Engineered extracellular vesicles/exosomes as a new tool against neurodegenerative diseases

Neurodegenerative diseases are commonly generated by intracellular accumulation of misfolded/aggregated mutated proteins. These abnormal protein aggregates impair the functions of mitochondria and induce oxidative stress, thereby resulting in neuronal cell death. In turn, neuronal damage induces chronic inflammation and neurodegeneration. Thus, reducing/eliminating these abnormal protein aggregates is a priority for any anti-neurodegenerative therapeutic approach. Although several antibodies against mutated neuronal proteins have been already developed, how to efficiently deliver them inside the target cells remains an unmet issue. Extracellular vesicles/exosomes incorporating intrabodies against the pathogenic products would be a tool for innovative therapeutic approaches.

Researchers from the Italian National Institute of Health identify and describe the major molecular targets associated with neurodegenerative diseases, as well as the antibodies already developed against them. Finally, they propose a novel targeting strategy based on the endogenous engineering of extracellular vesicles/exosomes constitutively released by cells of the central nervous system.

Exosome model for delivering intrabodies against NDs

The model proposed relies on Nefmut-based endogenously engineered extracellular vesicles (EVs), produced in vivo by cells expressing vectors based endogenously engineered extracellular vesicles (EVs), produced in vivo by cells expressing vectors encoding a Nefmut-scFv fusion intrabody specific for the ND molecular target of interest. Such a bifunctional intrabody may bind its intracellular target both in the DNA-expressing cells and in bystander cells, upon release and cell-to-cell transfer of Nefmut-scFv-engineered EVs, by exploiting Nefmut ability to be uploaded into exosomes in large amounts. To enhance the targeting of cells that are relevant to ND pathogenesis, EVs could be doubly engineered with an additional fusion product encompassing a membrane-associated protein and a protein domain specifically able to bind CNS cellular targets, such as, for instance, the RVG-29 peptide, which binds nicotinic AchR.

Ferrantelli F, Chiozzini C, Leone P, Manfredi F, Federico M. (2020) Engineered Extracellular Vesicles/Exosomes as a New Tool against Neurodegenerative Diseases. Pharmaceutics [online ahead of print]. [abstract]

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