Current Opinion in Molecular Therapeutics最新文献

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. Although ASCs originate from mesodermal lineages, recent preclinical studies have demonstrated that the use of ASCs in regenerative medicine is not limited to mesodermal tissue, but can also extend to both exodermal and endodermal tissues and organs. This review summarizes and discusses current preclinical and clinical data on the use of ASCs in regenerative medicine and discusses the future applications of such cell-based therapies.

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. By targeting exon 51, approximately 13% of patients with DMD could be treated, the largest proportion of patients that could benefit from targeting a single dystrophin exon. A proof-of-concept clinical trial of PRO-051 in patients with DMD demonstrated that a single intramuscular administration of PRO-051 induced exon skipping within muscle fibers adjacent to the injection site, while biopsies revealed dystrophin expression in treated but not control muscle fibers. At the time of publication, a phase I/IIa trial to evaluate subcutaneous delivery of PRO-051 had been completed, although full results were yet to be published.

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. The validation of long-term clinical benefit will first require well-controlled studies in appropriate preclinical animal models to develop procedures that enhance cell retention, integration and viability. This review highlights new developments that will benefit long-term cardiomyocyte survival and function of human cardiovascular progenitors as a prelude to achieving clinically significant outcomes in stem cell therapies for cardiac repair.

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. The mechanisms of action of these blood components by which virus particles are inactivated are also discussed. In addition, important blood components that act as barriers to the systemic delivery of therapeutic viruses are identified, and recent advances in overcoming these barriers are highlighted. Particular attention is given to the field of oncolytic virotherapy in which adequate intravenous virus delivery is critical for therapeutic success.

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. Many improvements to adeno-associated virus and lentivirus vectors have led to increased airway transduction efficiencies, although achieving consistent repeated administration remains problematic because of immune system activation. Non-viral vectors appear to be less efficient, but can be successfully re-administered. The modification of plasmid sequences also offers maximum flexibility in increasing and extending the duration of transgene expression in the airways. This review describes recent developments in achieving persistent transgene expression in the airways by specifically targeting the cells of the respiratory epithelium lining the nose and lung.

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.

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. In addition, coadministration of dalotuzumab with other anticancer agents, such as taxanes, enhanced the in vitro and in vivo antitumor activity of dalotuzumab. Preliminary data from phase I clinical trials suggest that dalotuzumab is safe, well tolerated and significantly inhibits tumor proliferation. At the time of publication, several clinical trials evaluating dalotuzumab, alone and in combination with other anticancer agents, were ongoing in patients with various types of solid tumor and in patients with multiple myeloma. Although preliminary results appear promising, only future clinical and translational data will clarify the best clinical setting and treatment combinations for the optimal use of dalotuzumab in clinical practice.

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 beta-blockers, and focuses on recent advances and medium-term expectations for the field.

The recent development of technologies for whole-genome sequencing, copy number analysis and expression profiling enables the generation of comprehensive descriptions of cancer genomes. However, although the structural analysis and expression profiling of tumors and cancer cell lines can allow the identification of candidate molecules that are altered in the malignant state, functional analyses are necessary to confirm such genes as oncogenes or tumor suppressors. Moreover, recent research suggests that tumor cells also depend on synthetic lethal targets, which are not mutated or amplified in cancer genomes; functional genomics screening can facilitate the discovery of such targets. This review provides an overview of the tools available for the study of functional genomics, and discusses recent research involving the use of these tools to identify potential novel drug targets in cancer.