Brief Communications in 2013

The authors employ targeted next-generation sequencing to identify driving oncogenic alterations in patients with lung cancer with no known oncogenes. They discover two gene fusions involving NTRK1 that lead to constitutive activation of the kinase TRKA and can drive transformation. The fusions can be targeted with available kinase inhibitors and may represent therapeutic targets.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by loss of the translational repressor protein FMRP. Now, Joel D. Richter and his colleagues report that knocking down the expression of the translational activator protein CPEB can restore normal levels of translation and rescue behavioral deficits in a mouse model of FXS.

Mutations in mitochondrial DNA that inhibit the normal function of this organelle can result in disease if a sufficient percentage of mitochondria in the body's cells harbor such alterations. Using transcription activator–like effector nuclease (TALEN) technology, Carlos Moraes and his colleagues show that mutant mitochondria can be selectively targeted and eliminated, allowing for a sufficient percentage increase of normal mitochondria and thus restoration of normal respiration in a cell-based model.

An adeno-associated virus (AAV) vector encoding a variant of human lipoprotein lipase was recently approved in Europe as the first gene therapy for the treatment of LPL deficiency. Here Manfred Schmidt and his colleagues report their analysis of AAV integration sites after injection of the gene therapy construct in LPL-deficient patients and in mice.

Rifampicin and isoniazid are often used together as a co-therapy to treat tuberculosis, but their combined use often leads to hepatoxicity in humans. Xiaochao Ma and colleagues now report the mechanisms behind this side effect, thus opening a possible avenue to the safer use of these effective drugs.

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.