Stem Cell Applications in Lysosomal Storage Disorders: Progress and Ongoing Challenges

Köse, Sevil; Aerts‐Kaya, Fatima; Çetinkaya, Duygu Uçkan; Korkusuz, Petek

doi:10.1007/5584_2021_639

Cited by 4 publications

(4 citation statements)

References 150 publications

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“…Autophagy is a multi-step process where damaged organelles and molecular aggregates are degraded and recycled. The process starts with the formation of autophagosomes that can fuse with early and late endosomal vesicles, such as MVBs, to form amphisomes, to eventually fuse with lysosomes [4,7] . Under homeostatic conditions, cells maintain a constitutive basal level of autophagy; however, the process can be induced in response to cellular and metabolic stress [67] .…”

Section: Ev Release In Lsds: a New Route In Understanding Disease Pat...mentioning

confidence: 99%

“…Under homeostatic conditions, cells maintain a constitutive basal level of autophagy; however, the process can be induced in response to cellular and metabolic stress [67] . In several LSDs, it has been shown that lysosomal dysfunction leads to the accumulation of autophagosomes and autophagic substrates, such as damaged mitochondria [4,68,69] . However, accumulation of autophagosomes does not necessarily indicate an increased induction of autophagy as this increase could also be caused by blockage of fusion with the lysosome.…”

Section: Ev Release In Lsds: a New Route In Understanding Disease Pat...mentioning

confidence: 99%

“…The accumulation leads to enlargement of the organelle and functional inhibition of genetically correct enzymes and proteases which further limits their processing abilities [1][2][3] . This sets off a cascade of alterations in the endolysosomal pathway due to impaired fusion that can affect autophagy, but also in other organelles including the endoplasmic reticulum and mitochondria [4] . This may further lead to altered calcium homeostasis, oxidative stress, energy imbalance, and apoptosis [5,6] .…”

Section: Introductionmentioning

confidence: 99%

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A kaleidoscopic view of extracellular vesicles in lysosomal storage disorders

Hegeman¹,

Jong²,

Lorenowicz³

2022

Extracell Vesicles Circ Nucleic Acids

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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.

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Section: Ev Release In Lsds: a New Route In Understanding Disease Pat...mentioning

confidence: 99%

Section: Ev Release In Lsds: a New Route In Understanding Disease Pat...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A kaleidoscopic view of extracellular vesicles in lysosomal storage disorders

Hegeman¹,

Jong²,

Lorenowicz³

2022

Extracell Vesicles Circ Nucleic Acids

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“…In the past, hematopoietic stem cell transplantation (HSCT) has been performed in patients with different LSDs. Because of its burdensome treatment procedure and variable success, it became superseded by other treatment modalities [ 14 , 15 ]. Building on HSCT, the concept of gene therapy is to ameliorate the metabolic deficiency in target cells by introducing correct genetic material for the deficient enzyme.…”

Section: Introductionmentioning

confidence: 99%

Patients’ view on gene therapy development for lysosomal storage disorders: a qualitative study

Eskes

Beishuizen

Corazolla

et al. 2022

Orphanet J Rare Dis

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Introduction Several new treatment modalities are being developed for lysosomal storage disorders (LSDs), including gene therapy. As the currently available treatment options and their influence on disease progression differ greatly within the spectrum of LSDs, willingness to undergo gene therapy might vary among patients with LSDs and/or their representatives. The width of the LSD spectrum is illustrated by the differences between type 1 Gaucher disease, Fabry disease and Mucopolysaccharidosis type III (MPS III). For type 1 Gaucher and Fabry disease several therapies are available, resulting in a near normal or improved, but individually varying, prognosis. No treatment options are available for MPS III. Aim To identify factors influencing patients’ and/or their representatives’ decisions regarding undergoing gene therapy. Methods Focus group discussions and semi-structured interviews were conducted with patients with type 1 Gaucher disease, Fabry disease and MPS III. Parents of MPS III patients were included as patients’ representatives. Results Nine Gaucher patients, 23 Fabry patients, two adult MPS III patients and five parents of MPS III patients participated in the study. The five main themes that arose were: outcome of gene therapy, risks and side effects, burden of gene therapy treatment, current situation and ethical aspects. Participants’ views ranged from hesitance to eagerness to undergo gene therapy, which seemed to be mostly related to disease severity and currently available treatment options. Severe disease, limited treatment options and limited effectiveness of current treatment augmented the willingness to choose gene therapy. Gaucher and Fabry patients deemed the burden of treatment important. Fabry and MPS III patients and parents considered outcome important, suggesting hope for improvement. When asked to rank the factors discussed in the focus group discussions, Gaucher patients ranked outcome low, which could indicate a more cautious attitude towards gene therapy. Conclusion This study underlines the importance of exploring patients’ needs and expectations before using limited resources in the development of therapies for patient groups of which a significant subset may not be willing to undergo that specific therapy.

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Lysosomal storage disorders: Clinical and therapeutic aspects

Pastores

2023

Handbook of Clinical Neurology

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Stem Cell Applications in Lysosomal Storage Disorders: Progress and Ongoing Challenges

Cited by 4 publications

References 150 publications

A kaleidoscopic view of extracellular vesicles in lysosomal storage disorders

A kaleidoscopic view of extracellular vesicles in lysosomal storage disorders

Patients’ view on gene therapy development for lysosomal storage disorders: a qualitative study

Lysosomal storage disorders: Clinical and therapeutic aspects

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