Molecular therapeutics of HBV

The hepatitis B virus (HBV) infection is a public health problem worldwide, particularly in East Asia. The current therapy of HBV infection is mostly based on chemical agents and cytokines that have been shown to provide limited efficacy and are also toxic to the human body. Gene therapy is a new therapeutic strategy against HBV infection, involving the transmission of gene drugs into liver cells by specific delivery systems and methods. Although this new anti-HBV infection technique is under active investigation, various promising anti-HBV viral gene drugs have been developed for gene therapy, including antisense RNA and DNA, hammerhead ribozymes, dominant negative HBV core mutants, single chain antibody, co-nuclease fusion protein, and antigen. In order to optimize their antiviral effects and/or enhance anti-HBV immunity, various novel gene delivery systems have also been developed to (specifically) deliver such DNA constructs into liver cells; some of them are viral vectors, such as adenoviral vectors, retroviral vectors and poxviral vectors, and even hepatitis B viral for its hepatocellular specificity. Others are non-viral vectors, in which naked DNA and liposomes are frequently used for DNA vaccine or nucleotide analogs for inhibiting HBV DNA polymerase. This review addresses various aspects of gene therapy for HBV infection, including gene drugs, delivery methods, animal model, and liver transplantation with combination therapy. It also discusses the problems that remain to be solved.     

Monoclonal antibodies and therapeutics

More than 25 years after their discovery, monoclonal antibodies are now the most rapid expanding pharmaceutical viable drugs in clinical trials. The emergence of these antibodies was made possible by the development of genetic recombinant techniques. It is now possible to obtain engineered antibodies: chimearic or humanized or fully human monoclonal antibodies via the use of phage display technology or of transgenic mice. These antibodies are tolerable to the human immune system and eleven have been approved for therapeutic by the US Food and Drug Administration (FDA), the majority of them in the past four years. At least an additional 400 monoclonal antibodies are in clinical trials to treat cancer, transplant rejection or to combat autoimmune or infectious diseases. Important advances have been made in the design of highly specific fragment antibodies, fused or not with drugs or radioisotopes, and in the large industrial scale production with different expression systems (bacteria, yeasts, mammalian cells and transgenic plants and animals). In the next future new molecular promising strategies will enhance affinity, stability and expression levels and reduce the price of these engineering monoclonal to permit their use to treat a large number of diseases.     

Antioxidant therapeutics for schizophrenia

Pharmaceutical treatment for millions worldwide who have schizophrenia is limited to a handful of antipsychotics. Despite the proven efficacy of these drugs, the overall outcome for schizophrenia remains suboptimal. Thus, alternative treatment options are urgently needed. One possible approach may be antioxidant therapy. The extant evidence for the role of oxidative stress in the pathophysiology of schizophrenia offers a hypothesis-derived therapeutic approach in the form of antioxidants. Vitamins C and E, for example, are suitable for human clinical trials because they are readily available, inexpensive, and relatively safe. Research into the therapeutic use of antioxidants in schizophrenia can be grouped into two main clusters: for psychopathology and for side effects. Of these studies, some have been carefully conducted, but majority are open label. Use of antioxidants for treatment-related side effects has been more extensively investigated. The totality of the evidence to date suggests that specific antioxidants, such as N-acetyl cysteine, may offer tangible benefits for the clinical syndrome of schizophrenia, and vitamin E may offer salutary effects on glycemic effects of antipsychotics. However, a great deal of fundamental clinical research remains to be done before antioxidants can be routinely used therapeutically for schizophrenia and treatment-related complications.     

Immunogenicity of protein therapeutics

Protein therapeutics, such as monoclonal antibodies, enzymes and toxins, hold significant promise for improving human health. However, repeated administration of protein therapeutics, whether natural or recombinant, often leads to the induction of undesirable anti-drug antibodies (ADAs), which interfere with or neutralize the effect of the drug. Although an immune response to foreign proteins can be expected and is well understood, the basis for the development of responses to therapeutic autologous proteins is the subject of some debate. Inflammatory components of the drug delivery vehicle, T cell responses, T and B cell epitopes in the protein drug, and the associated B cell response are all targets for interventions aimed at reducing ADA responses. Here, we review some theories put forward to explain the immunogenicity of therapeutic proteins and describe some emerging protein-engineering approaches that might prevent the development of anti-drug antibodies.     

Resurrecting DNAzymes as sequence-specific therapeutics

In a mouse model of skin cancer, intratumoral injection of a sequence-specific mRNA-cleaving DNA enzyme caused potent inhibition of tumor growth and unusually benign pharmacodynamic profiles.     

Redox-based therapeutics for lung diseases

Because oxidative stress is such a common factor of lung diseases, we cannot help asking why so many diseases are caused by the same oxidative stress. It is likely to be a consequence of diversity in sources and location of oxidative stress, and concomitant factors. The aim of this forum is to characterize the disease-specific involvement of oxidative stress and to make use of it for therapeutics. It is also of note that oxidative-stress biomarkers are useful tools for disease management. Exhaled nitric oxide has been established as a marker of bronchial asthma in clinical practice. By using recent noninvasive techniques, such as exhaled breath condensate, other markers of lipid peroxidation or antioxidants are now under evaluation. Antioxidant therapy, as represented by N-acetylcysteine, has widely been tested as a treatment for lung disorders, but it has had limited success in clinical practice. The clinical outcome might be improved by combination therapy or better patient selection. Novel antioxidant drugs are also under investigation. Molecular targeted therapy against redox-sensitive signaling pathways could be an alternative therapeutic approach. Moreover, disease-specific pathways have been identified whose regulation could be more efficient and less toxic than regulating universal pathways.     

Adenosinergic approaches to stroke therapeutics

Basic neuroscience research findings during the past five years have established a clear relationship between the excitatory amino acid (EAA) neurotransmitters (glutamic and aspartic acid) and various pathological states. A major mechanism of neural tissue degeneration following cerebral ischemia, and perhaps other neurodegenerative diseases, seems to involve overactivity of the EAA system in brain. This process is called delayed excitotoxicity and it has become a focal point for the design of new drugs that inhibit its course (EAA receptor blockers). Very recently it has been shown that it is possible to block delayed excitotoxicity using adenosine A1 receptor agonists which inhibit EAA release pre-synaptically. This approach is very effective in reducing post-stroke neurological damage in a number of animal models and has certain advantages when compared to the EAA receptor blocker strategy. Adenosine agonists not only inhibit excitotoxicity but they also block granulocyte activation and the capillary no-reflow phenomenon which results. An additional adenosinergic approach involves brain permeable adenosine uptake blockers which would serve to increase adenosine levels somewhat selectively at ischemic foci thereby inhibiting EAA release. The adenosinergic approach to stroke therapeutics may be a potentially effective strategy for new drug development in neurology, and may have general applicability to other neurodegenerative disease states where excitotoxicity is being implicated.     

Recent developments in Alzheimer's disease therapeutics

Alzheimer's disease is a devastating neurological disorder that affects more than 37 million people worldwide. The economic burden of Alzheimer's disease is massive; in the United States alone, the estimated direct and indirect annual cost of patient care is at least $100 billion. Current FDA-approved drugs for Alzheimer's disease do not prevent or reverse the disease, and provide only modest symptomatic benefits. Driven by the clear unmet medical need and a growing understanding of the molecular pathophysiology of Alzheimer's disease, the number of agents in development has increased dramatically in recent years. Truly *disease-modifying' therapies that target the underlying mechanisms of Alzheimer's disease have now reached late stages of human clinical trials. Primary targets include beta-amyloid, whose presence and accumulation in the brain is thought to contribute to the development of Alzheimer's disease, and tau protein which, when hyperphosphorylated, results in the self-assembly of tangles of paired helical filaments also believed to be involved in the pathogenesis of Alzheimer's disease. In this review, we briefly discuss the current status of Alzheimer's disease therapies under study, as well the scientific context in which they have been developed.     

Mechanisms and therapeutics of glucocorticoid-induced osteoporosis

Mechanisms of glucocorticoid-induced osteoporosis (GIOP) are categorized into local and systemic effects. In the local mechanisms, direct inhibitory effect of glucocorticoid on bone formation is thought to be one of the important mechanisms of GIOP. In contrast, secondary hyperparathyroidism induced by negative balance of calcium due to inhibition of absorption and increase of excretion is an important systemic mechanism of GIOP. Other mechanisms of GIOP are also shown in this review. From clinical points of view, serum markers for evaluation of GIOP have been discussed. Osteocalcin, procollagen type I N-terminal peptide, and bone-specific alkaline phosphatase as markers of bone formation are decreased in GIOP. Collagen I N-terminal telopeptide and tartrate resistent acid phosphatase isoform 5b as markers of bone resorption are increased in GIOP. Clinical guidelines have recommended that bisphosphonate is the first choice for the treatment of GIOP. Teriparatide is recombinant human parathyroid hormone 1-34, which should be considered as a therapeutic option for those at high risk of bone fracture. Denosumab, an anti receptor activator of nuclear factor-β ligand approved as a drug for postmenopausal osteoporosis was also effective for GIOP in clinical trials.     

Food allergy: mechanisms and therapeutics

The immunologic mechanisms responsible for the development of allergic sensitization rather than tolerance to foods are not well understood, although there have been a number of recent advances in our understanding of why some foods are inherently allergenic. In addition, the involvement of alternative routes of exposure that are not inherently tolerogenic may play a role in sensitization to foods. Although there are no currently accepted therapeutic approaches to food allergy, there are a number of approaches to treatment in preclinical or clinical trials. Here, we review selected findings published since 2009 that advance our understanding of mechanisms and new therapeutics for IgE-mediated food allergy.