Volume 19 Issue 3, March 2013

As Sanofi’s new chief scientific officer and chair of the company's strategic development and scientific advisory council, Nabel faces the gargantuan task of reinvigorating the company’s drug pipeline. He sat down with Elie Dolgin to discuss his plan of fostering a new culture of scientific innovation at Sanofi.

The massive rise of patient advocacy in the US has led to an aggressive, if inadvertent, contest between disease-specific lobbyists. Advocacy groups say they're just trying to get taxpayer-backed research dollars distributed equitably according to public health need and they deny any outright competition with one another. But with research budgets shrinking, advocacy becomes a zero-sum game. Some scientists worry that pitting one disease against another threatens the leadership of government funding bodies—not to mention the basic research enterprise. Virginia Hughes reports.

After years of decline in the public eye, drug companies should implment a bioethics accreditation or rating program to help appropriately restore the industry's good name and improve its effectiveness in advancing global health and new treatments.

The treatment of acute lymphoblastic leukemia (ALL) is one of the great success stories in oncology. However, patients who fail to achieve remission or relapse after chemotherapy continue to have a very poor prognosis, and the mechanisms underlying therapy failures are largely unknown. A new study suggests that gain-of-function mutations in NT5C2, a gene that encodes an enzyme that metabolizes chemotherapeutic drugs used against ALL, contribute to chemotherapy resistance (pages 368–371).

Metabolically driven, chronic, low-grade inflammation has a crucial role in the pathogenesis of obesity and type 2 diabetes, and multiple stress-signaling cascades link insulin resistance and the immune response. An approved immunomodulatory drug is now shown to inhibit the kinases IKKε and TBK1, suppress inflammation and improve metabolic homeostasis in mouse models of obesity (pages 313–321).

The long-term behavioral deficits observed in depression are associated with altered spine synapses in specific neuronal circuits. A new study shows that chromatin remodeling decreases the expression of Ras-related C2 botulinum toxin substrate 1 (Rac1) and that the deficit in this small Rho GTPase is sufficient and necessary for altered spines and behavioral abnormalities in mice after social defeat (pages 337–344).

Regulatory T (T_reg) cells are important for protecting against pathogenic T cell responses, and impaired T_reg functions have been linked with autoimmune diseases. A recent study reveals a new mechanism for the inflammatory cytokine tumor necrosis factor-α (TNF-α) in rheumatoid arthritis, showing that it disables T_reg cells by affecting the phosphorylation and function of a key transcription factor expressed in these cells (pages 322–328).

Cancer resistance to targeted therapies seems to be a field of active research. But there are still open questions as to what drives drug resistance not only in metastatic tumor cells but also in disseminated tumor cells (DTCs) during adjuvant treatment, before metastases are established in other organs. Targeting this residual cancer disease or keeping these DTCs in a dormant state may be a way to stop progression to metastatic disease. For this, a further understanding of the biology of these cells is necessary. In 'Bedside to Bench', Bernhard Polzer and Christopher Klein put forward several scenarios to explain the different resistant mechanisms that might account for DTCs unresponsiveness to cancer drugs and emphasize the relevance of synchronizing targeted therapies with the changing responsive or dormant state of disseminated cancer cells in the clinic. In 'Bench to Bedside', Julio A Aguirre-Ghiso, Paloma Bragado and Maria Soledad Sosa discuss possible cell-intrinsic and microenvironment-derived signaling pathways that may be exploited to maintain dormancy in DTCs and explore the possibility of using dormancy gene signatures to identify individuals with dormant disease.

Rapid and effective host responses keep herpes simplex virus-2 (HSV-2) at bay, preventing genital mucosa lesions. However, periodic shedding and frequent reactivation of the latent virus allow for silent transmission, posing a challenge to virus elimination. The rapid clearance of HSV-2 in the genital mucosa by resident and virus-specific immune cells that persist in the mucosa suggests new ways to harness the immune system to develop effective therapies.

Patients with sickle cell disease or β-thalassemia are treated with drugs that aim to reactivate production of fetal hemoglobin, but these drugs are not effective in all patients and have side effects. Lihong Shi et al. identify a new therapeutic strategy for these anemias, showing that a drug used to treat depression, tranylcypromine, can raise fetal hemoglobin levels in human erythroid cells and transgenic mice harboring the human β-globin locus, most likely by inhibiting a lysine demethylase that controls fetal globin gene expression.

John Chute and his colleagues show that the cytokine EGF protects mouse bone marrow hematopoietic stem cells from radiation injury. EGF signaling in these cells inhibited cell death through repression of the proapoptotic protein PUMA. EGF administration rescued mice from death after total-body irradiation, suggesting a new therapeutic strategy for radioprotection.

The inability of the heart to efficiently relax as it beats, termed diastolic dysfunction, is a major underlying cause of heart disease. As a new strategy for treating diastolic dysfunction, Joseph Metzger and his colleagues engineered directed substitutions in the calcium-binding protein Parvalbumin to optimize its ability to promote cardiac myocyte relaxation. Gene transfer of this Parvalbumin variant promoted cardiac myocyte relaxation of rabbit and canine heart failure models in vitro and corrected heart function in two in vivo mouse models of diastolic dysfunction.

Alan Saltiel and his colleagues report that the approved drug amlexanox, currently used to treat asthma and canker sores, is a relatively specific inhibitor of the noncanonical IκB kinases IKK-ɛ and TANK-binding kinase 1 (TBK1) and that it improves metabolic disease in mouse genetic and dietary models of obesity. These results suggest this drug may be repurposed to treat obesity and insulin resistance.

TNF-α suppresses regulatory T (T_reg) cell function, however the mechanism remains unclear. Here Jingwu Z Zhang and colleagues find that in activated T cells, phosphorylation of FOXP3 promotes its transcriptional activity. TNF-α induces protein phosphatase 1 expression, leading to dephosphorylation of FOXP3 and inhibition of T_reg cell function. In individuals with rheumatoid arthritis, TNF-α–specific antibody treatment restores T_reg cell activity and FOXP3 phosphorylation, suggesting that post-translational modifications, including phosphorylation, regulate FOXP3 activity and T_reg cell–mediated suppression.

Oncolytic viruses are under development for tumor treatment. David Kirn and colleagues now report their results of a randomized phase 2 dose-finding trial of JX-594, an oncolytic immunotherapeutic vaccinia virus, in patients with advanced hepatocellular carcinoma. The study shows that high-dose JX-594 was associated with significantly improved overall survival and induced radiographic responses and antitumor immunity.

Chronic stress and depression induce structural and functional plasticity; however, the mechanisms responsible for these alterations remain incompletely characterized. Here Scott J Russo and colleagues demonstrate that the Rac1 promoter is epigenetically modified, and its expression is reduced in the nucleus accumbens of mice after chronic defeat stress and in subjects with major depressive disorders. Reduced Rac1 expression is sufficient to induce depression-related behavior and stubby spine formation in mice.

Usher syndrome is a congenital form of deafness and vestibular dysfunction characterized by mutations in the USH1C gene encoding harmonin. Michelle L. Hastings and her colleagues show in a mouse model of Usher syndrome that early treatment with antisense oligonucleotides corrects defective pre-mRNA splicing of mutant USH1C, increasing full-length harmonin expression and restoring low-frequency hearing and vestibular function.

Neurons within the CA3 region of the hippocampus are relatively resistant to cell death after ischemia. Alastair M. Buchan and his colleagues demonstrate that the product of the TSC1 gene, hamartin, is upregulated in CA3 neurons in response to ischemia. Hamartin promotes survival by inhibiting mTORC1 and increasing autophagic flux in neurons.

Stefan Kiechl and colleagues show that blockade of receptor activator of nuclear factor-κB (RANKL) signaling in hepatocytes by cell type–specific genetic deletion of its receptor promotes greater insulin sensitivity in both a genetic and a nutritional model of type 2 diabetes. They also show epidemiological evidence that elevated serum concentrations of soluble RANKL are a risk factor for the development of this disease.

Staphylococcus aureus is an important causative agent of many skin infections and produces numerous toxic phenol-soluble modulins that mediate its virulence. Michael Otto and colleagues have now identified the S. aureus genes that encode the peptide transporter responsible for the export of these toxins from the bacteria and reveal its crucial role in abscess formation in the skin.

Mutations in the cytosolic 5′-nucleotidase II gene accelerate the inactivation of chemotherapeutic nucleoside analogs in acute lymphoblastic leukemia (ALL)-promoting lymphoblasts. Increased nucleotide metabolism may therefore constitute an important resistance mechanism in chemotherapy-resilient ALL.

A limited T cell receptor (TCR) repertoire after allogeneic hematopoietic stem cell transplantation can be associated with poor clinical outcomes and greater susceptibility to infections. Jeroen van Heijst and colleagues have combined 5′ RACE PCR with deep sequencing technology to provide a reproducible and quantitative measure of the recovery of TCR diversity during the first year of transplantation with three commonly used stem cell sources in patients with various hematologic malignancies.