TPP1 Delivery to Lysosomes with Extracellular Vesicles and their Enhanced Brain Distribution in the Animal Model of Batten Disease.
Extracellular vesicles (EVs) are promising natural nanocarriers for delivery of various types of therapeutics. Earlier engineered EV-based formulations for neurodegenerative diseases and cancer are reported. Herein, the use of macrophage-derived EVs for brain delivery of a soluble lysosomal enzyme tripeptidyl peptidase-1, TPP1, to treat a lysosomal storage disorder, Neuronal Ceroid Lipofuscinoses 2 (CLN2) or Batten disease, is investigated. TPP1 is loaded into EVs using two methods: i) transfection of parental EV-producing macrophages with TPP1-encoding plasmid DNA (pDNA) or ii) incorporation therapeutic protein TPP1 into naive empty EVs. For the former approach, EVs released by pretransfected macrophages contain the active enzyme and TPP1-encoding pDNA. To achieve high loading efficiency by the latter approach, sonication or permeabilization of EV membranes with saponin is utilized. Both methods provide proficient incorporation of functional TPP1 into EVs (EV-TPP1). EVs significantly increase stability of TPP1 against protease degradation and provide efficient TPP1 delivery to target cells in in vitro model of CLN2. The majority of EV-TPP1 (≈70%) is delivered to target organelles, lysosomes. Finally, a robust brain accumulation of EV carriers and increased lifespan is recorded in late-infantile neuronal ceroid lipofuscinosis (LINCL) mouse model following intraperitoneal administration of EV-TPP1.
['Haney|Matthew J|MJ|', 'Klyachko|Natalia L|NL|', 'Harrison|Emily B|EB|', 'Zhao|Yuling|Y|', 'Kabanov|Alexander V|AV|', 'Batrakova|Elena V|EV|0000-0002-9386-3790']
D000626:Aminopeptidases D000818:Animals D001921:Brain D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases D004195:Disease Models, Animal D000067128:Extracellular Vesicles D006801:Humans D008247:Lysosomes D051379:Mice D009472:Neuronal Ceroid-Lipofuscinoses D016716:PC12 Cells D051381:Rats D057057:Serine Proteases D000091346:Tripeptidyl-Peptidase 1
brain Batten disease EVs drug delivery systems lysosomal storage diseases