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Therapeutic Proteins to Cells

Engineered Extracellular Vesicles Could Deliver Gene Editors, Therapeutic Proteins to Cells




New research from scientists at the Karolinska Institutet in Sweden and their collaborators elsewhere describes a way of improving extracellular vesicles’ ability to transport things like therapeutic proteins and gene editors into cells. Specifically, their approach involves adding a small part of a bacterial protein called an intein and a fusogenic protein from a virus to the vesicles.

Full details are provided in a new Nature Communications paper titled, “Engineering of extracellular vesicles for efficient intracellular delivery of multimodal therapeutics including genome editors.” In the paper, the researchers explain that their work offers solutions to the “major bottlenecks of EV-mediated delivery of protein therapeutics, the enrichment of liberated active cargo into EVs, and their subsequent endosomal escape in recipient cells.” The added fusogenic protein, vesicular stomatitis virus G glycoprotein, helps the engineered vesicles fuse with the endosomal membrane and release their contents in the cell. Meanwhile, the added intein, which is derived from Mycobacterium tuberculosis recA, can cut itself to help release the therapeutic proteins inside the cell.

In experiments using cells and live animals, the researchers report being able to efficiently deliver Cre recombinase, a protein that can cut and paste DNA, and Cas9/sgRNA complexes for editing genes. When the extracellular vesicles loaded with Cre recombinase were injected into mice brains, the scientists observed a significant change in cells of the hippocampus and cortex. Specifically, the mice had “greater than 40% and 30% recombined cells in the hippocampus and cortex, respectively,” the researchers wrote. They also demonstrated how the technique could be used to treat systemic inflammation in mice by using engineered vesicles to deliver a super-repressor of NF-ĸB activity.

Commenting on the study, Samir EL Andaloussi, PhD, senior author on the study and a professor in Karolinska’s department of laboratory medicine, said that the engineering strategy overcomes barriers such as “poor endosomal escape and limited intracellular release.” Furthermore, “our in vivo findings highlight the potential of engineered EVs as a versatile platform for delivering therapeutics to treat a broad range of conditions, including systemic inflammation, genetic diseases, and neurological disorders,” he said.

Xiuming Liang, PhD, first author on the study and a research specialist in the department of laboratory medicine at Karolinska, added that “improving the efficiency and reliability of therapeutic delivery into target cells” could “significantly broaden the application of advanced medicines.” It opens up the possibility of using “CRISPR/Cas9 gene scissors or similar tools to treat severe genetic diseases of the central nervous system, such as Huntington’s disease and spinal muscular atrophy,” he said.

gene expression, genetic mutation, DNA sequencing, genome editing, CRISPR-Cas9, hereditary traits, gene therapy, molecular genetics, transcription factors, RNA splicing, epigenetics, SNP analysis, genome mapping, recombinant DNA, genetic code, protein synthesis, genotype, phenotype, chromosomal abnormalities, gene regulation

#GeneExpression, #GeneticMutation, #DNASequencing, #GenomeEditing, #CRISPRCas9, #HereditaryTraits, #GeneTherapy, #MolecularGenetics, #TranscriptionFactors, #RNASplicing, #Epigenetics, #SNPAnalysis, #GenomeMapping, #RecombinantDNA, #GeneticCode, #ProteinSynthesis, #Genotype, #Phenotype, #ChromosomalAbnormalities, #GeneRegulation

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