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

Cells. 2023 May 29;12(11):1497. doi: 10.3390/cells12111497.

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.

Keywords: Batten disease; autophagy; drug delivery; extracellular vesicles; lysosomal storage disorders; neuroprotection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopeptidases / genetics
  • Animals
  • Autophagy
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / metabolism
  • Extracellular Vesicles* / metabolism
  • Lipofuscin / metabolism
  • Lipofuscin / therapeutic use
  • Lysosomal Storage Diseases* / metabolism
  • Lysosomes / metabolism
  • Mice
  • Neuronal Ceroid-Lipofuscinoses* / metabolism
  • Neuroprotection
  • Serine Proteases / genetics
  • Tripeptidyl-Peptidase 1

Substances

  • Serine Proteases
  • Aminopeptidases
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
  • Lipofuscin
  • Tripeptidyl-Peptidase 1

Supplementary concepts

  • Ceroid Lipofuscinosis, Neuronal, 2