CAAR T cells run over autoimmunity
Chimeric antigen receptor (CAR) technology can be used to specifically eliminate autoantibody-producing B cells, broadening the technology's potential reach from cancer to autoimmunity. Autoimmune disease is treated through general immune suppression, but even when it is successful, such treatment necessarily increases the risk of infections. CAR T cells, meanwhile, have had their greatest success in eliminating B cells. In their studies, the authors created a chimeric autoantibody receptor (CAAR) T cell that targeted B cells producing antibodies to Dsg3. An autoimmune reaction to Dsg3 leads to pemphigus vulgaris, a blistering skin disease that is life-threatening. Such cells persisted in animal models and were specifically able to target the problematic B cells. The authors from the University of Pennsylvania noted that though short-term safety and efficacy observations in animals are "inherently limited," B cells were unlikely to be able to escape through no longer expressing the target antigen, because once they do so they would also no longer cause disease. Cytokine release syndrome is also less likely when targeting autoimmune B cells, as CAR T cells target all B cells, while CAAR T cells target only the small fraction that express the autoantibodies. "CAAR-T cells may provide an effective and universal strategy for specific targeting of autoreactive B cells in antibody-mediated autoimmune disease," the authors concluded. Their findings appeared in the July 1, 2016, issue of Science.
P53 and the proteasome
P53 is best known as a tumor suppressor that causes problems when it is inactivated. But p53 can also turn into an oncogene through gain-of-function mutations. Now, researchers have demonstrated that multiple different oncogenic p53 missense mutations led the mutated p53 to affect the proteasome. As a result, global protein homeostasis was disturbed and multiple tumor suppressors no longer functioned. P53 missense mutations cooperated with other mutations to contribute to resistance to the proteasome inhibitor Kyprolis (carfilzomib), but combining a p53-inactivating agent with Kyprolis "was effective in overcoming chemoresistance in triple-negative breast cancer cells, creating a therapeutic opportunity for treatment of solid tumors and metastasis with mutant p53." The authors, from the Italian National Laboratory CIB, published their work in the July 4, 2016, issue of Nature Cell Biology.
ALS: Location, location, location
Mutations in the TDP-43 are associated with the development of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but what makes the mutated protein so neurotoxic has not been worked out. Now, researchers have shown that the mutated protein increased levels of TDP-43 specifically in the mitochondria, where the protein interfered with energy production by causing the disassembly of one of the protein complexes for ATP production. In cell culture, preventing TDP-43 from moving into mitochondria also prevented mitochondrial dysfunction and neuronal death. The team from Case Western Reserve University concluded that "our studies link TDP-43 toxicity directly to mitochondrial bioenergetics and propose the targeting of TDP-43 mitochondrial localization as a promising therapeutic approach for neurodegeneration." Their work appeared in the July 4, 2016, issue of Nature Medicine.
Lack of LAC depresses rats
Genetically predisposed rats lacking acetyl-L-carnitine (LAC) are prone to depression-like symptoms, which can be reversed through supplementing LAC, which is a metabolic regulator that works via an epigenetic mechanism of action. Now, researchers have shown that after acute stress, LAC supplementation remained successful at warding off depression-like symptoms in some LAC-deficient animals, while others became resistant. Gene expression profiling in key brain regions revealed that metabolic changes in the hippocampus were important both for developing depression-like symptoms in the first place and for developing resistance to LAC under stress. "These findings establish CNS energy regulation as a factor to be considered for the development of better therapeutics," the authors from Rockefeller University wrote. "Agents such as LAC that regulate metabolic factors and reduce glutamate overflow could rapidly ameliorate depression and could also be considered for treatment of insulin resistance in depressed subjects." They published their results in the June 27, 2016, online issue of the Proceedings of the National Academy of Sciences.
HIV antibodies suppress viremia for months
Studies indicated that broadly neutralizing antibodies (bnAbs) to HIV could suppress viremia and delay rebound for extended periods of time, but it is likely antibodies will need to be used in combination for prolonged effectiveness. A phase I trial reported in the June 22, 2016, online issue of Nature showed that treatment with the bnAb 3BNC117 during treatment interruption of antiretroviral therapy (ART) delayed viral rebound by five to nine weeks. In 30 percent of patients, viral rebound did not occur until antibody levels waned, and HIV in most of those patients showed no sign of resistance on 3BNC117. However, in the majority of patients emerging viruses showed increased resistance, leading the Nature paper's authors from Rockefeller University to "speculate that combinations of bNAbs will also be needed to increase the frequency of individuals that remain suppressed by antibody" during planned treatment interruptions.