Drug Discovery Opinion

Hearing loss is one of the most common conditions affecting older adults; more than half of people over the age of 60 are hard of hearing or deaf. The causes of age-related hearing impairment, also known as prebycusis, have not been fully established but it is known that the condition seems to run in families. Now a whole genome association study has linked GRM7, the gene encoding metabotropic glutamate receptor type 7 (mGluR7), with prebycusis. The study, published in Human Molecular Genetics identified variants in GRM7 in individuals with hearing loss. Follow-up histochemical studies in human and mouse showed that mGluR7 is expressed in hair cells and spiral ganglion cells of the inner ear. The data link common alleles of GRM7 to an individual’s risk of developing prebycusis, possibly by altering susceptibility to glutamate excitotoxicity. The identification of a genetic cause for age-related hearing loss could lead to the development of treatments for the condition, although the next step will be to develop an animal model to test potential treatments.

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Phosphotidylserine is an anionic phospholipid that is normally present on the inner surface of cell membranes. In cells infected with a wide range of enveloped viruses, however, the phosphotidylserine becomes exposed on the outside of the cell membrane. The monoclonal antibody, bavituximab, binds to the exposed phospholipid and alerts the immune system to attack the virally infected cells. Bavituximab is currently undergoing clinical trials for the treatment of hepatitis C virus infection.

New animal studies now show that bavituximab is able to protect against a broader range of viruses. Guinea pigs were infected with Pichinide virus, which is similar to human Lassa fever virus. Whilst all the untreated animals died, half of those treated with bavituximab recovered. The surviving animals also had long-term immunity to further infection with the Pichinide virus. This is the first report of an effective treatment against advanced Lassa-like fever infections in animals. Bavituximab treatment also cured mice infected with cytomegalovirus, an opportunistic infection that causes disease in immunosuppressed individuals such as transplant and AIDS patients.

Other viruses that cause phospholipids to become externalised on infected cells include influenza virus, herpes simplex virus and members of the smallpox and rabies virus families as well as hepatitis C virus and HIV.

If externalisation of phospholipids is a general feature of cells infected with enveloped viruses, treatment with antibodies such as bavituximab may prove to be a broad-spectrum antiviral treatment. Since phosphatidylserine on virus-infected cells is host-derived, resistance may also be less likely to develop than against treatments that target components of the virus.

The study was carried out by scientists at the University of Texas Southwestern Medical Center and Peregrine Pharmaceuticals Inc. and is published in the Nov 23 online edition of the journal Nature Medicine.

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Tumours are heterogeneous and contain both oxygenated and hypoxic regions. Cells in regions with low oxygen levels mainly use glucose for glycolytic energy production and release lactic acid in the process. It had been thought that tumour cells with an ample oxygen supply primarily used glucose for oxidative energy production, but a new study published in the Journal of Clinical Investigation shows that lactate plays a major role in fuelling the oxidative metabolism of these cells. Cells in different regions of a tumour are thus able to mutually regulate their access to energy metabolites, reserving glucose for use by cells in hypoxic regions and recycling their waste product. The study also identified the monocarboxylate transporter 1 (MCT1) as the main route of lactate uptake and, using three different tumour models, showed that blocking MCT1 with α-cyano-4-hydroxycinnamate or siRNA caused a switch from lactate-fuelled respiration to glycolysis. This switch in metabolism of oxygenated cells induces necrosis of distant hypoxic cells by effectively starving them of glucose. These hypoxic cells are known to be very aggressive and difficult to kill with conventional treatments. The reduced oxygen consumption by surviving tumour cells after MCT1 inhibition also rendered the tumours more sensitive to the effects of radiotherapy.

Since MCT1 is expressed in a variety of primary human tumours, the study demonstrates the therapeutic potential of MCT1 inhibitors, as well as the likely benefit of combining these with radiotherapy.

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Cigarette smoking is recognised to be a major risk factor for disease, but once started, the habit is hard to quit. Nicotine is mainly responsible for dependence on tobacco and, historically, nicotine addiction has been one of the hardest to break. Now scientists at Scripps Florida have found that blocking the orexin A receptor in animal models abolishes the stimulatory effects of nicotine on brain reward circuitries and significantly reduces the desire for nicotine. In the study, the selective orexin A receptor antagonist, SB-334867, was found to decrease nicotine self-administration in rats and also reduced motivation to seek and obtain the drug.



If Orexin A is also involved in sustaining nicotine addiction in human smokers, blocking the orexin A receptor could be a potential target for developing new smoking cessation treatments. The Scripps group are hoping to discover new orexin A antagonists that would help smokers quit the habit. The study was published in the Nov 24 online Early Edition of the Proceedings of the National Academy of Sciences.


The orexin A receptor appears to be widely involved in regulating motivated behaviour and other studies have shown that SB-334867 also reduces alcohol-seeking behaviour in rats.

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Gout is one of the most excruciating conditions known and is caused by the accumulation of sodium urate crystals in the joints, leading to inflammation and severe pain. It usually affects the big toe, but can develop in any joint in the body. Risk factors for developing gout such as drinking alcohol, being overweight and eating a diet rich in red meat, offal and shellfish have led to the popular image of gout as a disease of the rich and privileged. Over the last 30 years, however, cases of gout in the UK have more than doubled, possibly due to increased levels of obesity and increased consumption of sugary drinks containing fructose which inhibits the excretion of uric acid. It is estimated that about 1.4% of men and 0.6% of women have gout.

For over 40 years, allopurinol has been used to reduce blood levels of uric acid and so prevent attacks of gout. Many gout patients, however, have impaired kidney function and are unable to take large enough doses of allopurinol to be fully effective. Now an FDA advisory committee have unanimously voted in favour of Takeda’s application for uloric, a new drug that also reduces levels of uric acid in the blood. Unlike allopurinol, uloric is not significantly excreted by the kidneys and so should provide relief for gout sufferers with impaired renal function.

SOURCES: FDA, “Briefing Document for the Arthritis Advisory Committee Meeting, Uloric/febuxostat,” Nov. 24, 2008. Takeda Pharmaceuticals North America Inc., “Briefing Document for Advisory Committee, Division of Anesthesia, Analgesia, and Rheumatology Products,” Nov. 24, 2008.

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Bone is living growing tissue and is remodelled constantly throughout life. The process involves two major types of bone cells: osteoclasts, which break down old or worn bone and osteoblasts, which make new bone. If the amount of new bone equals the amount being dissolved, bones remain strong but, if resorption exceeds new bone formation, the bones become weak and fracture more easily, a condition known as osteoporosis. The balance tips in favour of bone loss at about age 30 and, for women, bone loss is fastest in the first few years after menopause.

It had been thought that the skeleton controlled bone growth, but scientists at Columbia University Medical Center have shown that bone growth is controlled by the neurotransmitter, serotonin, which is produced mainly in the gut. The study had initially focussed on two rare human diseases, one that causes drastic bone loss and one that causes extremely high bone mass, which are both caused by a mutation in a gene called Lrp5. The team found that Lrp5 regulates synthesis of serotonin in the gut and that, by turning on or off production of serotonin in the gut, they could control bone formation. Serotonin signals to cells in the skeleton to slow production of new bone and, by turning off the intestine’s release of serotonin, the team was able to prevent osteoporosis in mice undergoing menopause.

Most osteoporosis drugs prevent the breakdown of old bone but do not increase the formation of new bone and reducing serotonin production in the gut could provide a novel way to treat osteoporosis. In the United States alone, 10 million people have osteoporosis and 34 million have low bone density.

The study is published in full in the November 26 issue of the journal Cell.

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Anthrax is caused by the Gram-positive bacterium, Bacillus anthracis. The disease mainly affects herbivorous mammals which ingest or inhale the spores while grazing, but can also be passed to humans by contact with infected animal products. Once within the host, the bacteria begin to multiply and infection typically proves lethal within a few days or weeks. Virulence requires expression of both the anthrax toxin and capsule genes, and one of the first factors found to be important in controlling virulence was elevated levels of CO₂/bicarbonate which are thought to signal the presence of a mammalian host environment. It has been difficult to unravel the precise mechanism of virulence control because of the equilibrium between CO₂, H₂CO₃, HCO₃^-, and CO₃^2-, but a study by scientists at the Scripps Research Institute published in the journal PLos Pathogens has demonstrated that expression of a specific bicarbonate transporter is critical for virulence. Deletion of the genes for the transporter strongly decreased the rate of bicarbonate uptake ex vivo and abolished induction of toxin gene expression. Importantly, the strain lacking the transporter was avirulent in a mouse model of anthrax infection, demonstrating the importance of this pathway for recognition of the host environment and pathogenesis.

The identification of an essential bicarbonate transporter may be of relevance to other pathogens, such as Staphylococcus aureus, that also regulate expression of virulence factors in response to CO₂/bicarbonate levels, and suggests a novel target for antibacterial intervention. Similar transporters have been identified and characterized in photosynthetic bacteria, and the availability of 3-dimensional structures of the bicarbonate binding domain of the Synechococcus transporter may help with the design of new inhibitors.

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Since ancient times, mankind has sought the gift of eternal youth and many have claimed to have discovered the secret. Today, despite a plethora of products promising a more youthful appearance, ways to truly defy the passage of time remain elusive – and difficult to substantiate. Although determining chronological age is straightforward, establishing physiological age has remained subjective. Research by scientists at the Buck Institute for Age Research however, could now lead to biomarkers to test the claims of anti-ageing therapies. The work was carried out in nematode worms and, by looking at changes in gene expression, the group identified a suite of genes that are actively involved in the ageing process. This is the first step towards identifying similar, irrefutable, biomarkers in humans that would provide a way of testing the effectiveness of anti-ageing therapies. The technology would also provide a way of telling whether an individual is ageing more quickly or slowly than would be expected. By extending their studies to mice, the scientists hope to be able to answer questions about the effects of environmental and nutritional factors on ageing. The work is published in the November 20, 2008 online edition of Aging Cell.

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