923 results match your criteria Current Opinion in Molecular Therapeutics[Journal]


Gene therapy: Have the risks associated with viral vectors been solved?

Authors:
J Todd Auman

Curr Opin Mol Ther 2010 Dec;12(6):637-8

Gene therapy has the potential to cure monogenic diseases through the replacement of the deleterious gene with a functional copy. While the field of gene therapy has been plagued by serious adverse events associated with therapy, it is hoped that new, safer viral vectors have reduced these risks greatly. However, recently published reports indicate that these new viral vectors are a potential risk to patients receiving gene therapy. Read More

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December 2010
8 Reads

Teduglutide, a glucagon-like peptide-2 analog for the treatment of gastrointestinal diseases, including short bowel syndrome.

Authors:
Roger Yazbeck

Curr Opin Mol Ther 2010 Dec;12(6):798-809

The University of Adelaide, Department of Medicine, Adelaide, South Australia 5005, Australia.

Glucagon-like peptide-2 (GLP-2) is a potent intestinotrophic growth factor with therapeutic potential for the prevention or treatment of an expanding number of gastrointestinal diseases, including short bowel syndrome (SBS). Teduglutide, being developed by NPS Allelix and licensee Nycomed, is a protease-resistant analog of GLP-2 for the potential treatment of gastrointestinal disease. Teduglutide has prolonged biological activity compared with native GLP-2, and preclinical studies demonstrated significant intestinotrophic activity in models of SBS, experimental colitis and chemotherapy-induced intestinal mucositis. Read More

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December 2010
9 Reads

Dulaglutide, a long-acting GLP-1 analog fused with an Fc antibody fragment for the potential treatment of type 2 diabetes.

Curr Opin Mol Ther 2010 Dec;12(6):790-7

University of Copenhagen, Gentofte Hospital, Department of Internal Medicine F, Niels Andersens Vej 65, 2900 Hellerup, Denmark.

Dulaglutide (LY-2189265) is a novel, long-acting glucagon-like peptide 1 (GLP-1) analog being developed by Eli Lilly for the treatment of type 2 diabetes mellitus (T2DM). Dulaglutide consists of GLP-1(7-37) covalently linked to an Fc fragment of human IgG4, thereby protecting the GLP-1 moiety from inactivation by dipeptidyl peptidase 4. In vitro and in vivo studies on T2DM models demonstrated glucose-dependent insulin secretion stimulation. Read More

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December 2010
36 Reads

Corticorelin, a synthetic human corticotropin-releasing factor analog, for the treatment of peritumoral brain edema.

Authors:
Kiran S Panickar

Curr Opin Mol Ther 2010 Dec;12(6):780-9

US Department of Agriculture, Beltsville Human Nutrition Research Center, Diet, Genomics & Immunology Laboratory, Building 307C, Beltsville, MD 20705, USA.

Corticorelin is a synthetic analog of the naturally occurring human peptide corticotropin-releasing factor (CRF). Several studies have indicated the ability of CRF to reduce the brain edema caused by brain tumors. Peritumoral brain edema (PBE), caused by an intracerebral tumor, manifests several features of vasogenic edema, which is a type of edema characterized by disruption of the blood-brain barrier. Read More

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December 2010
7 Reads

Mogamulizumab, a humanized mAb against C-C chemokine receptor 4 for the potential treatment of T-cell lymphomas and asthma.

Authors:
Sabina A Antoniu

Curr Opin Mol Ther 2010 Dec;12(6):770-9

University of Medicine and Pharmacy, Gr. T. Popa Iasi, Faculty of Medicine, Department of Medicine II - Pulmonary Disease, Pulmonary Disease University Hospital, 30 Dr I Cihac Street, Iasi 700115, Romania.

Mogamulizumab (KW-0761; AMG-761), under development by Kyowa Hakko Kirin and Amgen, is a defucosylated humanized IgG1 mAb against C-C chemokine receptor 4 (CCR4) for the potential intravenous treatment of T-cell lymphomas and asthma. Chemokines and their receptors are signaling molecules constitutively responsible for lymphocyte and neutrophil chemotaxis, which can also be involved in pathogenic mechanisms of various diseases. In particular, CCR4 has been demonstrated to play a major role in adult T-cell leukemia/lymphoma (ATL), in which it is a marker of poor prognosis. Read More

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December 2010
23 Reads

Gevokizumab, an anti-IL-1β mAb for the potential treatment of type 1 and 2 diabetes, rheumatoid arthritis and cardiovascular disease.

Curr Opin Mol Ther 2010 Dec;12(6):755-69

NIHR-Leeds Musculoskeletal Biomedical Research Unit, Leeds Institute of Molecular Medicine, Wellcome Trust Brenner Building, St. James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.

The inflammatory cytokine IL-1β has an essential role in the innate immune response. High levels of IL-1β have been implicated in the development of many diseases, including type 1 and 2 diabetes (T1D and T2D), rheumatoid arthritis (RA) and cardiovascular disease. XOMA is developing gevokizumab (XOMA-052), an IgG2 humanized mAb against human IL-1β, for the potential treatment of these diseases. Read More

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December 2010
7 Reads

Rindopepimut, a 14-mer injectable peptide vaccine against EGFRvIII for the potential treatment of glioblastoma multiforme.

Curr Opin Mol Ther 2010 Dec;12(6):741-54

Stanford University, 300 Pasteur Drive, Edwards R213, Stanford, CA 94305, USA.

Celldex Therapeutics is developing rindopepimut (CDX-110), a 14-mer injectable peptide vaccine for the potential treatment of glioblastoma multiforme (GBM). Rindopepimut specifically targets a novel junctional epitope of the EGFR deletion mutant EGFRvIII, which is a constitutively active receptor that is expressed in approximately 60 to 70% of patients with GBM. EGFRvIII expression is correlated with worse prognosis and reduced overall survival. Read More

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December 2010
8 Reads

Rozrolimupab, symphobodies against rhesus D, for the potential prevention of hemolytic disease of the newborn and the treatment of idiopathic thrombocytopenic purpura.

Authors:
Roberto Stasi

Curr Opin Mol Ther 2010 Dec;12(6):734-40

St George's Hospital, Department of Hematology, Blackshaw Road, Tooting, London, SW17 0QT, UK.

Currently under codevelopment by Symphogen and Swedish Orphan Biovitrum, rozrolimupab is the first in a new class of recombinant polyclonal antibodies, known as symphobodies, produced using a proprietary technology from Symphogen. Rozrolimupab is being investigated for the prevention of hemolytic disease of the fetus and newborn (HDFN) and for the treatment of idiopathic thrombocytopenic purpura (ITP). Rozrolimupab comprises 25 genetically unique IgG1 antibodies, all of which are specific for the rhesus D (RhD) erythrocyte protein. Read More

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December 2010
7 Reads

IPH-2101, a fully human anti-NK-cell inhibitory receptor mAb for the potential treatment of hematological cancers.

Authors:
Evren Alici

Curr Opin Mol Ther 2010 Dec;12(6):724-33

Karolinska Institutet, Karolinska University Hospital Huddinge, Department of Medicine, SE-14186 Stockholm, Sweden.

NK-cell activity against tumor cells is regulated by a complex balance of inhibitory and activating signals, which are mediated by the binding of NK-cell receptors to activating and inhibitory ligands expressed on tumor cells. Thus, the disruption of the inhibitory cascade would shift the balance to activation. IPH-2101 (1-7F9), being developed by Innate Pharma, is a fully human IgG4 anti-killer immunoglobulin-like receptor (KIR) mAb for the treatment of hematological malignancies, such as acute myeloid leukemia (AML) and multiple myeloma (MM). Read More

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December 2010
11 Reads

Inflammation, stem cells and atherosclerosis genetics.

Curr Opin Mol Ther 2010 Dec;12(6):712-23

University of Miami Leonard M Miller School of Medicine, Department of Medicine, Rosenstiel Medical Science Building, 1600 NW 10th Avenue, Miami, FL 33136, USA.

Atherosclerosis and its associated complications remain the primary cause of death in humans. Aging is the main contributor to atherosclerosis, compared with any other risk factor, yet the specific manner in which age increases risk (the 'aging-risk' mechanism) remains elusive. A novel concept for atherosclerosis risk implicates a lack of endothelial progenitor cell (EPC)-dependent arterial repair in the development of the disease that is secondary to exhaustion of repair-competent EPCs. Read More

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December 2010
9 Reads

Molecularly targeted therapies for colorectal cancer: Strategies for implementing translational research in clinical trials.

Curr Opin Mol Ther 2010 Dec;12(6):703-11

Medizinische Universitätsklinik, Anichstrasse 35, A-6020 Innsbruck, Austria.

Few breakthroughs in preclinical research have translated into meaningful benefits, either in clinical terms or quality of life, for patients with advanced colorectal cancer, despite important preclinical discoveries regarding aberrant biological pathways associated with disease development and progression. The many reasons for the slow progress are diverse, ranging from the failure to codevelop biomarkers and targeted therapies, the regulatory burdens imposed on academic investigators, and the failure to collect serial tumor biopsies during clinical trials. This review discusses promising translational research that could help reduce the disparity between preclinical discovery and patient benefit, and advocate the concentration of efforts and resources on the most promising therapeutic targets in colorectal cancer, such as EGFR, VEGF and Fcγ receptor. Read More

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December 2010
13 Reads

The emerging role of microRNAs in drug responses.

Curr Opin Mol Ther 2010 Dec;12(6):695-702

The University of Chicago, Department of Medicine and Committee on Clinical Pharmacology and Pharmacogenomics, 900 East 57th Street, Chicago, IL 60637, USA.

In recent years, pharmacogenomic research has begun to integrate genetics, gene expression and pharmacological phenotypes. MicroRNAs (miRNAs), 21- to 25-nucleotide, non-coding RNAs that are present in almost all metazoan genomes, are a class of gene regulators that downregulate gene expression at the post-transcriptional level. Experimental evidence for the role of miRNAs in regulating pharmacology-related genes and drug responses is increasing. Read More

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3233195PMC
December 2010
8 Reads

Small non-coding RNAs in disease development and host-pathogen interactions.

Curr Opin Mol Ther 2010 Dec;12(6):684-94

Innsbruck Medical University, Biocenter, Division for Genomics and RNomics, Fritz Pregl Strasse 3, A-6020 Innsbruck, Austria.

Non-coding RNAs (ncRNAs) play critical roles in all physiological processes. Many ncRNAs have also been implicated in a variety of pathological disorders, including cancer. This review provides an overview of the roles of small ncRNAs in infectious diseases and genetic disorders, including diseases of the CNS and various cancers. Read More

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December 2010
7 Reads

New druggable targets in the Ras pathway?

Curr Opin Mol Ther 2010 Dec;12(6):674-83

Universidad de Cantabria, Instituto de Biomedicina y Biotecnología de Cantabria, Consejo Superior de Investigaciones Científicas, IDICAN, Departamento de Biología Molecular, Facultad de Medicina, c/Cardenal Herrera Oria s/n, Santander, 39011 Cantabria, Spain.

Ras proteins are key elements in the regulation of cellular proliferation, differentiation and survival. Mutational activation of Ras or of components of its effector pathways are detected in one-third of human cancers and are essential for the genesis and maintenance of the tumoral phenotype. Research efforts have been dedicated to the development of therapeutic agents that inhibit aberrant Ras signals and, subsequently, tumor progression. Read More

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December 2010
10 Reads

Cancer stem cells - A therapeutic target?

Curr Opin Mol Ther 2010 Dec;12(6):662-73

University of York, YCR Cancer Research Unit, Department of Biology, York YO1 5YW, UK.

Cancer stem cells (CSCs) form a highly tumorigenic core in most human tumors. Although there is no consensus regarding CSC phenotype from different tumor types, CSCs from different cancers share a primitive undifferentiated nature, including a capacity to expand and differentiate, albeit aberrantly, into the major cell types observed in the corresponding tumor. This review focuses on the development of therapeutics targeting CSCs, for which new assays that replace those reporting the inhibition of cell division and rapid tumor shrinkage will be required to account for the quiescent nature and properties of CSCs. Read More

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December 2010
8 Reads

Pharmacogenetics of small-molecule tyrosine kinase inhibitors: Optimizing the magic bullet.

Curr Opin Mol Ther 2010 Dec;12(6):654-61

Leiden University Medical Center, Department of Clinical Oncology, PO Box 9600, 2300RC Leiden, the Netherlands.

Cancer treatment has undergone revolutionary changes during the past decade, as a result of the introduction of tyrosine kinase inhibitors (TKIs) that selectively inhibit growth factor pathways critical for tumor growth. Unexpected toxicity profiles and disappointing response rates to these 'magic bullets' have prompted research to identify markers that can predict toxicity or response to such agents. This review discusses the results of pharmacogenetic studies that have used germline DNA to assess the effects of various polymorphisms on currently available small-molecule TKIs. Read More

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December 2010
6 Reads

Convection-enhanced delivery to achieve widespread distribution of viral vectors: Predicting clinical implementation.

Curr Opin Mol Ther 2010 Dec;12(6):647-53

Wake Forest University School of Medicine, Department of Neurosurgery, Brain Tumor Center of Excellence, Medical Center Boulevard, Winston-Salem, NC 27157, USA.

Convection-enhanced delivery (CED) has been introduced to overcome the inability of many pharmacological agents to cross the blood-brain barrier, making these agents potentially effective in situ and suitable for the treatment of brain disorders. To achieve CED, drugs are pumped continuously through stereotactically placed catheters directly into the brain, or into or within the vicinity of a tumor mass. This medical technology has been applied to the local delivery of small-molecule drugs, including standard chemotherapeutics, and novel experimental targeted drugs, including targeted cytotoxins. Read More

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December 2010
8 Reads

In vitro diagnostics in the development and use of cardiovascular medicines.

Authors:
Robert J Leadley

Curr Opin Mol Ther 2010 Dec;12(6):639-46

Lead BioPharma Consulting LLC, 7726 Brass Creek Court, Dexter, MI 48130, USA.

The list of potential cardiovascular biomarkers has expanded dramatically in recent years; however, the number of regulatory agency-approved diagnostic tests that guide treatment has been relatively unchanged compared with this growth in the discovery of putative biomarkers. Surrogate biochemical endpoints such as LDL and HDL are included in the current guidelines of various regulatory agencies for the management of cardiovascular diseases, as a result of many years of research. Inclusion of tests for these markers, as well as any future tests, in treatment guidelines requires data obtained from large-scale clinical trials comparing these endpoints with 'hard' clinical endpoints, such as morbidity and mortality. Read More

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December 2010
7 Reads

The long and winding road to clinical success in gene therapy.

Authors:
Josef Rosenecker

Curr Opin Mol Ther 2010 Oct;12(5):507-8

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October 2010
14 Reads

OBI-1, porcine recombinant Factor VIII for the potential treatment of patients with congenital hemophilia A and alloantibodies against human Factor VIII.

Authors:
Vincenzo Toschi

Curr Opin Mol Ther 2010 Oct;12(5):617-25

San Carlo Borromeo Hospital, Department of Hematology and Blood Transfusion, Via Pio II, 3, 20153, Milan, Italy.

Hemophilia A is caused by a deficiency in blood coagulation Factor (F)VIII. Treatment for acute bleeding in patients comprises prophylactic infusion with human plasma-derived (pd) or recombinant (r)FVIII to increase circulating FVIII levels. However, alloantibodies (inhibitor) may arise in patients, limiting the efficacy of replacement therapy, especially in patients who develop high-titer inhibitors. Read More

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October 2010
13 Reads

BC-819, a plasmid comprising the H19 gene regulatory sequences and diphtheria toxin A, for the potential targeted therapy of cancers.

Curr Opin Mol Ther 2010 Oct;12(5):607-16

Fox Chase Cancer Center, Section of Urologic Oncology, Department of Surgical Oncology, 333 Cottman Avenue, Philadelphia, PA 19111, USA.

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. Read More

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October 2010
14 Reads

TA-CIN, a vaccine incorporating a recombinant HPV fusion protein (HPV16 L2E6E7) for the potential treatment of HPV16-associated genital diseases.

Authors:
Sam Hibbitts

Curr Opin Mol Ther 2010 Oct;12(5):598-606

Cardiff University, HPV Research Laboratories, Section of Obstetrics & Gynaecology School of Medicine, Heath Park, Cardiff, CF14 4XN, UK.

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. Read More

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October 2010
6 Reads

Sotatercept, a soluble activin receptor type 2A IgG-Fc fusion protein for the treatment of anemia and bone loss.

Curr Opin Mol Ther 2010 Oct;12(5):586-97

Harvard Medical School, Massachusetts General Hospital Cancer Center, Division of Hematology-Oncology, PO Box 216, 55 Fruit Street, Boston, MA 02114, USA.

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. Read More

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http://investor.acceleronpharma.com/common/download/download
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October 2010
14 Reads

The ethics of gene therapy: balancing the risks.

Curr Opin Mol Ther 2010 Oct;12(5):578-85

Children's Medical Research Institute, Gene Therapy Research Unit, 214 Hawkesbury Road, Australia.

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. Read More

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October 2010
28 Reads

Gene therapy from the perspective of systems biology.

Curr Opin Mol Ther 2010 Oct;12(5):570-7

Johns Hopkins University School of Medicine, Department of Biomedical Engineering, 720 Rutland Avenue, Baltimore, MD 21205, USA.

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. Read More

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021921PMC
October 2010
8 Reads

Gene therapy for liver cancer: clinical experience and future prospects.

Curr Opin Mol Ther 2010 Oct;12(5):561-9

Clinica Universitaria de Navarra, Liver Unit, Avenida Pio XII 36, 31008 Pamplona, Spain.

In contrast to the large quantity of preclinical evidence for efficacy, few gene therapy agents have reached clinical development for the treatment of primary and secondary liver cancer. This review discusses the published clinical trials that have explored the feasibility, safety and efficacy of gene therapy strategies for the treatment of liver cancer. Strategies include restoration of tumor suppressor genes, genetic prodrug-activating therapy, genetic immunotherapy and oncolytic virotherapy. Read More

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October 2010
10 Reads

Adeno-associated virus for the treatment of muscle diseases: toward clinical trials.

Curr Opin Mol Ther 2010 Oct;12(5):553-60

University of North Carolina at Chapel Hill, Gene Therapy Center, 7113 Thurston Building, Chapel Hill, NC 27510, USA.

Muscle diseases include muscular dystrophies, cardiomyopathies, neuromuscular and metabolic disorders. The loss of normal muscle structure and function is associated with significant morbidity and mortality. Patients with Duchenne muscular dystrophy usually lose ambulation in their teenage years, and frequently experience severe respiratory problems and heart failure in later stages of life. Read More

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October 2010
7 Reads

The use of neural stem cells in cancer gene therapy: predicting the path to the clinic.

Curr Opin Mol Ther 2010 Oct;12(5):546-52

The University of Chicago, The Brain Tumor Center, 5841 South Maryland Avenue, MC 3026, Chicago, IL 60637, USA.

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. Read More

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2958255PMC
October 2010
14 Reads
27 Citations

Cell therapy for peripheral arterial disease.

Curr Opin Mol Ther 2010 Oct;12(5):538-45

Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Cardiovascular Surgery, Université Paris Descartes, INSERM U 633, Paris, France.

Peripheral arterial disease remains an often devastating condition, particularly in patients with diabetes, because of the high rate of functional disability, amputation and death. For those patients for whom conventional endovascular or surgical revascularization procedures have been unsuccessful, new options are eagerly awaited, among which cell therapy has gained increasing interest. Most clinical trials of cell therapy have used multiple intramuscular injections of bone marrow-derived mononuclear cells that have yielded encouraging suggestions of efficacy. Read More

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October 2010
6 Reads

Oncolytic adenoviruses for the treatment of brain tumors.

Curr Opin Mol Ther 2010 Oct;12(5):530-7

The University of Texas MD Anderson Cancer Center, Department of Neuro-Oncology, Unit 1002, 1515 Holcombe Boulevard, Houston, TX 77030, USA.

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. Read More

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October 2010
7 Reads

Gene therapy for Parkinson's disease: from non-human primates to humans.

Curr Opin Mol Ther 2010 Oct;12(5):519-29

University of California San Francisco, Neurosurgery Department, 1855 Folsom Street, Mission Center Building Room 226, San Francisco, CA 94103, USA.

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. Read More

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October 2010
8 Reads

Gene therapy for tolerance and vice versa: a case for hemophilia.

Curr Opin Mol Ther 2010 Oct;12(5):509-18

University of Maryland School of Medicine, Center for Vascular and Inflammatory Diseases, Departments of Surgery, Microbiology and Immunology, 800 West Baltimore Street, Suite 3, Baltimore, MD 21201, USA.

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. Read More

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October 2010
15 Reads

Gene transfer and cell-based therapies.

Authors:
Alick C Stephens

Curr Opin Mol Ther 2010 Aug;12(4):381-2

King's College London, Department of Asthma, Allergy and Respiratory Science, 5th Floor, Tower Wing Guy's Hospital, London, SE1 9RT, UK.

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August 2010
5 Reads

Allogeneic somatic cell therapy: process development challenges and future opportunities.

Curr Opin Mol Ther 2010 Aug;12(4):383-5

Cell-replacement therapy has emerged during the past decade as a potential solution for many diseases. However, for this promise to be fulfilled, numerous process development challenges specific to these products need to be overcome. This editorial overview highlights some key observations derived from research on an allogeneic somatic cell therapy product for the treatment of Parkinson's disease. Read More

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August 2010
10 Reads

AMG-386, a selective angiopoietin-1/-2-neutralizing peptibody for the potential treatment of cancer.

Curr Opin Mol Ther 2010 Aug;12(4):487-95

Stanford University Cancer Center, 875 Blake Wilbur Drive, Stanford, CA 94305-5826, USA.

The VEGF/VEGFR and angiopoietin/Tie-2 signaling pathways are important in the process of vascular endothelial growth (angiogenesis) and in the maintenance of tumor-associated blood vessels. While there are several agents targeting the VEGF/VEGFR signaling pathway, there are none available that target the angiopoietin/Tie-2 signaling pathway. The first such agent to reach clinical trials is AMG-386 (2xCon4C), being developed by Amgen Inc and licensed in Japan to Takeda Bio Development Center Ltd. Read More

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August 2010
5 Reads

PRO-051, an antisense oligonucleotide for the potential treatment of Duchenne muscular dystrophy.

Curr Opin Mol Ther 2010 Aug;12(4):478-86

Oxford University, Department of Physiology, Anatomy and Genetics, Le Gros Clark Building, South Parks Road, Oxford OX1 3QX, UK.

PRO-051 (GSK-2402968), being developed by GlaxoSmithKline plc, under license from Leiden University Medical Center and Prosensa Therapeutics BV, is a 2'-O-methyl phosphorothioate antisense oligonucleotide for the potential treatment of Duchenne muscular dystrophy (DMD). The PRO-051 oligonucleotide sequence induces skipping of exon 51 of the dystrophin gene by binding to a sequence within the dystrophin pre-mRNA and masking the exon inclusion signals that are used for splicing. Removal of exon 51 from an exon 45 to 50, 47 to 50, 48 to 50, 49 to 50, 50, 52 or 52 to 63 deleted transcript allows restoration of the open reading frame and synthesis of an internally truncated, semi-functional dystrophin protein. Read More

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August 2010
5 Reads

tgAAG76, an adeno-associated virus delivered gene therapy for the potential treatment of vision loss caused by RPE65 gene abnormalities.

Authors:
Knut Stieger

Curr Opin Mol Ther 2010 Aug;12(4):471-7

Justus-Liebig-University Giessen, Department of Ophthalmology, Friedrichstrasse 18, Giessen 35385, Germany.

The gene therapy vector tgAAG76 (rAAV 2/2.hRPE65p.hRPE65) is in joint development by Targeted Genetics Corp, Moorfields Eye Hospital and the University of London. Read More

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August 2010
7 Reads

Subcutaneous administration of biotherapeutics: current experience in animal models.

Curr Opin Mol Ther 2010 Aug;12(4):461-70

Bayer HealthCare Pharmaceuticals Inc, 2600 Hilltop Drive, Richmond, CA 94806, USA.

In recent years, many peptide- and protein-based biotherapeutics have been approved for subcutaneous (SC) delivery. The mechanisms and factors affecting the uptake and distribution of such large molecules following SC administration are not well understood. This review outlines the factors influencing uptake, transport, distribution and species differences following the SC administration of biotherapeutics; improved understanding of these factors will facilitate the appropriate selection of animal models and improve predictivity for the bioavailability of drugs in humans. Read More

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August 2010
19 Reads

Adipose-derived stem and stromal cells for cell-based therapy: current status of preclinical studies and clinical trials.

Authors:
Hiroshi Mizuno

Curr Opin Mol Ther 2010 Aug;12(4):442-9

Juntendo University School of Medicine, Department of Plastic and Reconstructive Surgery, 2-1-1 Hongo Bunkyo-ku, Tokyo 1138421, Japan.

The potential use of stem cell-based therapies for the repair and regeneration of various tissues and organs offers a paradigm shift that may provide alternative therapeutic solutions for several diseases. The clinical use of either embryonic stem cells or induced pluripotent stem cells remains limited because of cell regulations, ethical considerations and the requirement for genetic manipulation, although these cells are theoretically highly beneficial. Adipose-derived stem cells (ASCs) appear to be an ideal population of stem cells for practical regenerative medicine, given that they are plentiful, of autologous tissue origin and thus non-immunogenic, and are more easily available because of minimal ethical considerations. Read More

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August 2010
11 Reads

Stem cells for the treatment of heart failure.

Curr Opin Mol Ther 2010 Aug;12(4):432-41

Loma Linda University School of Medicine, Department of Pathology and Human Anatomy, 24760 Stewart Street, Loma Linda, CA 92350, USA.

An increasing number of clinical trials are enrolling patients in studies designed to examine the safety and efficacy of autologous stem cells for cardiac repair. Recent reports suggest that most patients receiving autologous cell-based therapies after myocardial infarction, or as a treatment for ischemic cardiomyopathy, benefit from a modest increase in global left ventricular function. Despite a significant amount of variability in efficacy reported among different treatment centers, most studies demonstrate an improvement in the ejection fraction that ranges between 2 and 7% after stem cell treatment. Read More

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August 2010
6 Reads

Adenovirus-based therapy for prostate cancer.

Curr Opin Mol Ther 2010 Aug;12(4):421-31

Queen Mary University of London, John Vane Science Centre, Centre for Molecular Oncology and Imaging, Barts and the London School of Medicine and Dentistry, Charterhouse Square, London, EC1M 6BQ, UK.

Prostate cancer is the second leading cause of cancer-related death in men in the Western world, despite efforts toward improving treatment strategies and earlier detection of this disease. A promising and relatively novel drug platform is virotherapy, which has demonstrated potent and selective antitumor efficacy in cancer cell lines and in preclinical in vivo tumor models, accompanied by minimal toxicity to normal cells. Safety and limited toxicity has also been demonstrated in many clinical trials targeting various solid cancers. Read More

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August 2010
6 Reads

Blood compatibility of enveloped viruses.

Curr Opin Mol Ther 2010 Aug;12(4):412-20

University of Oxford, Department of Clinical Pharmacology Research Building, Old Road Campus, Roosevelt Drive, Oxford, OX3 7DQ, UK.

A significant limitation to the use of viruses as systemic vectors is the susceptibility of the vector to inactivation and clearance by various blood components. Despite much focus on antibodies as the primary neutralizing molecules in blood, other mechanisms inactivate and clear virus particles from the bloodstream in both naïve and pre-immune hosts. This review provides an overview of the major blood components that interact with enveloped viruses. Read More

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August 2010
6 Reads

Design of virotherapy for effective tumor treatment.

Curr Opin Mol Ther 2010 Aug;12(4):403-11

University of Navarra, Center for Applied Medical Research, Gene Therapy Unit, Avenue Pio XII 55, 31008 Pamplona, Spain.

The use of viruses as therapeutic agents against cancer is an old concept that has had a significant revival in the past two decades, in parallel with advances in methods to modify viral genomes genetically. From the initial stage of proof of concept, the field of virotherapy quickly progressed to the clinical setting, where serious limitations, yet promising opportunities, were identified. After demonstrating good safety profiles in humans, the objective in virotherapy has become to improve the efficacy of oncolytic viruses. Read More

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August 2010
7 Reads

Potentiating oncolytic viruses by targeted drug intervention.

Curr Opin Mol Ther 2010 Aug;12(4):394-402

Children's Hospital of Eastern Ontario Research Institute, Apoptosis Research Centre, 401 Smyth Road, Ottawa, ON K1H 8L1, Canada.

Oncolytic virus therapy (OVT) is a promising treatment modality for cancer that uses tumor-specific defects to target cancer cells selectively. An increasing number of replicating viruses has been demonstrated to cure cancer in a diverse set of animal models. Accordingly, many such viruses have entered the clinic, with several phase III clinical trials having recently been approved or initiated. Read More

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August 2010
6 Reads

Strategies for long-term expression of transgenes in the respiratory epithelium.

Curr Opin Mol Ther 2010 Aug;12(4):386-93

University of Oxford, Gene Medicine Research Group, Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK.

Lung gene therapy is being developed to treat acute and chronic airway diseases, and many viral and non-viral gene transfer vectors have been evaluated in the airway epithelium lining the nose and lung. Stem cells have not been clearly defined in the airways and, currently, it is only possible to target progenitor cells to proliferate and repair the epithelium after inducing epithelial damage. However, the majority of airway epithelial cells are slowly dividing or terminally differentiated, thus necessitating repeated administration of gene transfer vectors for life-long transgene expression. Read More

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August 2010
6 Reads

Do pharmacogenetics, genomics and epigenetics hold promise for molecular therapeutics and health?

Authors:
Lukas A Huber

Curr Opin Mol Ther 2010 Jun;12(3):268-9

Pharmacogenetics, genomics and epigenetics have attracted the interest of both pharmaceutical research groups and the medical community. The promise of these rapidly developing research fields and the expected consequences for medicine and for the pharmaceutical industry are timely topics of interest in molecular therapeutics. Of particular interest is their role in supporting the ability to customize medical care to individual patients. Read More

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June 2010
6 Reads

Dalotuzumab, a recombinant humanized mAb targeted against IGFR1 for the treatment of cancer.

Curr Opin Mol Ther 2010 Jun;12(3):361-71

AO Ospedali Riuniti-Università Politecnica delle Marche, Clinica di Oncologia Medica, Via conca, 60020, Ancona, Italy.

Dalotuzumab (MK-0646; h7C10), being developed by Merck & Co Inc under license from Pierre Fabre SA, is a recombinant humanized IgG1 mAb against the IGFR1 for the potential intravenous treatment of cancer. Preclinical studies have demonstrated that dalotuzumab acts by inhibiting IGF-1- and IGF-2-mediated tumor cell proliferation, IGFR1 autophosphorylation and Akt phosphorylation. In multiple cancer cell lines and in mouse xenograft models, dalotuzumab displayed significant antitumor activity, in particular against NSCLC and breast cancer. Read More

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June 2010
21 Reads

Trastuzumab emtansine, an antibody-drug conjugate for the treatment of HER2+ metastatic breast cancer.

Curr Opin Mol Ther 2010 Jun;12(3):350-60

Institute of Cancer Research, Cancer Research Campaign Centre for Cancer Therapeutics, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK.

Roche Holding AG, and its subsidiaries Genentech Inc and Chugai Pharmaceutical Co Ltd, are developing trastuzumab emtansine (trastuzumab-DM1) for the treatment of HER2+ metastatic breast cancer. Trastuzumab emtansine is a tumor-activated prodrug resulting from the conjugation of the humanized anti-HER2 mAb trastuzumab, which has been used in the treatment of breast cancer for over 10 years, with ImmunoGen Inc's cytotoxic and antimitotic maytansine derivative DM1. The maytansinoids bind microtubules in a manner similar to the vinca alkaloids; however, maytansinoids have been recognized to be 20- to 100-fold more potent at blocking mitosis. Read More

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June 2010
12 Reads

Cancer therapy with bispecific antibodies: Clinical experience.

Curr Opin Mol Ther 2010 Jun;12(3):340-9

Barbara Ann Karmanos Cancer Institute, Wayne State University, Department of Medicine, Detroit, MI 48201, USA.

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. Read More

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3785321PMC
June 2010
7 Reads