Protein degradation system targeted to KRAS

KRAS no longer has the halo of complete undruggability, but targeting in early phase clinical trials has shown mixed results to date. Now, researchers at the University of Dundee have developed a broad system for targeted degradation of intracellular proteins called ligand-inducible affinity-directed protein missile (L-AdPROM), and used it to target both labeled and endogenous RAS proteins. An adcom for AdPROM remains a long way off, but the authors wrote that the highly versatile L-AdPROM system is useful for the inducible degradation of potentially any intracellular [protein of interest], and that “our findings imply that endogenous RAS proteins can be targeted for proteolysis, supporting the idea of an alternative therapeutic approach to these undruggable targets.” The results were published in back-to-back papers in the July 14, 2020, online issue of Cell Chemical Biology.

Bacteriophages find, fight microbiome’s dark side

Researchers at Osaka City University Graduate School of Medicine and the University of Tokyo have identified lysogenic bacteriophages that were specific to Clostridium difficile, as well as 10 specific enzymes or endolysins that were able to kill toxin-producing C. difficile strains and prevent death in mouse models. There are a number of bacterial strains, including C. difficile, Staphylococcus aureus and others, that can be either commensals or the causes of serious, sometimes deadly infections. Because those commensals exist within the complex mixture of the microbiome, they cannot currently be targeted specifically, and broad-spectrum antibiotics are as likely to cause problems as to solve them – C. difficile infections, for example, can be the result of antibiotic treatments for other infections. Bacteriophages are specific enough to solve that problem. The authors used metagenomic sequencing of the fecal microbiomes of about 100 healthy Japanese individuals to discover associations between specific pathobionts, or microbiome members that can turn into pathogens, and bacteriophages that infect them. In addition to the specific findings related to C. difficile, the authors wrote that their analyses “reveal not only host bacteria-phage associations in the human intestine but also provide vital information for the development of phage therapies against intestinal pathobionts. They reported their work in the July 10, 2020, online edition of Cell Host & Microbe.

Preventing T-cell rejection

Investigators at Baylor College of Medicine have developed a method to prevent the rejection of allogeneic T cells, making progress toward off-the-shelf immune cell therapies. Autologous engineered T cells have had a profound impact on the treatment of a few hematological cancers. But the necessity to engineer patient-derived cells for autologous treatments makes the treatment more expensive, slower and less predictable than allogeneic therapies could be. One obstacle to allogeneic therapies is immune rejection by the transplantee. When the host immune system gears up for rejection, both innate and adaptive immune cells express co-stimulation factors including 41BB. The authors were able to eliminate such cells by including an alloimmune defense receptor (ADR) in CAR T cells. “Co-expressing chimeric antigen receptors and ADRs persisted in mice and produced sustained tumor eradication in two mouse models of allogeneic T-cell therapy of hematopoietic and solid cancers,” the authors wrote. “This approach enables generation of rejection-resistant, ‘off-the-shelf’, allogeneic T-cell products to produce long-term therapeutic benefit in immunocompetent recipients.” They published their findings in the July 13, 2020, online issue of Nature Biotechnology.

X chromosome is finished

Scientists at the National Human Genome Research Institute and the University of California, Santa Cruz have performed the first full sequencing of a human X chromosome, including centromeric regions, pseudoautosomal regions and cancer-testis ampliconic gene families, which have significant gaps in the current human genome draft sequence. The draft sequence of the human genome still contains gaps, particularly in regions with repetitive sequences, which are hard to sequence with current methods. By using ultralong-read-nanopore sequencing along with novel validation methods, the team was able to sequence the gap regions. They wrote that “finishing the entire human genome is now within reach and the data presented here will enable ongoing efforts to complete the remaining human chromosomes.” Their work appeared in the July 14, 2020, advance online edition of Nature.

Mitochondria, interneurons, cognition link explored

Researchers at the University of Texas at Dallas have gained new insights into the relationship among NMDA receptor activity, mitochondrial function, interneuron activity and psychiatric symptoms. NMDA receptors play important roles in brain plasticity, and when they are insufficiently active during development, that can lead to reduced numbers of interneurons in the forebrain. Because interneurons are critical for synchronizing neural activity in sensory and information processing, reduced numbers lead to psychiatric-like symptoms in animal models. In previous work, the team demonstrated that the lack of interneurons was related to damage induced by the production of reactive oxygen species (ROS) by mitochondria. In their new story, they showed that genetic deletion of the mitochondrial matrix protein cyclophilin D prevented ketamine-induced ROS production, and their downstream effects on interneuron numbers and neuronal signaling in the forebrain. That also improved “behavioral deficits in cognitive flexibility, social interaction, and novel object recognition. Taken together, these data highlight how mitochondrial activity may play an integral role in modulating

Researchers at the University of Texas at Dallas have gained new insights into the relationship among NMDA receptor activity, mitochondrial function, interneuron activity and psychiatric symptoms. NMDA receptors play important roles in brain plasticity, and when they are insufficiently active during development, that can lead to reduced numbers of interneurons in the forebrain. Because interneurons are critical for synchronizing neural activity in sensory and information processing, reduced numbers lead to psychiatric-like symptoms in animal models. In previous work, the team demonstrated that the lack of interneurons was related to damage induced by the production of reactive oxygen species (ROS) by mitochondria. In their new story, they showed that genetic deletion of the mitochondrial matrix protein cyclophilin D prevented ketamine-induced ROS production, and their downstream effects on interneuron numbers and neuronal signaling in the forebrain. That also improved “behavioral deficits in cognitive flexibility, social interaction, and novel object recognition. Taken together, these data highlight how mitochondrial activity may play an integral role in modulating [interneuron]-mediated cognitive processes,” the authors wrote. They-mediated cognitive processes,” the authors wrote. They reported their results in the June 30, 2020, issue of the Journal of Neuroscience.


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