Extracellular Vesicles Released by Genetically Modified Macrophages Activate Autophagy and Produce Potent Neuroprotection in Mouse Model of Lysosomal Storage Disorder, Batten Disease

Abstract

Over the recent decades, the use of extracellular vesicles (EVs) has attracted considerable attention. Herein, we report the development of a novel EV-based drug delivery system for the transport of the lysosomal enzyme tripeptidyl peptidase-1 (TPP1) to treat Batten disease (BD). Endogenous loading of macrophage-derived EVs was achieved through transfection of parent cells with TPP1-encoding pDNA. More than 20% ID/g was detected in the brain following a single intrathecal injection of EVs in a mouse model of BD, ceroid lipofuscinosis neuronal type 2 (CLN2) mice. Furthermore, the cumulative effect of EVs repetitive administrations in the brain was demonstrated. TPP1-loaded EVs (EV-TPP1) produced potent therapeutic effects, resulting in efficient elimination of lipofuscin aggregates in lysosomes, decreased inflammation, and improved neuronal survival in CLN2 mice. In terms of mechanism, EV-TPP1 treatments caused significant activation of the autophagy pathway, including altered expression of the autophagy-related proteins LC3 and P62, in the CLN2 mouse brain. We hypothesized that along with TPP1 delivery to the brain, EV-based formulations can enhance host cellular homeostasis, causing degradation of lipofuscin aggregates through the autophagy–lysosomal pathway. Overall, continued research into new and effective therapies for BD is crucial for improving the lives of those affected by this condition.

Extracellular Vesicles from Immune Cells: A Biomedical Perspective

“…In the same context, a recent article published suggested that sEV derived from macrophages transfected with the lysosomal enzyme tripeptidyl peptidase-1 (TPP1), an enzyme used as a target for treating Batten disease (BD, a pathology that affects the nervous system in children), could be used as an alternative cure for this pathology. Being a disease that affects the nervous system, the administration of a localized drug is not easy, and in this case, the authors were able to administer TPP1 effectively and cumulatively through sEV via intrathecal and intraperitoneal routes in the BD mouse model, observing a significant therapeutic effect [ 51 ]. These results demonstrate the positive therapeutic effects that can be harnessed from macrophages, cells that cross the BBB and could deliver these sEV loaded with therapeutic agents.…”