Splice-Modulating Antisense Oligonucleotides as Therapeutics for Inherited Metabolic Diseases

BioDrugs, Год журнала: 2024, Номер 38(2), С. 177 - 203

Опубликована: Янв. 22, 2024

The last decade (2013-2023) has seen unprecedented successes in the clinical translation of therapeutic antisense oligonucleotides (ASOs). Eight such molecules have been granted marketing approval by United States Food and Drug Administration (US FDA) during decade, after first ASO drug, fomivirsen, was approved much earlier, 1998. Splice-modulating ASOs also developed for therapy inborn errors metabolism (IEMs), due to their ability redirect aberrant splicing caused mutations, thus recovering expression normal transcripts, correcting deficiency functional proteins. feasibility treating IEM patients with splice-switching supported FDA permission (2018) "N-of-1" study milasen, an investigational drug Batten disease. Although IEM, owing rarity individual disease and/or pathogenic mutation, only a low number may be treated that specifically suppress pattern mutant precursor mRNA (pre-mRNA), represent superior individualized molecular therapeutics IEM. In this work, we summarize technology respect its mechanisms action, chemical modifications nucleotides, rational design modified oligonucleotides; following that, precisely provide review current understanding developing splice-modulating ASO-based concluding section, suggest potential ways improve optimize development targeting

Язык: Английский

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The neuronal ceroid-lipofuscinoses (Batten disease)

Elsevier eBooks, Год журнала: 2024, Номер unknown, С. 59 - 79

Опубликована: Окт. 11, 2024

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Open-label evaluation of oral trehalose in patients with neuronal ceroid lipofuscinoses

Journal of Neurology, Год журнала: 2025, Номер 272(1)

Опубликована: Янв. 1, 2025

Язык: Английский

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Lysosomal positioning diseases: beyond substrate storage

Open Biology, Год журнала: 2022, Номер 12(10)

Опубликована: Окт. 1, 2022

Lysosomal storage diseases (LSDs) comprise a group of inherited monogenic disorders characterized by lysosomal dysfunctions due to undegraded substrate accumulation. They are caused deficiency in specific hydrolases involved cellular catabolism, or non-enzymatic proteins essential for normal functions. In LSDs, the lack degradation accumulated and its impairs lysosome functions resulting perturbation homeostasis and, turn, damage multiple organ systems. A substantial number studies on pathogenesis LSDs has highlighted how accumulation substrates is only first event cascade processes including secondary metabolites impairment trafficking, cell signalling, autophagic flux, mitochondria functionality calcium homeostasis, that significantly contribute onset progression these diseases. Emerging biology have described fundamental roles organelles variety physiological pathological conditions beyond their canonical activity waste clearance. Here, we discuss recent advances knowledge molecular mechanisms linking positioning trafficking LSDs.

Язык: Английский

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Lysosomal Dysfunction: Connecting the Dots in the Landscape of Human Diseases

Biology, Год журнала: 2024, Номер 13(1), С. 34 - 34

Опубликована: Янв. 7, 2024

Lysosomes are the main organelles responsible for degradation of macromolecules in eukaryotic cells. Beyond their fundamental role degradation, lysosomes involved different physiological processes such as autophagy, nutrient sensing, and intracellular signaling. In some circumstances, lysosomal abnormalities underlie several human pathologies with etiologies known storage disorders (LSDs). These can result from deficiencies primary enzymes, dysfunction enzyme activators, alterations modifiers that impact function, or changes membrane-associated proteins, among other factors. The clinical phenotype observed affected patients hinges on type location accumulating substrate, influenced by genetic mutations residual activity. this context, scientific community is dedicated to exploring potential therapeutic approaches, striving not only extend lifespan but also enhance overall quality life individuals afflicted LSDs. This review provides insights into a molecular perspective, particularly context diseases, highlights recent advancements breakthroughs field.

Язык: Английский

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Targeting autophagy impairment improves the phenotype of a novel CLN8 zebrafish model

Neurobiology of Disease, Год журнала: 2024, Номер 197, С. 106536 - 106536

Опубликована: Май 17, 2024

CLN8 is an endoplasmic reticulum cargo receptor and a regulator of lysosome biogenesis whose loss function leads to neuronal ceroid lipofuscinosis. has been linked autophagy lipid metabolism, but much remains be learned, there are no therapies acting on the molecular signatures in this disorder. The present study aims characterize pathways involved disease and, by pinpointing altered ones, identify potential therapies. To bridge gap between cell mammalian models, we generated new zebrafish model deficiency, which recapitulates pathological features disease. We observed, for first time, that dysfunction impairs autophagy. Using modulators, showed trehalose SG2 able attenuate phenotype mutant larvae, confirming impairment as secondary event progression. Overall, our successful modeling defects highlights novel vivo model's strong instrument exploring role cellular pathways, with view identifying small molecules treat rare

Язык: Английский

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KCTD7 mutations impair the trafficking of lysosomal enzymes through CLN5 accumulation to cause neuronal ceroid lipofuscinoses

Science Advances, Год журнала: 2022, Номер 8(31)

Опубликована: Авг. 3, 2022

Lysosomes are central organelles for cellular degradation and energy metabolism. Neuronal ceroid lipofuscinoses (NCLs) a group of the most common neurodegenerative lysosomal storage disorders characterized by intracellular accumulation in neurons. Mutations KCTD7 , gene encoding an adaptor CUL3-RING E3 ubiquitin ligase (CRL3) complex, categorized as unique NCL subtype. However, underlying mechanisms remain elusive. Here, we report various autophagic defects KCTD7-deficient cells. Mechanistically, CRL3-KCTD7 complex degrades CLN5, whereas patient-derived mutations disrupt interaction between KCTD7-CUL3 or KCTD7-CLN5 ultimately lead to excessive CLN5. The accumulated CLN5 disrupts CLN6/8 enzymes at endoplasmic reticulum (ER), subsequently impairing ER-to-Golgi trafficking enzymes. Our findings reveal previously unrecognized roles KCTD7-mediated proteolysis homeostasis demonstrate that biochemically linked function pathway.

Язык: Английский

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CLN5 deficiency impairs glucose uptake in Batten disease

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 2, 2025

Abstract CLN5 disease, a form of juvenile dementia within the neuronal ceroid lipofuscinosis (NCL), is associated with mutations in gene encoding lysosomal bis(monoacylglycero)phosphate (BMP) synthase, essential for BMP production and function. Limited knowledge cellular mechanisms unclear drug targets hinder translating this to children’s treatment, which remains symptomatic. We developed characterized new cln5 knock-out zebrafish model that replicates key features molecular signatures human disease. Loss Cln5 function vivo altered axonal growth retinal ON-bipolar cells revealing disease features. Additionally, multi-omic analyzes at different developmental stages, revealed an impaired glucose metabolism as original finding NCL. This work demonstrates profound metabolic impact dysfunction, offering promising avenue toward targeted therapies dementia.

Язык: Английский

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CLN5 deficiency impairs glucose uptake and uncovers PHGDH as a potential biomarker in Batten disease

Molecular Psychiatry, Год журнала: 2025, Номер unknown

Опубликована: Май 9, 2025

CLN5 disease, a form of juvenile dementia within the neuronal ceroid lipofuscinosis (NCL), is associated with mutations in gene encoding lysosomal bis(monoacylglycero)phosphate (BMP) synthase, essential for BMP production and function. Limited knowledge cellular mechanisms unclear drug targets hinder translating this to children's treatment, which remains symptomatic. We developed characterized new cln5 knock-out zebrafish model that replicates key features molecular signatures human disease. Loss Cln5 function vivo altered axonal growth retinal ON-bipolar cells disrupted calcium homeostasis cerebellum, revealing disease features. Additionally, multi-omic analyses at different developmental stages revealed an impaired glucose metabolism as original finding NCL. A novel biomarker, PHGDH, was validated skin fibroblasts harboring pathogenic variants CLN5, CLN7. also tested metformin improved expression PHGDH patient-derived cells, rescued behavior. This work demonstrates profound metabolic impact dysfunction, offering promising avenue toward targeted therapies dementia.

Язык: Английский

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Recent insights into the networking of CLN genes and proteins in mammalian cells

Journal of Neurochemistry, Год журнала: 2023, Номер 165(5), С. 643 - 659

Опубликована: Апрель 6, 2023

Ceroid lipofuscinosis neuronal (CLN) genes encode 13 proteins that localize throughout the endomembrane system to regulate a variety of cellular processes. In humans, mutations in CLN cause devastating form neurodegeneration called ceroid (NCL), commonly known as Batten disease. Each gene is associated with specific subtype disease differ from each other severity and age onset. The NCLs affect all ages ethnicities worldwide but primarily children. pathology underlying poorly understood, which has prevented development cure or effective therapy for most subtypes A growing body literature supports networking within cells, aligns broadly similar clinical manifestations among different NCL. Here, relevant reviewed provide comprehensive overview our current understanding how are networked mammalian cells an aim toward revealing new molecular targets development. Intriguingly, protein extends beyond recent work linked several forms such Alzheimer's Parkinson's Thus, deeper pathways processes impacted by will not only strengthen knowledge pathological mechanisms may also insight into related neurodegeneration.

Язык: Английский

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