Current Opinion in Molecular Therapeutics最新文献

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. OBI-1, being developed by Ipsen and Inspiration Biopharmaceuticals Inc, is a bioengineered form of porcine rFVIII that is highly purified. OBI-1 has the procoagulant and biochemical properties of porcine pdFVIII, with improvements in risk of toxicity, infection and ease of manufacture. OBI-1 demonstrated significantly less immunogenicity than pdFVIII in a murine model of hemophilia A. Moreover, in cynomolgus monkeys, OBI-1 did not generate detectable inhibitors. OBI-1 was effective in a phase II, open-label clinical trial in patients with hemophilia A and inhibitor against porcine FVIII, who were experiencing a non-life or -limb threatening bleed. OBI-1 was well tolerated, without drug-related serious adverse events and is promising for further studies.

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. Adeno-associated virus (AAV) vectors have been identified as promising gene delivery candidates because of their ability to transduce muscle tissue efficiently while transporting a genetic payload. There is currently significant momentum in the research of AAV-mediated delivery of muscle genes. Various AAV-based therapeutic strategies are undergoing preclinical and clinical testing, including the use of miniaturized and codon-optimized transgenes, exon skipping expression cassettes, novel tissue-specific promoters, AAV capsid mutants and chimeras, and localized intravascular administration procedures. These advancements in gene delivery have led to the generation of AAV vectors with targeted transgene expression, tissue-selective tropism and minimal off-target effects. This review describes advances in AAV gene therapy that are specific to the treatment of muscle diseases, and discusses the implications of their clinical application.

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. Globally, gene therapy has proven to be safe, with none of the agents tested reaching the MTD. Although none of the phase II trials provided significant response rates, objective remissions have occasionally been observed and proof-of-concept for the ability of gene therapy to produce significant tumor cell killing has been determined. Insufficient delivery following intravascular administration and short-lived transgene expression are likely to be the cause of this limited antitumor efficacy. The development of new gene therapy vectors with improved characteristics will increase the probability of success of gene therapy for the treatment of liver cancer.

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. Interim results from an ongoing phase I/II clinical trial assessing tgAAG76 in three patients with Leber congenital amaurosis type 2 were considered to accomplish the primary outcome of the trial, which was the safety of the procedure, with no severe side effects observed to date. One of the three patients had a significant increase in sensitivity to light and the better capacity to ambulate an obstacle course under dim light conditions compared with baseline. Completion of the clinical trial was anticipated in the second half of 2010.

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. Virotherapy approaches include incorporating therapeutic genes, evaluating alternative viruses with stronger oncolytic potential, employing new methods to improve biodistribution, and establishing greater insight into the influence of the immune system on both the success and failure of therapies. This review summarizes the most significant advances in recent years in the design of virotherapy for effective tumor treatment.

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. In the application of this technology for the treatment of tumors, cells that are genetically modified to overexpress suicide genes are encapsulated and implanted near solid tumors; this process is then followed by systemic prodrug administration. This review discusses the various cells types, suicide genes and prodrugs that have been used in preclinical and clinical trials, as well as the data that have been obtained from these studies. Future improvements for the production of second-generation approaches are also discussed.

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. AMG-386 significantly inhibited the growth of tumors in a variety of mouse xenograft models. In phase I trials of AMG-386 as a monotherapy or in combination with chemotherapy in patients with advanced solid tumors, AMG-386 demonstrated only mild toxicities, and one complete response and several partial responses were achieved in patients. Phase II trials of AMG-386 in combination with chemotherapy were ongoing in a variety of solid tumors, including breast, ovarian, colorectal, gastric and renal cell cancers. If safe and effective, AMG-386 could be an exciting addition to other antiangiogenic therapies in solid tumors.

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. As with most modalities that target cancer, which is a disease characterized by pronounced cellular heterogeneity and genetic instability, it is anticipated that the efficacy of OVT will benefit from combination therapy. During the past 5 years, significant efforts have been invested in evaluating the combination of OVT and existing chemotherapies, as well as rationally designing chemical-OVT combinations. This review provides an update on these two approaches to augmenting OVT, and suggests that unbiased, high-throughput genetic and chemical screening technologies may both compliment and offer several advantages when combined with these approaches in the pursuit of effective chemical-OVT combinations for the treatment of cancer.

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. Morphological differences between species, such as the presence or absence of the panniculus carnosus muscle, may have significant effects on SC delivery. Following SC administration, small molecules, peptides and small proteins (< or = 16 kDa) primarily diffuse through the blood vessel walls directly into capillaries, whereas large molecules are taken up into the more porous lymphatics. Critical parameters that may impact the availability in blood of compounds administered SC, other than molecular weight, include host-related factors, such as animal motility, age and gender, structural and functional characteristics of the SC interstitium and the lymphatics, and extrinsic factors, such as anesthesia, injection technique, potential precipitation or degradation at the injection site, and the use of SC delivery technology. A review of regulatory approval information for SC administered biotherapeutics is provided for comparison. Careful control of parameters during SC administration will reduce inter-individual and inter-species variability.

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. Results from early-stage trials in patients with hormone-refractory prostate cancers have revealed potential efficacy following intraprostatic or intravenous delivery of replication-selective oncolytic viruses in combination with chemotherapeutics or radiation therapy. This review describes the most promising developments in virotherapy for prostate cancer, focusing on replication-selective adenoviral mutants as multimodal therapeutic agents.