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Science Papers Describe NanoProCas9 System, Inflammatory Protein Biomarkers, LncRNA Affects Muscle Tissue Formation in Aging

A conditionally activatable CRISPR-Cas9 prodrug system that can be leveraged for precision medicine is described in this week's Science Advances. While CRISRP-Cas9 genome editing holds great therapeutic potential, the nonspecific distribution of Cas9 raises safety concerns relating to off-target activity at the tissue level. Aiming to overcome this limitation, Zhejiang University scientists developed a site-specific, activatable CRISPR-Cas9 nanoprodrug system, dubbed NanoProCas9, that combines the targeted delivery and the conditional activation of CRISPR-Cas9 in response to specific biological signals in vivo. NanoProCas9 consists of a cationic polymeric vector capable of complexing plasmid DNA-encoding destabilized Cas9 nuclease, a layer of biomimetic cell membrane coated on the vector/plasmid nanocomplexes for targeted delivery, and stimuli-responsive precursory molecules anchored on the exofacial membrane. In the study, the investigators demonstrate the therapeutic potential of systemic NanoProCas9 administration in mouse models of inflammatory disease. "As a number of physiological and pathological signals, such as ATP, redox, and pH, can be leveraged to develop different types of genome-editing prodrugs, our current study opens a new avenue to precisely regulate CRISPR-Cas–based systems in vivo for more complicated and diverse genome-editing contexts," they write.

An analysis of the effects of inflammatory protein biomarkers on inflammatory diseases is published in Science Advances this week, pointing to a protective rather than causal effect for most of these proteins. Despite the identification of large numbers of measured plasma proteins as potential biomarkers of disease, the causal relation between a protein biomarker and its associated disease is commonly not known. In particular, the direction in which high or low levels of a protein could affect the risk of developing disease is unclear. In their study, scientists from Uppsala University undertook a two-sample Mendelian randomization approach to estimate the causal effect of 85 known or suggested protein biomarkers for 18 inflammatory diseases using cohorts from the Northern Sweden Population Health Study and the UK Biobank. They found six proteins with causal protective effects on 11 of the diseases investigated including psoriasis, osteoarthritis, asthma, and rheumatoid arthritis. "Our results suggest that many proteins are expressed to protect against damage, rather than being causal for disease development, and these proteins are likely to be overexpressed in diseased individuals," the study's authors write. "These proteins represent potential intervention points for disease prevention and treatment."

The discovery of a long noncoding RNA (lncRNA) that promotes the formation of fast-twitch muscle tissue in aging is reported in Science Translational Medicine this week. Skeletal muscle undergoes substantial modulation in response to exercise and aging. Aging, in particular, is closely associated with the loss of fast-twitch muscle fibers, yet little is known about the mechanisms underlying this process. In the study, a team led by researchers from École Polytechnique Fédérale de Lausanne focused on lncRNAs given their dynamic expression pattern and key regulatory role in gene expression, finding that one — called CYTOR — is increased after exercise in humans, rats, and mice. They found that CYTOR enhanced myogenic differentiation and promoted type II muscle fibers in vitro, and that manipulating its expression altered skeletal muscle mass, strength, and performance in young and aged mice. A single-nucleotide polymorphism was also identified that was associated with increased CYTOR expression in human skeletal muscle and increased distance achieved during walk testing in aged individuals. "Our data support further exploration of pathways involving CYTOR and other lncRNAs in aging and muscle physiology," the authors conclude.