Selective inhibition of DNA methyltransferase enzymes as a novel strategy for cancer treatment

A common event in the development of human neoplasia is the loss of growth regulatory tumor suppressor functions. Methylation of 5'-CpG islands of tumor suppressor genes and elevated levels of the DNA-(cytosine-5)-methyltransferase enzymes (DNMT1, 3A and 3B) are also prevalent features of human neoplasia. However, direct evidence that elevated DNMT enzyme levels alter gene expression and influence oncogenesis has been difficult to obtain due to the lack of specific DNMT inhibitors. We have developed potent and selective antisense inhibitors of the known DNA methyltransferases. MG-98, a second-generation DNMT1-specific antisense inhibitor currently in phase II clinical trials, reactivates silenced tumor suppressor genes and inhibits the growth of cancer cells in vitro and in preclinical in vivo models. Here, we will review the discovery and development of MG-98 as a cancer therapeutic.     

Selective delivery of therapeutic agents for the diagnosis and treatment of cancer

Research activity aimed towards achieving specific and targeted delivery of cancer therapeutics has expanded tremendously in the last decade, resulting in new ways of directing drugs to tumours, as well as new types of drugs. The available strategies exploit differences in the nature of normal and cancer cells and their microenvironment. The discovery and validation of cancer-associated markers, as well as corresponding ligands, is pivotal for developing selective delivery technology for cancer. Although most current clinical trials are either monoclonal antibody- or gene-based, methodological advances in combinatorial libraries of peptides, single chain variable fragments and small organic molecules are expected to change this scenario in the near future. Nanotechnology platforms today allow systematic and modular combinations of therapeutic agents and tumour-binding moieties that may generate novel, personalised agents for selective delivery in cancer. This paper discusses recent developments and future prospects of targeted delivery technologies in the management of cancer.     

Selective delivery of therapeutic agents for the diagnosis and treatment of cancer

Research activity aimed towards achieving specific and targeted delivery of cancer therapeutics has expanded tremendously in the last decade, resulting in new ways of directing drugs to tumours, as well as new types of drugs. The available strategies exploit differences in the nature of normal and cancer cells and their microenvironment. The discovery and validation of cancer-associated markers, as well as corresponding ligands, is pivotal for developing selective delivery technology for cancer. Although most current clinical trials are either monoclonal antibody- or gene-based, methodological advances in combinatorial libraries of peptides, single chain variable fragments and small organic molecules are expected to change this scenario in the near future. Nanotechnology platforms today allow systematic and modular combinations of therapeutic agents and tumour-binding moieties that may generate novel, personalised agents for selective delivery in cancer. This paper discusses recent developments and future prospects of targeted delivery technologies in the management of cancer.     

Neurogenesis as a potential therapeutic strategy for neurodegenerative diseases

In the adult mammalian brain, new neurons are continuously generated from a proliferating population of neural progenitor/stem cells and become incorporated into the existing neuronal circuitry via a process termed adult neurogenesis. The existence of active functional adult neurogenesis raises the exciting possibility that manipulating endogenous neural progenitors, or transplanting the progeny of exogenously expanded neural progenitors, may lead to successful cell replacement therapies for various degenerative neurological diseases. Significant effort is being made to decipher the mechanisms regulating adult neurogenesis, which may allow us to translate this endogenous neuronal replacement system into therapeutic interventions for neurodegenerative diseases. This review focuses on adult neurogenesis as a strategy to derive potential therapies, and discusses future directions in the field.     

Neurogenesis as a potential therapeutic strategy for neurodegenerative diseases

In the adult mammalian brain, new neurons are continuously generated from a proliferating population of neural progenitor/stem cells and become incorporated into the existing neuronal circuitry via a process termed adult neurogenesis. The existence of active functional adult neurogenesis raises the exciting possibility that manipulating endogenous neural progenitors, or transplanting the progeny of exogenously expanded neural progenitors, may lead to successful cell replacement therapies for various degenerative neurological diseases. Significant effort is being made to decipher the mechanisms regulating adult neurogenesis, which may allow us to translate this endogenous neuronal replacement system into therapeutic interventions for neurodegenerative diseases. This review focuses on adult neurogenesis as a strategy to derive potential therapies, and discusses future directions in the field.     

Exploring RNA interference as a therapeutic strategy for renal disease

The short synthetic interfering RNA duplexes (siRNAs) can selectively suppress gene expression in somatic mammalian cells without nonselective toxic effects of double-stranded RNA (dsRNA). However, a selective in vivo delivery of siRNA transfer has not been reported in kidney. Here, we investigated whether injection of synthetic siRNAs via renal artery followed by electroporation could be effective and therapeutic in silencing specific gene in glomerulus. We investigated the effect of siRNA in rat cultured mesangial cells (MCs) and showed that siRNA sequence-specific suppression of transgene expression was over a 1000-fold more potent than that by antisense oligodeoxynucleotide (ASODN). Transfection of siRNA targeting luciferase into rat kidneys significantly inhibited expression of a cotransfected luciferase expression vector in vivo. The delivery of siRNA targeting enhanced green fluorescent protein (EGFP) in the transgenic 'green' rat reduced endogenous EGFP expression, mainly in glomerular MCs. Furthermore, RNAi targeting against TGF-beta1 significantly suppressed TGF-beta1 mRNA and protein expression, thereby ameliorated the progression of matrix expansion in experimental glomerulonephritis. In addition, vector-based RNAi also inhibited TGF-beta1 expression in vitro and in vivo. In conclusion, siRNA-directed TGF-beta1 silencing may be of therapeutic value in the prevention and treatment of fibrotic diseases.     

Prospects for immunotherapy as a novel therapeutic strategy against hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a highly aggressive malignant disease, with a poor clinical prognosis. Many standard therapies are often considered for HCC treatment today; however, these conventional therapies often fail to achieve sufficiently effective clinical results. Today, HCC therapy is set to undergo a major revolution, owing to rapid developments in cancer immunotherapy, particularly immune checkpoint inhibitor therapy. Cancer immunotherapy is a novel and promising treatment strategy that differs significantly from conventional therapies in its approach to achieve antitumor effects. In fact, many cancer immunotherapies have been tested worldwide and shown to be effective against various types of cancer; HCC is no exception to this trend. For example, we identified a specific cancer antigen called glypican-3 (GPC3) and performed clinical trials of GPC3-targeted peptide vaccine immunotherapy in patients with HCC. Here, we present an overview of the immune mechanisms for development and progression of HCC, our GPC3-based immunotherapy, and immune checkpoint inhibitor therapy against HCC. Finally, we discuss the future prospects of cancer immunotherapy against HCC. We believe that this review and discussion of cancer immunotherapy against HCC could stimulate more interest in this promising strategy for cancer therapy and help in its further development.     

Cellular and molecular therapeutic modalities for arterial obstructive syndromes

Arterial obstructive syndromes result in heart disease, stroke and limb loss, disability, and mortality. Currently available therapeutics for patients with these conditions are inadequate or fail in a significant number of patients. The development of novel therapies for severe coronary arterial disease (CAD), peripheral arterial disease (PAD), and cerebral vascular disease (CVD) is a major goal for modern medicine. Molecular and cell-based therapies for arterial obstructive syndromes have the potential to become clinically useful in the near future. Molecular therapy employs angiogenic proteins and genes in order to initiate the development of new blood vessels that by-pass an arterial occlusion. The induction of a collateral artery system is termed therapeutic angiogenesis or neovascularization. Proteins have been delivered either directly into the ischemic area or via a vector encoding an angiogenic gene. Both protein and gene therapies have been associated with promising preclinical and early phase human trial results in patients with PAD as well as CAD. However, to date, efficacy has not been demonstrated in placebo-controlled, large trails. Today's cell-based therapy is focused on stem cells (SCs) for the treatment of patients after acute myocardial infarction (AMI) or for patients with severe left ventricular dysfunction. Stem cells have shown to increase cardiac performance in uncontrolled, early phase human studies. This improvement is believed to have its origin in myogenesis and neovascularization. In the following review, we will cover current state of molecular- and cellular-based treatments for PAD and CAD that have reached the clinical arena.     

Immunotherapy as a strategy for the treatment of non-small-cell lung cancer

Positive modulation of a patient's immune system to produce antitumor immunity is an attractive strategy that may improve the dismal outcomes typically associated with non-small-cell lung cancer (NSCLC). Using methods that either augment specific antitumor immunity or positively influence the patient's immune system to allow the de novo generation of immunity to encompass current strategies used in recent clinical trials of NSCLC. Encouraging results of Phase II trials in antigen-specific immunotherapy have led to three subsequent Phase III trials, which are currently enrolling. Results of these trials will improve our understanding of the role that immunotherapy plays in the treatment of NSCLC. Successful application of a humoral vaccine in Cuba led to its approval for the treatment of advanced NSCLC patients in that country. To date, trials involving nonspecific immunotherapeutic interventions have failed to improve outcomes in NSCLC and may indicate a need to combine them with antigen-specific vaccines. Although these trials will greatly advance our knowledge of NSCLC immunotherapy, we believe truly efficacious immunotherapy may only result from implementation of strategies to both augment antitumor immunity and counteract tumor-mediated immunosuppression.     

Extracellular matrix administration as a potential therapeutic strategy for periodontal ligament regeneration

INTRODUCTION: The current strategies employed for the treatment of connective tissue disease include the application of stem cells, the use of functional molecules that can reorganize tissue integrity and cellular activities to recover connective tissue function. Approaches to the regeneration of periodontal tissue, which is the tooth-supporting connective tissue, have made some progress recently and provide a useful experimental model for the evaluation of future strategies to treat connective tissue diseases such as periodontal disease. AREAS COVERED: The ultimate goal of periodontal tissue regeneration is to reconstruct the ligament structure that will sustain the required mechanical force to connect with mineralized tissues such as cementum and alveolar bone. In this review, we discuss the proposed use of extracellular matrix (ECM) administration therapy as an additional therapeutic strategy to stem cell transplantation and cytokine administration in the current field of periodontal tissue regeneration therapy. EXPERT OPINION: Although various available tissue engineering technologies can now achieve periodontal tissue regeneration, ECM administration therapy is likely to play an essential future role in the development and regeneration of periodontal tissue and attenuate the signaling events that mediate tissue degradation. Hence, ECM administration could serve as a novel technology in periodontal tissue regeneration and also as a viable approach to alleviating connective tissue disorders such as Marfan's syndrome.     

Integrated strategy for the production of therapeutic retroviral vectors

The broad application of retroviral vectors for gene delivery is still hampered by the difficulty to reproducibly establish high vector producer cell lines generating sufficient amounts of highly concentrated virus vector preparations of high quality. To enhance the process for producing clinically relevant retroviral vector preparations for therapeutic applications, we have integrated novel and state-of-the-art technologies in a process that allows rapid access to high-efficiency vector-producing cells and consistent production, purification, and storage of retroviral vectors. The process has been designed for various types of retroviral vectors for clinical application and to support a high-throughput process. New modular helper cell lines that permit rapid insertion of DNA encoding the therapeutic vector of interest at predetermined, optimal chromosomal loci were developed to facilitate stable and high vector production levels. Packaging cell lines, cultivation methods, and improved medium composition were coupled with vector purification and storage process strategies that yield maximal vector infectivity and stability. To facilitate GMP-grade vector production, standard of operation protocols were established. These processes were validated by production of retroviral vector lots that drive the expression of type VII collagen (Col7) for the treatment of a skin genetic disease, dystrophic epidermolysis bullosa. The potential efficacy of the Col7-expressing vectors was finally proven with newly developed systems, in particular in target primary keratinocyte cultures and three-dimensional skin tissues in organ culture.     

Micro RNA-155 inhibitor as a potential therapeutic strategy for the treatment of acute kidney injury (AKI): a nanomedicine perspective

In this study, we have prepared miR-155 inhibitor-loaded liposome vesicles for the effective treatment of acute kidney injury. The efficacy of liposomal miR-155 inhibitor in the expression of miR-155, mortality in animals, the expression of TNF-α-IL6, and the expression of SOCS1–STAT1 were evaluated. The loading of miR-155 inhibitor into liposomes conferred the much needed colloidal stability and efficient delivery to the renal tissues. The study clearly shows that miR-I-LV significantly decreases the expression of miR-155 in kidneys compared to LPS. Administration of miR-I-LV remarkably reduced the pathological concerns of the kidneys with a marked decrease in inflammatory cell infiltration. Scrambled miR-155 did not have any effect on the expression of these markers; however miR-I-LV showed a remarkable ability to decrease the expression of TNF-α and IL-6 in kidney tissues indicating an ability to treat acute kidney infections. Overall, administration of miR-155 inhibitor effectively alleviated LPS-induced kidney injury by significantly suppressing TNF-α and IL-6 in kidney tissue and by remarkably increasing the expression of mRNA of SOCS1 and STAT1. The present results suggest that miR-155 inhibitor could be used in an effective targeting strategy for the treatment of acute kidney injury (AKI).

In this study, we have prepared miR-155 inhibitor-loaded liposome vesicles for the effective treatment of acute kidney injury.     

Anticonvulsants for the treatment of neuropathic pain syndromes

This article is an evidence-based summary of randomized clinical trials published in peer-reviewed journals regarding the efficacy of anticonvulsants for the treatment of neuropathic pain.