Current Opinion in Molecular Therapeutics

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...

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...

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...

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...

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...

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. In these trials, transgene expression of varying degrees has been detected...

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. These unmet medical needs have encouraged the development of genetic strategies targeting the underlying muscle disease processes...

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...

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...

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. It has been suggested that the use of autophagy inducers, such as rapamycin, can enhance the oncolytic potency of recombinant adenoviruses...

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...

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. Recent advances have been made in gene therapy in the field of hemophilia...

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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.

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. AMG-386 is an anti-angiopoietin peptibody comprising a peptide with angiopoietin-binding properties that is fused to the Fc (crystallizable fragment) region of an antibody and inhibits the interaction between the ligands angiopoietin-1 and angiopoietin-2 with the Tie-2 receptor...

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...

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. The vector is a recombinant adeno-associated virus vector that contains the human RPE65 gene under the control of the human RPE65 promoter region and the bovine growth hormone polyadenylation signal. The vector was designed for administration into the subretinal space of patients affected by a hereditary blinding disorder, Leber congenital amaurosis type 2, which is caused by mutations in the RPE65 gene...

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...

One of the first strategies for cancer gene therapy was the use of suicide gene/prodrug combinations, originally delivered to tumor cells using viral vectors. A major limitation of this approach was the inefficiency of suicide gene delivery. An alternative strategy, in which the suicide genes are physically juxtaposed to the tumor, involves the implantation of encapsulated, genetically modified cells. Cell encapsulation technologies were originally developed for the treatment of acquired and genetic diseases, such as diabetes...

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...