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Spinal muscular atrophy (SMA) is the second most common autosomal recessive disease and is a leading cause of infantile death. This disease has a carrier frequency of 1:35, affecting 1/6,000 live births and is the result of a homozygous loss of the survival of motor neuron 1 gene (SMN1). Humans carry a nearly identical copy gene, SMN2, that codes for very low levels of the full-length protein, ∼10% when compared to SMN1. This is due to one silent nucleotide transition at the 5' end of exon 7 that disrupts a critical splicing regulatory domain. The underlying protein coding region, however, is unaffected by this and other nucleotide differences between SMN1 and SMN2. SMN2 has, therefore, been envisioned as an outstanding target for therapeutic strategies that 1) increases SMN2 expression, 2) alters the pre-messenger RNA splicing of exon 7 or 3) stabilizes the SMN2-derived protein products. In this review, we summarize numerous therapeutic approaches including nucleic acid-based and drug-oriented therapies that have progressed toward treating SMA.

Dimebon (latrepirdine) was developed and used in Russia as an over-the-counter oral antihistamine for allergy treatment. In the early 1990s, Dimebon was characterized as a low-affinity NMDA receptor antagonist by Dr. Sergey Bachurin and his colleagues. An initial small-scale, open-label trial of Dimebon in 14 Alzheimer's disease (AD) patients demonstrated potential efficacy. Dimebon was then patented for the treatment of neurodegenerative disorders and licensed by Medivation. Extremely promising results were obtained in a double-blind, placebo-controlled, phase II AD trial in 183 patients; however, a phase II trial of Dimebon in 91 Huntington's disease patients was much less successful. Recently, a phase III AD trial of Dimebon in 598 patients failed to result in any significant improvement in primary or secondary outcomes. The failure of Dimebon may be in large part due to insufficient understanding of its mechanism of action. The NMDA receptor blocking activity of Dimebon is too weak to be physiologically relevant, while the proposed "novel mitochondrial mechanism of action" lacks credible scientific evidence or a molecular target. Independent studies indicate that the clinical effects of Dimebon most likely result from inhibition of histamine H₁ and serotonin 5-HT₆ receptors. Careful preclinical studies of novel potential therapies are needed to minimize chances of making similar costly mistakes in the future.

Activation of the nuclear factor-κB (NF-κB) family of transcription factors results in the expression of numerous genes involved in the regulation of the innate and adaptive immune responses, and has been implicated as a key mechanism in chronic inflammatory diseases including rheumatoid arthritis (RA). The IκB kinases (IKKs) are key components in the signaling pathway by which proinflammatory stimuli, such as lipopolysaccharide and tumor necrosis factor-α lead to the activation of NF-κB. The most widely studied of the IKKs is IKKβ. Inhibitors of the kinase activity of IKKβ offer opportunities for intervention in RA, as well as other inflammatory disorders. Some examples for which the most extensive data are available will here be reviewed.

The Royal Society of Chemistry Biotechnology Group and Chemical Biology Interface Forum held a 1-day symposium, on April 19, 2010, on Chemical and Biological Therapeutic Approaches to Neurological Disorders, at the Royal Society of Chemistry, Burlington House, London. The purpose of the meeting, organized by Colin Bedford, Irene Francois and Klaus Rumpel, was to give an update of new developments regarding the genetics, biochemistry and pathophysiology of the major neurological disorders. These developments should facilitate the discovery of better clinical biomarkers and improved medicines for the diagnosis, monitoring and treatment of patients with neurological disease. The presentations and posters covered neurological disorders including Parkinson's disease, Alzheimer's disease, multiple sclerosis, schizophrenia, autism, epilepsy and pain. The majority of these psychiatric and neurological disorders cause long-term suffering and disability and thus create an important global public health problem. This was the central issue of a participative discussion that took place at the end of the meeting.

Obesity has now reached pandemic proportions leading to a collection of morbidities referred to as metabolic syndrome including insulin resistance, type 2 diabetes and cardiovascular disease. The expansion of adipose tissue is a direct cause of these comorbidities due to excessive accumulation of triglycerides within adipocytes, causing disruption of normal adipose function. There are two major types of adipose tissue, white and brown. The former stores energy as triglycerides within large droplets, whereas the latter catabolizes lipids to produce heat. A strategy to combat obesity-associated disorders, therefore, includes enhancement of brown adipose tissue activity by targeting the recently identified regulators of brown adipocyte development and function, including its master regulator, PRDM16.

The main characteristic of attention deficit/hyperactivity disorder (ADHD) is a persistent pattern of inattention and/or hyperactivity-impulsivity which is more frequent and severe than is usually expected in individuals at a comparable level of development. ADHD is estimated to affect approximately 5.29% of school-aged children and is therefore the most common childhood onset psychological disorder. A conservative estimate of the annual societal cost of illness for ADHD in childhood and adolescence is USD 42.5 billion in the U.S. alone. Global sales of ADHD medicines could reach USD 4.3 billion by 2012. Despite the prevalence, high heritability and costs of ADHD, biological markers do not exist. Such biomarkers are in high demand as they would help eliminate the subjective diagnoses based on interviews and potentially allow for earlier diagnosis and personalized medicine. Lack of markers likely stems from several factors that complicate ADHD research and the assessment of pharmacological responses. This review analyses complicating factors in defining ADHD phenotype and etiology, identifying specific diagnostic markers and the difficulties in the assessment of pharmacogenomic markers. The dopamine transporter (DAT1) genotype and methylphenidate (MPH) response are detailed as an example of a biomarker. A recent report of a novel ADHD gene and its possible role as a biomarker is explored. Finally, suggestions for strategies and study designs for future research for the definition of effective ADHD biomarkers are made.

The 8th Annual Meeting of the International Society for Stem Cell Research (ISSCR) placed a particular emphasis on topics related to the engineering of induced pluripotent stem cells through reprogramming of mammalian somatic cells, embryonic and adult stem cells of different species, tissue regeneration, stem cell transplantation and cancer stem cells. This report provides an overview on the standpoint of stem cell research programs, which is based on the proceedings of the meeting.

New anticancer agents are needed in order to overcome the resistance of cancer cells to standard chemotherapy. At present, many of the molecular events that drive the malignant transformation and progression have been identified and there is optimism that the development of agents that specifically target such events will improve treatment outcomes. Cancer cells present common alterations in components of pathways that are involved in the normal cell cycle regulation and in mechanisms of DNA damage repair. Wee1-like protein kinase is a tyrosine kinase with a key role as an inhibitory regulator of the G2/M checkpoint that precedes entry into mitosis. Abrogation of this checkpoint through Wee1 inhibition may result in increased antitumor activity of agents that cause DNA damage such as radiation therapy or some cytotoxic agents. This has been confirmed in preclinical studies and results of clinical studies evaluating a Wee1 inhibitor are awaited to establish its activity in combination with chemotherapy. Here we review the role of Wee1 tyrosine kinase in the control of the G2/M checkpoint and the effects of G2/M checkpoint abrogation through Wee1 inhibition. We present results of preclinical studies with Wee1 inhibitors and the results of the first clinical trial recently reported, evaluating MK-1775, a small-molecule inhibitor of Wee1.

Nitric oxide (NO) is an organic gas ubiquitously synthesized in mammalian tissues by NO synthase (NOS). Over the past 20 years, remarkable progress has been made in explaining the mechanism/s of NO and its functions in different biological systems. NO is produced as metabolic endproduct in specific cell life phases, and may act as a atypical neuronal messenger. NO is an important regulator of homeostatic processes in the eye and changes in its synthesis could lead to a variety of eye diseases such as glaucoma, retinal degeneration and uveitis. Both overexpression and underexpression of NO could contribute to pathological conditions in the eye. Many works have highlighted the role of NO in a wide range of ocular diseases and recent studies from our laboratory and others have shown that a suppressive action of inducible NOS-derived NO production lowers the intraocular pressure. Indeed, from a clinical perspective, a precise regulation of NO may lead to new therapeutic options likely safer and more efficacious than currently available treatments for various sight-threatening eye diseases.