A PIKfyve Modulator Combined with an Integrated Stress Response Inhibitor to treat Lysosomal Storage Diseases
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ABSTRACT:
PROVIDER: PRJNA1096350 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28560511_1.fastq.gz | Fastqsanger.gz | |||
| SRR28560511_2.fastq.gz | Fastqsanger.gz | |||
| SRR28560512_1.fastq.gz | Fastqsanger.gz | |||
| SRR28560512_2.fastq.gz | Fastqsanger.gz | |||
| SRR28560513_1.fastq.gz | Fastqsanger.gz |
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Project description:Lysosomal degradation pathways coordinate the clearance of superfluous and damaged cellular components. Compromised lysosomal degradation is a hallmark of many degenerative diseases, including lysosomal storage diseases, which are caused by loss-of-function mutations within both alleles of a lysosomal hydrolase, leading to lysosomal substrate accumulation. Gaucher’s disease, characterized by <15% of normal glucocerebrosidase function, is the most common lysosomal storage disease and is a prominent risk factor for developing Parkinson’s disease. Here, we show that either of two structurally distinct small molecules that modulate PIKfyve activity, discovered from a high-throughput cellular lipid droplet clearance screen, can improve glucocerebrosidase function in Gaucher patient–derived fibroblasts through an MiT/TFE transcription factor that promotes lysosomal gene translation. An ISR antagonist used in combination with a PIKfyve modulator further improves cellular glucocerebrosidase activity, likely because integrated stress response (ISR) signaling appears to also be slightly activated by treatment by either small molecule at the higher doses employed, This strategy of combining a PIKfyve modulator with an integrated stress response inhibitor improves mutant lysosomal hydrolase function in cellular models of additional lysosomal storage diseases.
2024-06-11 | GSE263252 | GEO
Project description:The cellular cytotoxicity of APY0201, a PIKfyve inhibitor, against multiple myeloma was initially identified in an unbiased in vitro chemical library screen. Activity was confirmed in all 25 cell lines tested and 40% of 100 ex vivo patient derived primary samples, and positively correlated with samples harboring trisomies and inversely related to t(11;14). The broad anti- multiple myeloma activity of PIKfyve inhibitors was further demonstrated in confirmatory screens and showed the superior potency of APY0201 when compared to the PIKfyve inhibitors YM201636 and apilimod, with a mid-point EC50 at nanomolar concentrations respectively in 65%, 40%, and 5% of the tested cell lines. An up-regulation of genes in the lysosomal pathway and increased cellular vacuolization was observed in vitro in cell lines following APY0201 treatment however this cellular response did not correlate well with responsiveness. We confirm that PIKfyve inhibition is associated with activation of the transcription factor EB, a master regulator of lysosomal biogenesis and autophagy. Furthermore, we established an assay measuring autophagy as a predictive marker of APY0201 sensitivity. Overall, these findings suggest promising activity of PIKfyve inhibitors secondary to disruption of autophagy in multiple myeloma and a strategy to enrich for likely responders.
2019-09-19 | GSE134598 | GEO
Project description:Despite the remarkable clinical success of immunotherapies in a subset of cancer patients, many fail to respond to treatment and exhibit primary resistance. Here, we found thatgenetic or pharmacologic inhibitionof the lipid kinase PIKfyve, a regulator of autophagic flux and lysosomal biogenesis,upregulated surface expression of major histocompatibility complex class I (MHC-I) in cancer cells via impairing autophagic flux, resulting in enhanced cancer cell killing mediated by CD8+ T cells. Genetic depletion or pharmacologic inhibition of PIKfyve elevated tumor-specific MHC-I surface expression, reduced tumor proliferation, and increased intratumoral functional CD8+T cellsinsyngeneic mouse models. Importantly, enhanced antitumor responses by Pikfyve-depletion was CD8+T cell- and MHC-I-dependent,as CD8+ T cell depletion or B2m knockout rescued tumor growth. Furthermore, PIKfyve inhibition improved response to various immunotherapies, including immune checkpoint blockade (ICB), adoptive cell therapy, and therapeutic vaccines. High expression of PIKFYVE was also predictive of poor response to ICB and prognostic of poor survival in ICB-treated cohorts. Collectively, our findings show that targeting PIKfyve enhances immunotherapies by elevating surface expression of MHC-I in cancer cells, and PIKfyve inhibitors have potential as novel agents to increase immunotherapy response in cancer patients.
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Project description:In-frame premature termination codons (PTCs) (also referred to as nonsense mutations) comprise ~10% of all disease-associated gene lesions. PTCs reduce gene expression in two ways. First, PTCs prematurely terminate translation of an mRNA, leading to the production of a truncated polypeptide that often lacks normal function and/or is unstable. Second, PTCs trigger degradation of an mRNA by activating nonsense-mediated mRNA decay (NMD), a cellular pathway that recognizes and degrades mRNAs containing a PTC. Thus, translation termination and NMD are putative therapeutic targets for the development of treatments for genetic diseases caused by PTCs. Over the past decade, significant progress has been made in the identification of compounds with the ability to suppress translation termination of PTCs (also referred to as readthrough). More recently, NMD inhibitors have also been explored as a way to enhance the efficiency of PTC suppression. Due to their relatively low threshold for correction, lysosomal storage diseases are a particularly relevant group of diseases to investigate the feasibility of nonsense suppression as a therapeutic approach. In this review, the current status of PTC suppression and NMD inhibition as potential treatments for lysosomal storage diseases will be discussed.
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Project description:Lysosomes are cytoplasmic organelles that contain a variety of different hydrolases. A genetic deficiency in the enzymatic activity of one of these hydrolases will lead to the accumulation of the material meant for lysosomal degradation. Examples include glycogen in the case of Pompe disease, glycosaminoglycans in the case of the mucopolysaccharidoses, glycoproteins in the cases of the oligosaccharidoses, and sphingolipids in the cases of Niemann-Pick disease types A and B, Gaucher disease, Tay-Sachs disease, Krabbe disease, and metachromatic leukodystrophy. Sometimes, the lysosomal storage can be caused not by the enzymatic deficiency of one of the hydrolases, but by the deficiency of an activator protein, as occurs in the AB variant of GM2 gangliosidosis. Still other times, the accumulated lysosomal material results from failed egress of a small molecule as a consequence of a deficient transporter, as in cystinosis or Salla disease. In the last couple of decades, enzyme replacement therapy has become available for a number of lysosomal storage diseases. Examples include imiglucerase, taliglucerase and velaglucerase for Gaucher disease, laronidase for Hurler disease, idursulfase for Hunter disease, elosulfase for Morquio disease, galsulfase for Maroteaux-Lamy disease, alglucosidase alfa for Pompe disease, and agalsidase alfa and beta for Fabry disease. In addition, substrate reduction therapy has been approved for certain disorders, such as eliglustat for Gaucher disease. The advent of treatment options for some of these disorders has led to newborn screening pilot studies, and ultimately to the addition of Pompe disease and Hurler disease to the Recommended Uniform Screening Panel (RUSP) in 2015 and 2016, respectively.
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Project description:comparison of Alveolar macrophge gene expression in wild type and PIKfyve ko We identifed gene that important for alveolar macrophage development
2017-03-01 | GSE93849 | GEO
Project description:Lysosomal storage diseases (LSDs) are a class of metabolic disorders caused by mutations in proteins critical for lysosomal function. Such proteins include lysosomal enzymes, lysosomal integral membrane proteins, and proteins involved in the post-translational modification and trafficking of lysosomal proteins. There are many recognized forms of LSDs and, although individually rare, their combined prevalence is estimated to be 1 in 8000 births. Over two-thirds of LSDs involve central nervous system (CNS) dysfunction (progressive cognitive and motor decline) and these symptoms are often the most debilitating. Although the genetic basis for these disorders is clear and the biochemistry of the proteins well understood, the cellular mechanisms by which deficiencies in these proteins disrupt neuronal viability remain ambiguous. In this review, we provide an overview of the widespread cellular perturbations occurring in LSDs, how they might be linked and interventions that may specifically or globally correct those defects.
| S-EPMC3153126 | biostudies-literature
Project description:To understand the mechanism of Pikfyve inhibition in dendritic cells, we cultured conventional dendritic cells isolated from the bone marrow of wild-type mice and performed transcriptome profiling on RNA extracted from cells treated with DMSO or apilimod for 3 or 8 hours on Day 6 in culture. Taken together, these data demonstrate the PIKfyve mediates suppression of DC transcriptional maturation programs through the alternate/non-canonical NF-κB regulatory pathway.
2023-06-26 | GSE235599 | GEO
Project description:To understand the mechanism of Pikfyve loss in dendritic cells, we cultured conventional dendritic cells isolated from the bone marrow of Pikfyvef/f (“WT”) and mice with ItgaxTg/0 Pikfyvef/f (“KO”) mice and performed transcriptome profiling on RNA extracted from cells on Day 9 in culture. Taken together, these data demonstrate the PIKfyve mediates suppression of DC transcriptional maturation programs through the alternate/non-canonical NF-κB regulatory pathway.
2023-06-26 | GSE235596 | GEO
Project description:A biomarker is generally an analyte that indicates the presence and/or extent of a biological process, which is in itself usually directly linked to the clinical manifestations and outcome of a particular disease. The biomarkers in the field of lysosomal storage diseases (LSDs) have particular relevance where spectacular therapeutic initiatives have been achieved, most notably with the introduction of enzyme replacement therapy (ERT). There are two main types of biomarkers. The first group is comprised of those molecules whose accumulation is directly enhanced as a result of defective lysosomal function. These molecules represent the storage of the principal macro-molecular substrate(s) of a specific enzyme or protein, whose function is deficient in the given disease. In the second group of biomarkers, the relationship between the lysosomal defect and the biomarker is indirect. In this group, the biomarker reflects the effects of the primary lysosomal defect on cell, tissue, or organ functions. There is no "gold standard" among biomarkers used to diagnosis and/or monitor LSDs, but there are a number that exist that can be used to reasonably assess and monitor the state of certain organs or functions. A number of biomarkers have been proposed for the analysis of the most important LSDs. In this review, we will summarize the most promising biomarkers in major LSDs and discuss why these are the most promising candidates for screening systems.
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