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2.  Cancer therapy with bispecific antibodies: Clinical experience 
The binding of at least two molecular targets simultaneously with a single bispecific antibody is an attractive concept. The use of bispecific antibodies as possible therapeutic agents for cancer treatment was proposed in the mid-1980s. The design and production of bispecific antibodies using antibody- and/or receptor-based platform technology has improved significantly with advances in the knowledge of molecular manipulations, protein engineering techniques, and the expression of antigens and receptors on healthy and malignant cells. The common strategy for making bispecific antibodies involves combining the variable domains of the desired mAbs into a single bispecific structure. Many different formats of bispecific antibodies have been generated within the research field of bispecific immunotherapeutics, including the chemical heteroconjugation of two complete molecules or fragments of mAbs, quadromas, F(ab’)2, diabodies, tandem diabodies and single-chain antibodies. This review describes key modifications in the development of bispecific antibodies that can improve their efficacy and stability, and provides a clinical perspective on the application of bispecific antibodies for the treatment of solid and liquid tumors, including the promises and research limitations of this approach.
PMCID: PMC3785321  PMID: 20521223
Bispecific antibody; cytotoxic T-lymphocyte; Fc receptor; immunotherapy; mAb; targeted T-cell; T-cell; tumor antigen
3.  Novel functions for small RNA molecules 
Small RNAs are short (~ 18 to 30 nucleotides), non-coding RNA molecules that can regulate gene expression in both the cytoplasm and the nucleus via post-transcriptional gene silencing (PTGS), chromatin-dependent gene silencing (CDGS) or RNA activation (RNAa). Three classes of small RNAs have been defined, including microRNAs (miRNAs), siRNAs and Piwi-interacting RNAs (piRNAs). Research has indicated that small RNAs play important roles in cellular processes such as cell differentiation, growth/proliferation, migration, apoptosis/death, metabolism and defense. Accordingly, small RNAs are critical regulators of normal development and physiology. More interestingly, increasing evidence indicates that small RNAs are involved in the pathogenesis of diverse diseases including cancer, cardiovascular disease, stroke, neurodegenerative disease, diabetes, liver disease, kidney disease and infectious disease. More than 20 clinical trials are ongoing to evaluate therapies based on small RNA. Additionally, small RNAs may serve as novel biomarkers and therapeutic targets for the majority of diseases.
PMCID: PMC3593927  PMID: 20072941
Biomarker; cell biology; disease; microRNA; small RNA; therapy
4.  Evading the immune response upon in vivo gene therapy with viral vectors 
Gene therapy has the potential to provide minimally invasive and long-term treatment for many inherited disorders that otherwise have poor prognoses and limited treatment options. The sustained therapeutic correction of genetic disease by viral gene transfer has been accomplished in patients with severe immune deficiencies, or by the transduction of an immune privileged site for the treatment of ocular disease. For other diseases and target tissues, immune responses to vectors or transgene products often present major obstacles for therapy. Innate and adaptive immunity, sometimes including preexisting or memory responses, may contribute by varying degrees to immune-mediated rejection and immunotoxicity. This review provides an overview of the immune responses to in vivo gene transfer with the most commonly used viral gene therapy vectors, and discusses strategies and protocols employed in evading the immune system in order to provide optimal gene therapy.
PMCID: PMC3584155  PMID: 19806497
Gene therapy; immune tolerance; AAV; adenovirus; lentivirus; immunity
5.  VCL-CB01, an injectable bivalent plasmid DNA vaccine for potential protection against CMV disease and infection 
Vaccines for the prevention of human CMV (hCMV) infection and disease are a major public health priority. Immunization with DNA vaccines encoding key proteins involved in the immune response to hCMV has emerged as a major focus of hCMV vaccine research. Validation of the protective effect of DNA vaccination in animal models has provided support for clinical trials. VCL-CB01, under development byVical Inc for the prevention of hCMV infection and disease, is a poloxamer-formulated, bivalent DNA vaccine that contains plasmids encoding hCMV tegument phosphoprotein 65 and the major hCMV surface glycoprotein B. In a phase I trial in healthy adults, VCL-CB01 was well tolerated. In interim results from a phase II trial in hCMV-seropositive hematopoietic cell transplant recipients, VCL-CB01 increased T-cell responses compared with placebo. The final results from the phase II trial will be of value for developing strategies to prevent hCMV disease in hCMV-seropositive transplant recipients, and may lead to other trials of VCL-CB01 or related vaccines for the prevention of congenital hCMV infection.
PMCID: PMC3539801  PMID: 19806506
6.  Cancer vaccines: current directions and perspectives in prostate cancer 
Numerous ongoing studies are investigating the use of cancer vaccines as a potential therapeutic modality for various tumor types. The efficacy of cancer vaccines has improved thanks to advances in the characterization of tumor-associated antigens, the development of better vaccine delivery systems, and the combination of vaccines with cytokines and other immunostimulants to enhance immune responses. Although cancer vaccines are being studied in many different tumor types, several characteristics of prostate cancer make it an ideal target for immunotherapy. Prostate cancer’s relative indolence allows sufficient time to generate immune responses, which usually take weeks or months to mount. In addition, prostate cancer-associated antigens direct the immune response to prostate cancer cells, thus sparing normal tissue. This review focuses on promising new approaches for combining vaccines with other therapeutic strategies, as well as novel perspectives in the treatment of prostate cancer.
PMCID: PMC3488286  PMID: 19169957
7.  Combining radiation and immunotherapy for synergistic antitumor therapy 
The combination of radiation therapy and immunotherapy holds enticing promise as a strategy for cancer treatment. Preclinical studies have shown that radiation may act synergistically with immunotherapy to enhance or broaden antitumor immune responses, in part due to radiation-induced phenotypic alterations of tumor cells that render them more susceptible to immune-mediated killing. Clinical trials employing the combination of therapeutic vaccines with radiation have confirmed many of these findings, and clinical endpoint human studies are both ongoing and planned. This review examines a) the evidence that radiation induces immunologic death, b) the mechanisms by which radiation therapy can induce or augment antitumor immune responses, and c) translational studies demonstrating that immunotherapy can be effectively combined with radiation therapy. Finally, we review recent and current clinical trials combining radiation therapy with immunotherapy.
PMCID: PMC3474202  PMID: 19169958
therapeutic vaccine; radiotherapy; cancer; immunopotentiation
8.  Recent advances in neuroproteomics 
The last few years have seen a rapid growth in the use of proteomic methods to study normal brain function as well as in the analysis of changes in protein expression that underlie the onset and progression of neuronal disease. However, the field of neuroproteomics faces special challenges given the complex cellular and sub-cellular architecture of the central nervous system. This article presents a review of recent progress in studies of neuroproteomics, and highlights the strengths and limitations of current proteomic profiling technologies used in studies of neuronal protein expression.
PMCID: PMC3373961  PMID: 17608026
Proteome; brain; gel electrophoresis; 2-DE; DIGE; LC-MS/MS; organelle; post-synaptic density; fractionation; phosphorylation; affinity chromatography
9.  siRNA-based topical microbicides targeting sexually transmitted diseases 
Sexually transmitted infections (STIs) are a major cause of morbidity and mortality worldwide. Although a vaccine is available for HPV, no effective vaccines exist for the HIV-1 and HSV-2 viral pathogens, and there are no cures for these infections. Furthermore, recent setbacks in clinical trials, such as the failure of the STEP trial to prevent HIV-1 infection, have emphasized the need to develop alternative approaches to interrupt transmission of these pathogens. One alternative strategy is represented by the use of topically applied microbicides, and such agents are being developed against various viruses. RNAi-based microbicides have recently been demonstrated to prevent HSV-2 transmission, and may be useful for targeting multiple STIs. In this review, microbicides that are under development for the prevention of STIs are described, with a focus on topically applied microbicidal siRNAs.
PMCID: PMC3282625  PMID: 20373263
HIV-1; HSV-2; microbicide; RNA interference; sexually transmitted infection; targeted therapy
10.  Emerging role of microRNAs in drug response 
Current pharmacogenomic studies have begun to integrate genetics, gene expression and pharmacologic phenotypes. MicroRNAs (miRNAs), small RNAs (21–25 nucleotides) found in almost all metazoan genomes, have been discovered to be a novel class of gene regulators that generally down-regulate gene expression at the post-transcriptional level. Experimental evidence for the roles of miRNAs in regulating pharmacology-related genes and drug response is now accumulating. Given the universal roles of miRNAs in various diseases such as human cancer, their potential effects on therapeutic treatments (e.g., chemotherapy) for these diseases could be expected. The on-going efforts of pharmacogenomics to incorporate miRNAs could provide more insights into the complex phenotype of drug response, though more studies may be necessary to evaluate their effects in patients since most of the current findings are indirect or in vitro.
PMCID: PMC3233195  PMID: 21154161
microRNA; gene expression; gene regulation; drug response; pharmacogene; pharmacogenomics
11.  The use of neural stem cells in cancer gene therapy: Predicting the path to the clinic 
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.
PMCID: PMC2958255  PMID: 20886386
Brain malignancy; cell carrier; gene therapy; glioma; NSC; neural stem cell; targeted tumor therapy
12.  Gene Therapy from the perspective of Systems Biology 
Gene therapy research has expanded from its original concept of replacing absent or defective DNA with functional DNA for transcription. Genetic material may be delivered via multiple vectors, including naked plasmid DNA, viruses and even cells with the goal of increasing gene expression; and the targeting of specific tissues or cell types is aimed at decreasing 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 pre-clinical models to clinical trials. Systems Biology, whose arsenal includes high-throughput experimental and computational studies that account for the complexities of host-disease-therapy interactions, holds significant promise in aiding the development and optimization of gene therapies, including personalized therapies and the identification of biomarkers for success of these strategies. In this review we describe 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; we also make references to anti-angiogenic gene therapy in cancer. The opportunities for Systems Biology and in silico modeling to improve on current outcomes are highlighted.
PMCID: PMC3021921  PMID: 20886389
Mathematical model; computational model; bioinformatics; angiogenesis; gene delivery; coronary artery disease; peripheral artery disease
13.  Splicing therapeutics in SMN2 and APOB 
Splicing therapeutics are defined as the deliberate modification of RNA splicing to achieve therapeutic goals. Various techniques for splicing therapeutics have been described, and most of these involve the use of antisense oligonucleotide-based compounds that target key elements in the pre-mRNA to control splicing in the nucleus. In this review, recent developments in splicing therapeutics for the treatment of two specific diseases are described: correcting the alternative splicing of survival of motor neuron (SMN)2 pre-mRNA to compensate for the defective SMN1 gene in spinal muscular atrophy, and re-engineering the splicing of apolipoprotein B pre-mRNA to lower circulating cholesterol levels.
PMCID: PMC3140428  PMID: 19330716
Antisense oligonucleotide; APOB; apolipoprotein B; cholesterol; RNA splicing; SMN2; spinal muscular atrophy
14.  Lentivirus as a Potent and Mechanistically Distinct Vector For Genetic Immunization 
T cell mediated immunity is critical for the prevention and control a broad range of infectious diseases and human malignancies. Genetic immunization is a promising approach for the elicitation of T-cell immunity. Recombinant lentivectors are now being developed and evaluated as antigen delivery platforms for genetic immunization and immune engineering. Early results are promising. Third generation lentivectors have been engineered to improve biosafety and reduce anti-vector immune responses. The ability of third generation lentivectors to efficiently transduce non-dividing cells, including dendritic cells, suggests important advantages compared to other antigen delivery platforms. Recent studies suggest that immunization with lentivectors induces remarkably potent and durable primary and memory T-cell immunity. The combination of skin targeted immunization and potentially unique mechanisms of immune induction likely contribute to the potent immunogenicity observed. Taken together, this accumulating evidence supports the ongoing development and clinical translation of lentivector-based genetic immunization strategies.
PMCID: PMC3065304  PMID: 17932808
genetic Immunization; vaccine; lentivirus; antigen presentation; skin immune system; dendritic cells
15.  Progress toward genetic tailoring of heart failure therapy 
Heart failure (HF) is a modern epidemic and a heterogeneous disorder with many therapeutic options. While the average response to each individual treatment is favorable, significant interindividual variation exists in the response to HF therapeutics. As a result, the optimal regimen for an individual patient or subgroup of patients is elusive, with current treatment being mainly empirical. Pharmacogenetic customization of HF therapy may provide an important opportunity to improve the treatment of HF. Common genetic variations exist in genes related to most classes of HF drugs, many of which have known functional consequences for or established relationships with drug response. This review summarizes the current understanding of the pharmacogenetics of HF therapeutics, including angiotensin-converting enzyme inhibitors and β-blockers, and focuses on recent advances and medium-term expectations for the field.
PMCID: PMC3048822  PMID: 20521218
Aldosterone antagonist; angiotensin-converting enzyme inhibitor; angiotensin receptor blocker; β-blocker; heart failure; personalized medicine; pharmacogenetics
16.  Non-Viral Ocular Gene Therapy: Assessment and Future Directions 
The purpose of this review is to give the general reader a brief overview of the current state of the field of non-viral ocular gene therapy. For multiple reasons the eye is an excellent organ for gene therapy application and while non-viral gene therapy modalities have been around for quite some time; they have only been applied to the eye in the last few years. This review will cover the exciting current trends in non-viral gene therapy and their application to the eye in addition to a brief summary of the status of ocular gene therapy in general.
PMCID: PMC2938038  PMID: 18830921
gene therapy; retina; nanoparticle; non-viral; minicircle; integrase
17.  Adeno-associated virus vector integration 
Adeno-associated virus (AAV) vectors efficiently transduce various cell types and can produce long-term expression of transgenes in vivo. Although AAV vector genomes can persist within cells as episomes, vector integration has been observed in various experimental settings, either at non-homologous sites where DNA damage may have occurred or by homologous recombination. In some cases, integration is essential for the therapeutic or experimental efficacy of AAV vectors. Recently, insertional mutagenesis resulting from the integration of AAV vectors was associated with tumorigenesis in mice, a consideration that may have relevance for certain clinical applications.
PMCID: PMC2929125  PMID: 19649989
Adeno-associated virus; gene integration; homologous recombination; insertional mutagenesis; vector
18.  Protein biomarkers in cancer: Natural glycoprotein microarray approaches 
Protein glycosylation is the most versatile and common protein modification and plays important roles in various biological processes and disease progression. In this review, the development of microarray technology for protein glycosylation analysis is described. Three types are discussed: carbohydrate, lectin and natural glycoprotein microarrays. The advantages of microarray technology to study protein glycosylation are high-volume throughput coupled with a highly miniaturized platform. These techniques show great promise for detecting interactions that involve carbohydrates and as a screening tool to detect glycan patterns important for the early diagnosis of disease.
PMCID: PMC2920894  PMID: 19051138
Carbohydrate microarray; glycoprotein microarray; glycosylation; lectin; lectin microarray
19.  Challenges To The Translation Of Genomic Information Into Clinical Practice And Health Policy: Utilization, Preferences, And Economic Value 
It is important to understand how knowledge of genomics can be translated from basic research into clinical practice and health policies. The objective of this paper is to review existing evidence on three key factors in the adoption of personalized medicine – utilization, preferences, and economic value - using two cancer examples: HER2/neu testing and trastuzumab (Herceptin®) and genetic testing for Lynch syndrome. Our findings suggest where further research is needed to build an evidence base addressing utilization of, preferences for, and the potential costs and benefits of personalized medicine. Major challenges include a lack of linked data, the need for relevant research frameworks and methodologies, and the clinical complexities of genomic-based diagnostics and treatment.
PMCID: PMC2910510  PMID: 18535933
Personalized medicine; health policy; health services research; economics; utilization; preferences
20.  An analysis of retinal gene therapy clinical trials: successful translation will depend on successful translation 
In 2008 the initial results from the first three retinal gene therapy trials using adeno-associated viral vectors to treat an inherited retinal degeneration were published. There were no significant vector-related side effects and there was evidence of successful gene transfer with improved vision in several patients. The success of these trials heralds the beginning of a new era in treatments for retinal diseases. Much can be learnt by comparing the results of the studies as each has subtle differences, both in surgical technique and in vector design. In contrast to laboratory models, humans generally harbour missense rather than null mutations and are treated much later, when recipient cells are compromised by the disease process. Intracellular stress responses, such as those regulated by endoplasmic reticulum protein kinase (PERK) and the mammalian target of rapamycin kinase (mTOR) pathways, are likely to inhibit translation of transgenic mRNA by mechanisms that will not be evident in null laboratory models treated early in the disease process. Understanding ways to overcome stress responses is likely to be a critical step in translating applications of gene therapy from animal models to other human retinal diseases.
PMCID: PMC2896974  PMID: 19806502
RPE65; LCA; AAV; clinical trial; retinitis pigmentosa; RP; genetics
22.  Transcriptional gene silencing mediated by non-coding RNAs 
Chromatin remodelling guided by non-coding RNA (ncRNA) contributes mechanistically to the establishment of chromatin structure and to the maintenance of epigenetic memory. Various ncRNAs have been identified as regulators of chromatin structure and gene expression. The widespread occurrence of antisense transcription in eukaryotes emphasizes the prevalence of gene regulation by natural antisense transcripts. Recently, antisense ncRNAs have been implicated in the silencing of tumor suppressor genes through epigenetic remodeling events. Characterization of the antisense RNAs involved in the development or maintenance of oncogenic states may define ncRNAs as early biomarkers for the emergence of cancer, and could have a significant impact on the development of tools for disease diagnosis and treatment. In this review, current knowledge on the mechanisms of ncRNA-mediated transcriptional gene silencing in humans is discussed, and parallels between the establishment of a silent chromatin state mediated by siRNAs and long antisense ncRNAs are highlighted.
PMCID: PMC2861437  PMID: 20373265
Antisense transcription; chromatin; epigenetic; non-coding RNA; siRNA; transcriptional gene silencing
23.  Progress toward therapy with antisense-mediated splicing modulation 
Antisense oligonucleotides (AO) or antisense RNA can complementarily bind to a target site in pre-mRNA and regulate gene splicing, either to restore gene function by reprogramming gene splicing or to inhibit gene expression by disrupting splicing. These two applications represent novel therapeutic strategies for several types of diseases such as genetic disorders, cancers and infectious diseases. In this review, the recent developments and applications of antisense-mediated splicing modulation in molecular therapy are discussed, with emphasis on advances in antisense-mediated splice targeting, applications in diseases and systematic delivery.
PMCID: PMC2753608  PMID: 19330717
Alternative splicing; antisense oligonucleotide; cancer; genetic disorders; molecular therapy; splicing modulation
24.  Clinical testing of engineered oncolytic measles virus strains in the treatment of cancer: An overview 
Viruses have adapted through millennia of evolution to effectively invade and lyse cells through diverse mechanisms. Strains of the attenuated measles virus Edmonston (MV-Edm) vaccine lineage can preferentially infect and destroy cancerous cells while sparing the surrounding tissues. This specificity is predominantly due to overexpression of the measles virus receptor CD46 in tumor cells. To facilitate in vivo monitoring of viral gene expression and replication, these oncolytic strains have been engineered to either express soluble marker peptides, such as the human carcinoembryonic antigen (CEA; MV-CEA virus), or genes that facilitate imaging and therapy, such as the human thyroidal sodium iodide symporter (NIS) gene (MV-NIS). Preclinical efficacy and safety data for engineered oncolytic MV-Edm derivatives that led to their clinical translation are discussed in this review, and an overview of the early experience in three ongoing clinical trials of patients with ovarian cancer, glioblastoma multiforme and multiple myeloma is provided. The information obtained from these ongoing trials will guide the future clinical application and further development of MV strains as anticancer agents.
PMCID: PMC2717625  PMID: 19169959
Brain tumor; clinical trial; measles virus; multiple myeloma; ovarian cancer; virotherapy
25.  MyoCell, a cell-based, autologous skeletal myoblast therapy for the treatment of cardiovascular diseases 
Cell therapy is fast emerging as a potential therapeutic option in cardiovascular therapeutics. Because of their inherent myogenic differentiation potential, skeletal myoblasts (SkMs) have been extensively assessed in preclinical and clinical studies for their feasibility, safety and effectiveness for myocardial repair. Bioheart Inc is developing MyoCell, autologous SkMs delivered by MyoCath and MyoStar catheter delivery systems for the treatment of cardiovascular diseases such as myocardial infarction and congestive heart failure. MyoCell is undergoing phase II/III clinical development and has so far demonstrated safety and efficacy, including improvements in cardiac function in phase I/II clinical trials.
PMCID: PMC2668534  PMID: 19051139

Results 1-25 (26)