Proteopathy: the next therapeutic frontier?

The abnormal conformation and assembly of proteins is a probable cause of many degenerative diseases of old age. These proteopathies include such clinically disparate neurological disorders as Alzheimer's disease. Parkinson's disease and Creutzfeldt-Jakob disease, as well as a variety of non-neurological maladies. The involvement of protein pathology in these diseases is well established and we are beginning to understand the process whereby proteins self-assemble and injure tissues; however, we remain largely in the dark regarding the fundamental origins of the proteopathies. Our present knowledge suggests three broad therapeutic approaches to abrogating the proteopathic cascade: reduce the production of the offending proteins, prevent their self-assembly, or promote their removal.     

The role of tetrodotoxin-resistant sodium channels in pain states: are they the next target for analgesic drugs?

Neuropathic pain, a persistent chronic pain resulting from damage to the central or peripheral nervous system, is a condition that severely affects the quality-of-life of millions of individuals worldwide. The treatment of neuropathic pain is still an unmet medical need; however, recent advances in our understanding of mechanisms underlying the perception and transmission of painful stimuli offer significant potential for improvement of therapies directed to neuropathic pain. Ectopic activity in damaged and dysfunctional sensory afferents is believed to have a role in the generation and maintenance of neuropathic pain. One of the mechanisms underlying this ectopic firing involves abnormal modulation of voltage-gated sodium channels (NaVs) in the soma and axonal membranes of dorsal root ganglion (DRG) sensory neurons. In fact, NaV blockers have been clinically validated as treatments for neuropathic pain. However, current drugs are weak, non-selective inhibitors of NaVs with dose-limiting CNS and cardiovascular side effects that prevent their use in long-term therapy. Selective NaV tetrodotoxin-resistant channels (NaV 1.8 and NaV 1.9) are expressed exclusively in nociceptive neurons in the DRGs where they play a key role in normal and/or pathological pain sensation, providing an opportunity for the development of novel peripheral analgesics with a better safety profile.     

Dendritic nanoparticles: the next generation of nanocarriers?

Dendritic polymers have attracted a great deal of scientific interest due to their well-defined unique structure and capability to be multifunctionalized. Here we present a comprehensive overview of various dendrimer-based nanomaterials that are currently being investigated for therapeutic delivery and diagnostic applications. Through a critical review of the old and new dendritic designs, we highlight the advantages and disadvantages of these systems and their structure-biological property relationships. This article also focuses on the major challenges facing the clinical translation of these nanomaterials and how these challenges are being (or should be) addressed, which will greatly benefit the overall progress of dendritic materials for theranostics.     

Biologics: the next generation of analgesic drugs?

For many decades, there have been few novel therapies for pain, and the number of promising targets that have been genuinely validated in the clinic is small. Discovery and development of biologic therapies for analgesia provides a better opportunity to test such targets, potentially providing new and effective therapies. Biologics have revolutionised the treatment of many diseases, with the greatest advances seen in oncology and inflammatory disorders. Across a broad spectrum of severe, chronic pain disorders - including inflammatory pain, neuropathic pain and cancer pain - biologics could offer patients safer and more-effective alternatives to currently available treatments. As such, progression of large-molecule therapies is becoming a strategic priority for companies as they look to advance their portfolios.     

After the failure of citalopram for depression, what next?

The choice of treatment after failure of selective serotonin re-uptake inhibitors in the treatment of depression largely depends on the preferences of the physician. The STAR*D (Sequenced Treatment Alternatives to Relieve Depression) trials set out to rationalise the treatment of depression after the failure of citalopram. When subjects who were unresponsive or intolerant to citalopram were switched to sustained-release bupropion, sertaline or extended-release venlafaxine, remission rates were similar (21, 18 and 25%, respectively). When subjects who were unresponsive to citalopram had sustained-release bupropion or buspirone added to citalopram, there were similar remission rates of 29.7 and 30.1%, respectively. The interpretation of this data are complicated by the lack of placebo groups. One interpretation is that sustained-release bupropion, sertaline or extended-release venlafaxine are equally effective in subjects with major depression after the failure of citalopram, and that sustained-release bupropion or buspirone are equally effective when added to citalopram in subjects with major depression after the failure of citalopram. An alternative explanation is that none of the drugs are effective in citalopram failure, and the responses are the placebo effect.     

Non-optical screening platforms: the next wave in label-free screening?

The use of optical biosensors for compound screening was first demonstrated in the mid-1990s, but there has been limited uptake in the market owing to issues of limited throughput and a lack of applications for key receptor classes. Recently, several start-up and established tools companies have exploited non-optical detection modalities that seek to address the shortcomings of more established optical approaches. Platforms based on acoustic resonance, electrical impedance, microcantilevers, nanowires and differential calorimetry are beginning to appear with commercially available products targeted at post-high-throughput screening hit confirmation and mode-of-action studies. This article highlights key advances in commercial label-free analysis platforms, which complement more traditional optical system and which also allow novel assay formats for the analysis of previously intractable targets.     

Recombinant polyclonal antibodies: the next generation of antibody therapeutics?

Antibodies have been used as therapeutics in various forms for over a century. Traditional immunoglobulin therapy has the advantage of reflecting the diversity of the natural immune response but has very limited clinical applications. However, over the past ten years more than 30 monoclonal antibodies have been successfully introduced on to the drug market. The monoclonal approach provides the advantage of specificity, but lacks efficacy in the treatment of diseases caused by complex antigens. Recombinant polyclonal antibodies, the third generation of antibody therapeutics, have the ability to tackle complex and highly mutagenic targets, and will undoubtedly offer a promising commercial future.     

Antisense technology for the prevention or the treatment of cardiovascular disease: the next blockbuster?

Antisense technology might be a gateway to the treatment of diseases by targeting the expression of genes rather than permanently altering them. Thus, there will be fewer ethical concerns. Antisense oligonucleotides (ASO) can alter target gene expression by binding to RNA. Once bound, the ASO either disables or induces the degradation of the target RNA. This technology may be used to treat various conditions (including cancer, diabetes, and hypertension, as well as autoimmune and cardiovascular diseases). ASOs are potentially potent, selective and well-tolerated drugs. Mipomersen (ISIS 301012) inhibits human apolipoprotein (apo)B-100 synthesis and lowers circulating apoB and low-density lipoprotein cholesterol levels. ASO technology may provide a spectrum of agents targeting other vascular risk factors or mediators of atherosclerosis.     

Phytocannabinoids beyond the Cannabis plant – do they exist?

It is intriguing that during human cultural evolution man has detected plant natural products that appear to target key protein receptors of important physiological systems rather selectively. Plants containing such secondary metabolites usually belong to unique chemotaxa, induce potent pharmacological effects and have typically been used for recreational and medicinal purposes or as poisons. Cannabis sativa L. has a long history as a medicinal plant and was fundamental in the discovery of the endocannabinoid system. The major psychoactive Cannabis constituent Δ⁹-tetrahydrocannabinol (Δ⁹-THC) potently activates the G-protein-coupled cannabinoid receptor CB₁ and also modulates the cannabinoid receptor CB₂. In the last few years, several other non-cannabinoid plant constituents have been reported to bind to and functionally interact with CB receptors. Moreover, certain plant natural products, from both Cannabis and other plants, also target other proteins of the endocannabinoid system, such as hydrolytic enzymes that control endocannabinoid levels. In this commentary we summarize and critically discuss recent findings.This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit http://dx.doi.org/10.1111/j.1476-5381.2010.00831.x     

Will chymase inhibitors be the next major development for the treatment of cardiovascular disorders?

Chymase is contained in the secretory granules of mast cells. In addition to the synthesis of angiotensin II, chymase is involved in transforming growth factor-β activation and cleaves Type I procollagen to produce collagen. NK301 and BCEAB are orally-active inhibitors of chymase. NK301 was tested in a dog model of vascular intimal hyperplasia after balloon injury and shown to reduce the increased chymase activity in the injured arteries and prevent intimal thickening. In a hamster model of cardiac fibrosis associated with cardiomyopathy, BCEAB reduced the increased cardiac chymase activity in cardiomyopathy and reduced fibrosis. Chymase inhibitors may be an important development for the treatment of cardiovascular injury associated with mast cell degranulation.     

Will chymase inhibitors be the next major development for the treatment of cardiovascular disorders?

Chymase is contained in the secretory granules of mast cells. In addition to the synthesis of angiotensin II, chymase is involved in transforming growth factor-beta activation and cleaves Type I procollagen to produce collagen. NK301 and BCEAB are orally-active inhibitors of chymase. NK301 was tested in a dog model of vascular intimal hyperplasia after balloon injury and shown to reduce the increased chymase activity in the injured arteries and prevent intimal thickening. In a hamster model of cardiac fibrosis associated with cardiomyopathy, BCEAB reduced the increased cardiac chymase activity in cardiomyopathy and reduced fibrosis. Chymase inhibitors may be an important development for the treatment of cardiovascular injury associated with mast cell degranulation.     

Controlling persistent organic pollutants-what next?

Within the context of current international initiatives on the control of persistent organic pollutants (POPs), an overview is given of the scientific knowledge relating to POP sources, emissions, transport, fate and effects. At the regional scale, improvements in mass balance models for well-characterised POPs are resulting in an ability to estimate their environmental concentrations with sufficient accuracy to be of help for some regulatory purposes. The relevance of the parameters used to define POPs within these international initiatives is considered with an emphasis on mechanisms for adding new substances to the initial lists. A tiered approach is proposed for screening the large number of untested chemical substances according to their long-range transport potential, persistence and bioaccumulative potential prior to more detailed risk assessments. The importance of testing candidate POPs for chronic toxicity (i.e. for immunotoxicity, endocrine disruption and carcinogenicity) is emphasised as is a need for the further development of relevant SAR (structure activity relationship) models and in vitro and in vivo tests for these effects. Where there is a high level of uncertainty at the risk assessment stage, decision-makers may have to rely on expert judgement and weight-of-evidence, taking into account the precautionary principle and the views of relevant stake-holders. Close co-operation between the various international initiatives on POPs will be required to ensure that assessment criteria and procedures are as compatible as possible.     

Oncolytic viruses: what's next?

Cancer is a complex disease that often eludes successful treatment due to its propensity to evolve or adapt in the face of current therapeutic regimes. It is reasonable to suggest that sophisticated therapeutics that can attack cancers in multiple, but targeted ways, will be necessary in order to improve current success rates. It is the thesis of this article that Oncolytic Viruses (OVs), are a new generation of "smart therapeutics" for cancer with tremendous potential to revolutionize the management of what has become one of mankind's scourges. A number of viruses are being developed around the world for this purpose (one has already been approved for human use in China [1]) and I propose that it is now essential to embrace the technology and use our recent and evolving understanding of the molecular biology of cancer to fully exploit the oncolytic virus platform. In the remainder of this article I speculate on some of the next important steps in OV development and directions the platform may be headed in the future.