleles can be targeted with exquisite specificity in cultured cells or living animals. Among its many potential biomedical applications, silencing of disease-linked genes stands out as a promising therapeutic strategy for many incurable disorders. Neurodegenerative diseases represent one of the more attractive targets for the development of therapeutic RNAi. In this group of diseases, the progressive loss of neurons leads to the gradual appearance of disabling neurological symptoms and premature death. Currently available therapies aim to improve the symptoms but not to halt the process of neurodegeneration. The increasing prevalence and economic burden of some of these diseases, such as Alzheimer's disease (AD) or Parkinson's disease (PD), has boosted the efforts invested in the development of interventions, such as RNAi, aimed at altering their natural course. This review will summarize where we stand in the therapeutic application of RNAi for neurodegenerative diseases. The basic principles of RNAi will be reviewed, focusing on features important for its therapeutic manipulation. Subsequently, a stepwise strategy for the development of therapeutic RNAi will be presented. Finally, the different preclinical trials of therapeutic RNAi completed in disease models will be summarized, stressing the experimental questions that need to be addressed before planning application in human disease.     

RNA干扰与神经退行性疾病的治疗

目的：神经退行性病变是人类神经系统的严重疾病之一，对于神经退行性疾病的治疗目前尚无有效方法，本文探讨RNA干扰技术运用于该病动物模型中的有效性，从而为进一步运用于临床提供可能。 资料来源：应用计算机检索PubMed 1990—01／2006—03期间的有关神经退行性病变和RNA干扰的文献，检索词“RNAinterference，neurodegenerative disorders，functional recovery，mouse model，transfection”，并限定文章语言种类为English。研究对象为进行RNA干扰治疗的各类型神经退行性病变的动物小鼠模型。 资料选择：选取试验包括各类型神经退行性病变RNA干扰治疗组和对照组的脑内致病基因的表达，细胞组织形态学，行为学变化比较的相关文献，进行初审，删除明显不符合动物模型试验的研究，然后查找余下的文献全文，进一步判断是否为随机动物模型试验。纳入标准：①随机动物模型试验，无论是否为单盲、双盲、或非盲法。②平行对照组，即未进行RNA干扰治疗的神经退行性病变的小鼠动物模型或健康对照；治疗组为进行RNA干扰治疗的神经退行性病变的小鼠动物模型。排除标准：明显不随机的动物模型试验或非动物模型研究。质量评价主要考察资料的真实性，试验设计是否合理，观测检验过程是否严格，统计学处理是否有说服力。 资料提炼：共检索32篇关于研究RNA干扰治疗与神经退行性病变的试验，3类4种神经退行性病变共22篇符合纳入标准。排除的6篇是重复的同一研究，4篇不符合小鼠模型试验。 资料综合：3类4种神经退行性病变共69个动物模型，分别对进行RNA干扰治疗或未治疗的神经退行性病变小鼠动物模型进行脑内致病基因的表达，细胞组织形态学，行为学变化的比较分析。 结论：RNA干扰对神经退行性病变的3类4种小鼠动物模型均有效，为RNA干扰治疗进入临床铺垫了基础。     

RNA干扰与神经退行性疾病的治疗

目的:神经退行性病变是人类神经系统的严重疾病之一,对于神经退行性疾病的治疗目前尚无有效方法,本文探讨RNA干扰技术运用于该病动物模型中的有效性,从而为进一步运用于临床提供可能。资料来源:应用计算机检索PubMed1990-01/2006-03期间的有关神经退行性病变和RNA干扰的文献,检索词“RNAinterference,neurodegen-erativedisorders,functionalrecovery,mousemodel,transfection”,并限定文章语言种类为English。研究对象为进行RNA干扰治疗的各类型神经退行性病变的动物小鼠模型。资料选择:选取试验包括各类型神经退行性病变RNA干扰治疗组和对照组的脑内致病基因的表达,细胞组织形态学,行为学变化比较的相关文献,进行初审,删除明显不符合动物模型试验的研究,然后查找余下的文献全文,进一步判断是否为随机动物模型试验。纳入标准:①随机动物模型试验,无论是否为单盲、双盲、或非盲法。②平行对照组,即未进行RNA干扰治疗的神经退行性病变的小鼠动物模型或健康对照;治疗组为进行RNA干扰治疗的神经退行性病变的小鼠动物模型。排除标准:明显不随机的动物模型试验或非动物模型研究。质量评价主要考察资料的真实性,试验设计是否合理,观测检验过程是否严格,统计学处理是否有说服力。资料提炼:共检索32篇关于研究RNA干扰治疗与神经退行性病变的试验,3类4种神经退行性病变共22篇符合纳入标准。排除的6篇是重复的同一研究,4篇不符合小鼠模型试验。资料综合:3类4种神经退行性病变共69个动物模型,分别对进行RNA干扰治疗或未治疗的神经退行性病变小鼠动物模型进行脑内致病基因的表达,细胞组织形态学,行为学变化的比较分析。结论:RNA干扰对神经退行性病变的3类4种小鼠动物模型均有效,为RNA干扰治疗进入临床铺垫了基础。     

Antiviral therapy for respiratory viral infections in immunocompromised patients

Introduction: Respiratory viruses (influenza, parainfluenza, respiratory syncytial virus, coronavirus, human metapneumovirus, and rhinovirus) represent the most common causes of respiratory viral infections in immunocompromised patients. Also, these infections may be more severe in immunocompromised patients than in the general population. Early diagnosis and treatment of viral infections continue to be of paramount importance in immunocompromised patients; because once viral replication and invasive infections are evident, prognosis can be grave.

Areas covered: The purpose of this review is to provide an overview of the main antiviral agents used for the treatment of respiratory viral infections in immunocompromised patients and review of the new agents in the pipeline.

Expert commentary: Over the past decade, important diagnostic advances, specifically, the use of rapid molecular testing has helped close the gap between clinical scenarios and pathogen identification and enhanced early diagnosis of viral infections and understanding of the role of prolonged shedding and viral loads. Advancements in novel antiviral therapeutics with high resistance thresholds and effective immunization for preventable infections in immunocompromised patients are needed.     

Viral-based modelling and correction of neurodegenerative diseases by RNA interference

Experimental recapitulation of recessive human genetic neurodegenerative disease in rodents can be classically addressed through genetic disruption of the related gene. Although very informative, this specific gene targeting is restricted to mice and precludes a species scale-up towards non-human primates. Concomitantly, this requirement to silence a specific gene in a broad range of animal models is important in the design of therapeutic approaches to dominantly inherited neurodegenerative diseases. The emergence of RNA interference (RNAi), a highly specific mechanism of post-translational gene silencing, has opened a plethora of biological application ranging from reverse genetic analysis to therapeutic schemes. Recombinant viral vectors, by promoting a long-lasting delivery of genetic instructions in a broad range of cellular types of different species origins, represent potential platforms mandating silencing of specific gene products through RNAi. This review aims at providing an overview of the different viral systems engineered so far for efficient in vitro and in vivo delivery of RNAi instructions. Additionally, the potential of RNAi for functional analysis and therapy for polyglutamine disorders or amyotrophic lateral sclerosis is discussed.     

Prospects and RISC score of viral gene therapy for sarcoma

Soft tissue sarcomas are a challenge for medical oncology and gene therapy. Protective and sensitising approaches that target normal and malignant tissue, respectively, both have their role for opening the therapeutic window. Recent data show that an intensive maintenance chemotherapy significantly reduces metastatic spread and improves disease-free survival in selected patient groups. However, delays of treatment due to cytopenia are frequent. Cytostatic drug resistance gene transfer to haematopoietic progenitor cells using retroviral vectors may allow further improvement of therapy results. In recent years, retroviral vector design, transduction techniques and engraftment capability of transduced cells have been optimised. Safety considerations of retroviral gene transfer have attracted public attention and can be addressed by analysis of genomic vector integration sites. A data bank project, 'retroviral insertion estimate of chromosomal integration' (RISC), containing > 200 integration sequences, has been set up by the authors' group to recognise critical genomic regions and genes involved with possible transforming capacity. Monitoring these parameters will allow the selection of the most suitable vectors for clinical application. Sarcoma cells seem to be highly susceptible to a variety of vectors, such as recombinant adeno-associated virus-2 (rAAV-2) vectors, adenoviral vectors or oncolytic herpes simplex viruses. Results from the first clinical trials with adenoviral vectors encoding for cytokines are promising. The other systems await further development towards clinical applications. Perspectives for further research are discussed in this review.     

Neuroimmunological diseases: update

During the past 10 to 20 years, disease modifying drugs have been introduced into clinical practice relating to neuroimmunological diseases such as multiple sclerosis, myasthenia gravis, and Guillain-Barré syndrome. Based on the mechanism of each disease, therapies are currently being developed that target crucial molecules involved in the disease process. Monoclonal antibodies, such as natalizumab against VLA-4 and alemtuzumab against CD52 antibody, have been found to be very effective for reducing relapse rates and for preventing disease progression in multiple sclerosis. However, molecular-targeted therapy may disrupt the immune balance of patients and unexpectedly induce other autoimmune diseases or opportunistic infections. Therefore, to overcome intractable neuroimmunological diseases utilizing molecular-targeted therapies, future research needs deeper insights into the mechanism of each disease along with close observations of clinical courses.     

An update on RNA interference-mediated gene silencing in cancer therapy

Introduction: Based on our previous review, this article presents the new progress in RNA interference (RNAi)-mediated gene silencing in cancer therapy, and reviews the hurdles and how they might be overcome.

Areas covered: RNAi-mediated gene silencing approaches have been demonstrated in humans, and ongoing clinical trials hold promise for treating cancer or providing alternatives to traditional chemotherapies. Here we describe the broad range of approaches to achieve targeted gene silencing for cancer therapy, discuss the progress made in developing RNAi as therapeutics for cancer and highlight challenges and emerging solutions associated with its clinical development.

Expert opinion: Although the field of RNAi-based cancer therapy is still an emerging one, we have yet to get solutions for overcoming all obstacles associated with its clinical development. The current rapid advances in development of new targeted delivery strategies and noninvasive imaging methods will be big steps to explore RNAi as a new and potent clinical modality in humans.