Kanchi, K. | bioRxiv Science

bioRxiv2024

Auto-loaded TRAIL-exosomes derived from induced neural stem cells for brain cancer therapy

Transdifferentiation (TD), a somatic cell reprogramming process that eliminates pluripotent intermediates, creates cells that are ideal for personalized anti-cancer therapy. Here, we provide the first evidence that extracellular vesicles (EVs) from TD-derived induced neural stem cells (Exo-iNSCs) are an efficacious treatment strategy for brain cancer. We found that genetically engineered iNSCs generated EVs loaded with the tumoricidal gene product TRAIL at nearly twice the rate as their parental fibroblasts, and the TRAIL produced by iNSCs were naturally loaded into the lumen of EVs and arrayed across their outer membrane (Exo-iNSC-TRAIL). Uptake studies in ex vivo organotypic brain slice cultures showed Exo-iNSC-TRAIL selectively accumulates within tumor foci, and co-culture assays showed that Exo-iNSC-TRAIL killed metastatic and primary brain cancer cells more effectively than free TRAIL. In an orthotopic mouse model of brain cancer, Exo-iNSC-TRAIL reduced breast-to-brain tumor xenografts around 3000-fold greater than treatment with free TRAIL, with all Exo-iNSC-TRAIL treated animals surviving through 90 days post-treatment. In additional in vivo testing against aggressive U87 and invasive GBM8 glioblastoma tumors, Exo-iNSC-TRAIL also induced a statistically significant increase in survival. These studies establish a new easily generated, stable, tumor-targeted EV to efficaciously treat multiple forms of brain cancer.

cancer biology↗

bioRxiv2018

Exome sequencing identifies high impact trait-associated alleles enriched in Finns

As yet undiscovered rare variants are hypothesized to substantially influence an individuals risk for common diseases and traits, but sequencing studies aiming to identify such variants have generally been underpowered. In isolated populations that have expanded rapidly after a population bottleneck, deleterious alleles that passed through the bottleneck may be maintained at much higher frequencies than in other populations. In an exome sequencing study of nearly 20,000 cohort participants from northern and eastern Finnish populations that exemplify this phenomenon, most novel trait-associated deleterious variants displayed frequencies 10-173 times higher than in other European populations. These enriched alleles underlie 30 novel associations with 20 disease-related quantitative traits and demonstrate a geographical clustering equivalent to that of Mendelian disease mutations characteristic of the Finnish population. Sequencing studies in populations without this unique history would require hundreds of thousands to millions of participants for comparable power.

genomics↗