Current Opinion in Molecular Therapeutics

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. Thus, caution is required when recruiting patients for clinical trials of gene therapies to ensure the benefit of the therapy outweighs the risks...

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...

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. Pharmacokinetic studies demonstrated a t1/2 in humans of up to 90 h, making dulaglutide an ideal candidate for once-weekly dosing...

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. Traditionally, PBE has been treated using corticosteroids, primarily dexamethasone. Introduced more than four decades ago, dexamethasone revolutionized the treatment of PBE, but the side effects and withdrawal symptoms associated with corticosteroids propelled the investigation of other drugs...

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...

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. Gevokizumab has a high affinity for IL-1β and a long t1/2, which would allow for once-monthly dosing and offer a considerable advantage for patients over agents requiring more frequent dosing...

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. Importantly, EGFRvIII is not expressed in normal brain tissue, making it an excellent therapeutic target...

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...

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)...

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. Molecular evidence derived from genetic techniques indicates atherosclerotic lesions may begin to form as arterial repair fails, rather than merely following arterial injury...

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...

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. Given the universal roles of miRNAs in various diseases, including cancer, miRNAs (eg, chemotherapy) are anticipated to have potential therapeutic effects in various diseases...

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. There is a focus on the consequences of microRNA (miRNA) de-regulation in human diseases, and recent progress in understanding other disease-related classes of ncRNAs, such as small nucleolar RNAs (snoRNAs), is presented...

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. However, many of these initiatives have proven less successful than expected...

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...

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...

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...

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...

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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. For these patients, FVIII-bypassing agents are proposed, but there is a rare risk of thrombotic events. Porcine pdFVIII successfully achieves hemostatic FVIII levels in patients in whom human FVIII was ineffective, but possible residual viral contamination and immunogenicity prevents routine use...