Gilead’s Idelalisib: Could It Be A Respiratory Disease Drug?

A team from the British University of Cambridge identified a mutation that can predispose immunodeficient patients to recurring respiratory infections. In their work, the authors sequenced the exomes of 35 individuals with primary immunodeficiences, and found a mutation in the enzyme phosphoinositide 3-kinase (PI3K) delta in 17 patients from four separate families, but not in several thousand healthy control individuals. PI3K delta was hyperactive as a result of that mutation, and affected individuals were susceptible to recurrent respiratory diseases. Their symptoms could be improved by treatment with PI3K delta-targeting drugs, including idelalisib (GS-1101, Gilead Sciences Inc.), an experimental cancer drug in a Phase III trial in chronic lymphocytic leukemia that was just halted early for efficacy. (See BioWorld Today, Oct. 11, 2013.) The new findings appeared in the Oct. 17, 2013, advance online edition of Science.

Antisense Protects from ALS Mutation

Using autologous induced pluripotent stem (iPS) cells from amyotrophic lateral sclerosis (ALS) patients, scientists from Johns Hopkins University have developed an antisense oligonucleotide that appears to counteract toxicity responsible for some cases of both ALS and frontotemporal dementia. The RNA in question is a usually untranslated repeat of six base pairs within the gene C9orf72. In their work, the authors showed that when the repeat was transcribed, the resulting RNA interacted with multiple RNA-binding proteins, essentially blocking their availability for the synthesis of other proteins and disrupting the production of multiple proteins. In iPS cells, treatment with antisense oligonucleotides could reverse some of the expansion’s toxic effects. Mutations in C9orf72 account for roughly 40 percent of inherited and 10 percent of sporadic cases of ALS, and the authors said their findings “provide candidate antisense therapeutics and candidate human pharmacodynamic markers for therapy.” The paper appeared in the Oct. 16, 2013, issue of Neuron.

Kinase Contributes to Heart Damage

A team from Temple University identified a heart cell-specific kinase that is responsible for some of the damage of reperfusion injury. During a heart attack, damage to heart muscle cells occurs at two points. The first and more obvious one is damage that is due to a lack of oxygen and nutrients during the time the artery is blocked. But once that block is removed, there is a second wave of damage during so-called reperfusion injury when blood flow is restored and cells essentially overshoot in their reaction. In their work, the authors showed that the heart muscle cell-specific troponin I interacting kinase (TNNI3K) promoted reperfusion injury. They then developed small-molecule inhibitors of the kinase and found that when they were given to mice with induced heart attack at the time of reperfusion, they reduced acute and chronic damage to heart muscle cells. The authors concluded that TNNI3K was a tractable target for preventing heart damage that occurs in the wake of a heart attack, and that inhibiting the kinase was likely to have a favorable side-effect profile. Their findings appeared in the Oct. 16, 2013, issue of Science Translational Medicine.

Which Epstein-Barr Goes Bad

Researchers from the German Cancer Research Center have identified a strain of Epstein-Barr virus that is more prone to causing cancer than average. The majority of the global population is infected with Epstein-Barr virus, and in most cases, that does not lead to any illness. But a minority of patients will suffer serious consequences from Epstein-Barr infection, such as mononucleosis or cancer. In their work, the authors sequenced a strain of Epstein-Barr virus that was isolated from a tumor, and they found that its sequence was similar to that of other strains from cancer patients but different from strains that were not causing disease in their hosts. They found that the strain was more likely to infect epithelial cells and less likely to infect B cells, and that it replicated at high levels. They concluded that strain differences are likely to account for why some Epstein-Barr virus infections cause such serious disease when most do not. Their findings suggested that the success of vaccination strategies to prevent serious disease will depend on using the right strain. The work appeared in the Oct. 10, 2013, issue of Cell Reports.

Building a Better BAT Blocker

Researchers from Oregon Health & Science University have combined bacterial and eukaryotic biogenic amine transporters (BATs), which are targeted by multiple classes of antidepressants, to gain structural insights into how they function. BATs regulate the levels of transmitters that play a role in depression and other neurological disorders, and they are targeted by many drugs, including three separate classes of antidepressants. Their structure had been impossible to determine with X-ray crystallography, however. In their work, the authors used a bacterial BAT, which can be studied using X-ray crystallography, and engineered it to contain key amino acids from the human BAT. The paper, which in the words of its authors provides “molecular guideposts for the development of new therapeutic agents,” was published in the Oct. 13, 2013, advance online issue of Nature.

Checking out GPCRs

Scientists from D.E. Shaw Research and Monash University have made progress in understanding the structure of another drug target class: G protein-coupled receptors (GPCRs), which are the target of a third of all currently marketed drugs. GPCRs can be affected therapeutically in two ways: through molecules which compete directly for the binding sites with the natural ligand and through so-called allosteric modulators, which bind to a different part of the drug and affect the receptor’s response to its natural binding partner. In their work, the authors determined the structure of the GPCR bound to an allosteric modulator. By understanding the details of that structure, they were able to modify the modulators in ways that changed its effects on the GPCR. Their findings, they said, “provide a structural basis for the rational design of allosteric modulators” that target GPCRs. They appeared in the Oct. 13, 2013, advance online issue of Nature.

Shock to the Fly System

Fruit flies are an astonishingly useful model for the workings of the brain. Now, scientists from the University of Wisconsin at Madison have shown that they can be used to better understand the molecular mechanisms that underlie traumatic brain injury. Traumatic brain injury is a leading cause of neurological deficits and often has strong effects on the quality of life even in individuals. In their paper, the authors described a method to induce traumatic brain injury in flies, as well as the gene expression profiles resulting from such injuries, which suggested that many of the genes involved in longevity play a role in the response to brain injury. Beyond their specific results, the authors pointed out that their findings will allow researchers to “take advantage of the wealth of experimental tools available in flies” for the study of brain injury, which they hope will lead to “key insights into human TBI that may ultimately provide unique opportunities for therapeutic intervention.” Their paper was published in the Oct. 14, 2013, advance online edition of the Proceedings of the National Academy of Sciences.

Immune Regulator mTOR?

Given that each person is host to bacterial guests numbering in the trillions, and far more of them are useful than pathological, the immune system has needed to become finely attuned to which is a threat and which is not. Scientists from Yale University have identified one mechanism by which macrophages distinguish friend from foe. The authors compared the consequences of two different strain of the bacterium Legionella pneumophila, only one of which causes disease. They found that detection of the pathogenic strain selectively induced the production of cytokines via the signaling hub mTOR, which is typically thought of as a protein complex that integrates information about nutrient status with growth fate decisions. The findings were published in the Oct. 13, 2013, issue of Nature Immunology.

Bone Density and Free Radicals

A team from the German University of Frankfurt has demonstrated that the enzyme NOX4 is a contributor to bone loss in osteoporosis. Bones are the only organ of the body that have a cell type dedicated to their destruction, the bone-chomping osteoclasts, as well as one for their formation, the osteoblasts. Osteoclasts and osteoblasts need to be in equilibrium with each other for bones to remain healthy. In their work, the authors looked at NOX4 because the enzyme produces reactive oxygen species, which have been implicated in bone diseases. They found that in animal models of osteoporosis, knockdown or inhibition or NOX4 led to reduced bone loss. A GWAS study in patients showed that a specific SNP in the NOX4 gene was associated with high bone turnover and reduced bone density. The authors concluded that “NOX4 is involved in bone loss and represents a potential therapeutic target for the treatment of osteoporosis.” The paper appeared in the Oct. 15, 2013, issue of the Journal of Clinical Investigation.

New MS Target

Researchers from the German University of Bonn have identified a G protein-coupled receptor (GPCR) that plays a role in the differentiation of oligodendrocytes and could be targeted for the treatment of multiple sclerosis. The receptor, GPR17, was known to have a role in oligodendrocyte maturation, but has been very hard to affect selectively because it is closely related to several other GPCRs. In their work, the authors developed a highly specific agonist, and found that such activation blocked oligodendrocytes, which form the myelin sheath that enables high-speed neuronal communication, from forming from their precursor cells. Mature oligodendrocytes are lacking in multiple sclerosis because they are destroyed by autoimmune attacks, and the authors said that “inhibiting GPR17 emerges as a therapeutic strategy to relieve the oligodendrocyte maturation block and promote myelin repair” in multiple sclerosis. The paper appeared in the Oct. 18, 2013, issue of Science.