A kaleidoscopic view of extracellular vesicles in lysosomal storage disorders

Abstract

Extracellular vesicles (EVs) are a heterogeneous population of stable lipid membrane particles that play a critical role in the regulation of numerous physiological and pathological processes. EV cargo, which includes lipids, proteins, and RNAs including miRNAs, is affected by the metabolic status of the parental cell. Concordantly, abnormalities in the autophagic-endolysosomal pathway, as seen in lysosomal storage disorders (LSDs), can affect EV release as well as EV cargo. LSDs are a group of over 70 inheritable diseases, characterized by lysosomal dysfunction and gradual accumulation of undigested molecules. LSDs are caused by single gene mutations that lead to a deficiency of a lysosomal protein or lipid. Lysosomal dysfunction sets off a cascade of alterations in the endolysosomal pathway that can affect autophagy and alter calcium homeostasis, leading to energy imbalance, oxidative stress, and apoptosis. The pathophysiology of these diseases is very heterogenous, complex, and currently incompletely understood. LSDs lead to progressive multisystemic symptoms that often include neurological deficits. In this review, a kaleidoscopic overview will be given on the roles of EVs in LSDs, from their contribution to pathology and diagnostics to their role as drug delivery vehicles. Furthermore, EV cargo and surface engineering strategies will be discussed to show the potential of EVs in future LSD treatment, both in the context of enzyme replacement therapy, as well as future gene editing strategies like CRISPR/Cas. The use of engineered EVs as drug delivery vehicles may mask therapeutic cargo from the immune system and protect it from degradation, improving circulation time and targeted delivery.

From pathological mechanisms in Krabbe disease to cutting‐edge therapy: A comprehensive review

“…9 EVs represent a diverse group of stable lipid membrane particles and play a crucial role in modulating various physiological and pathological processes. 53 They participate in cell-to-cell communication, the transmission of signals, and inflammation. 54 They achieve this by transporting RNA (including mRNA and long noncoding RNAs), lipids, and proteins, including lysosomal enzymes.…”

“…54 They achieve this by transporting RNA (including mRNA and long noncoding RNAs), lipids, and proteins, including lysosomal enzymes. 9,53 Considering that research has demonstrated the ability of EVs to traverse the blood-brain barrier (BBB), 9,50 we propose exploring their involvement in neurodegeneration within the PNS in KD. Additionally, given that in the initial phase of the disease, there was an elevated presence of EVs, 9,50 with a subsequent decline in the later stages, and we suggest that EVs had a crucial role in the early infantile KD form rather than other forms.…”

“…According to Reiter et al ., EVs could potentially serve as a mechanism for cells to evade or reduce the harmful effects of an overload of toxic levels of GalSph 9 . EVs represent a diverse group of stable lipid membrane particles and play a crucial role in modulating various physiological and pathological processes 53 . They participate in cell‐to‐cell communication, the transmission of signals, and inflammation 54 .…”

“…They participate in cell‐to‐cell communication, the transmission of signals, and inflammation 54 . They achieve this by transporting RNA (including mRNA and long noncoding RNAs), lipids, and proteins, including lysosomal enzymes 9,53 . Considering that research has demonstrated the ability of EVs to traverse the blood–brain barrier (BBB), 9,50 we propose exploring their involvement in neurodegeneration within the PNS in KD.…”