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Single, off-the-shelf treatment of Neuropathic Mucopolysaccharidoses with iPSC-derived microglia [bulk RNA-seq]

ABSTRACT: Lysosomal storage disorders (LSDs) are a group of inherited metabolic disorders . A subgroup of LSDs is called Mucopolysaccharidoses (MPS), where accumulation of glycosaminoglycans causes a progressive degenerative disorder. The central nervous system (CNS) is particularly impacted with developmental delays, neurological regression, and early mortality. Current treatments are often insufficient to fully address the clinical need. Here we report the use of microglia derived from healthy human induced pluripotent stem cells (hiPSCs) as a potential one-time, allogeneic off-the-shelf cell therapy for several MPS. iPSC-derived microglia, termed MG01 , are replete with wild-type levels of lysosomal enzymes and we show that MG01 can deliver the functional enzyme into four different MPS knockout cell lines via mannose-6-phosphate receptor-mediated endocytosis in vitro. We then show that a single administration of MG01 provides sufficient enzyme to prevent behavioral deficits in two different animal models of MPS, efficacious to at least eight months after transplantation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE222969 | GEO | 2024/07/22

REPOSITORIES: GEO

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Single, off-the-shelf treatment of Neuropathic Mucopolysaccharidoses with iPSC-derived microglia [scRNA-seq]

Project description:Lysosomal storage disorders (LSDs) are a group of inherited metabolic disorders . A subgroup of LSDs is called Mucopolysaccharidoses (MPS), where accumulation of glycosaminoglycans causes a progressive degenerative disorder. The central nervous system (CNS) is particularly impacted with developmental delays, neurological regression, and early mortality. Current treatments are often insufficient to fully address the clinical need. Here we report the use of microglia derived from healthy human induced pluripotent stem cells (hiPSCs) as a potential one-time, allogeneic off-the-shelf cell therapy for several MPS. iPSC-derived microglia, termed MG01 , are replete with wild-type levels of lysosomal enzymes and we show that MG01 can deliver the functional enzyme into four different MPS knockout cell lines via mannose-6-phosphate receptor-mediated endocytosis in vitro. We then show that a single administration of MG01 provides sufficient enzyme to prevent behavioral deficits in two different animal models of MPS, efficacious to at least eight months after transplantation.

2024-07-22 | GSE224136 | GEO

Microarray analysis of Normal and MPS VII mouse aorta

Project description:Mucopolysaccharidosis VII (MPS VII) is due to mutations within the gene encoding the lysosomal enzyme beta-glucuronidase, and results in the accumulation of glycosaminoglycans. MPS VII causes aortic dilatation and elastin fragmentation. In this study we performed microarray analysis of ascending aortas from normal and MPS VII mice, trying to find out possible genes responsible for the phenotype observed. In addition, during our breeding strategy, we noticed that some MPS VII mice had less dilated aortas, and we proposed that an yet-unidentified gene could be responsible for the difference observed. We therefore included in the analysis two MPS VII mice with aortas that were not dilated. Total RNA extracted from ascending aortas from 3 Normal mice, 3 MPS VII mice with dilated aortas and 2 MPS VII mice with aortas that were not dilated.

2011-10-09 | E-GEOD-30657 | biostudies-arrayexpress

Microarray analysis of Normal and MPS VII mouse aorta

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Single, off-the-shelf treatment of Neuropathic Mucopolysaccharidoses with iPSC-derived microglia

Project description:Single, off-the-shelf treatment of Neuropathic Mucopolysaccharidoses with iPSC-derived microglia

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Patient iPSC-derived neural stem cells display progressive enlargement of lysosomes and disruptions of glycosaminoglycan pathway and autophagy in concordance with clinical severity of Mucopolysaccharidosis I

Project description:Mucopolysaccharidosis type I (MPS I) is caused by genetic defects in alpha-L-iduronidase (IDUA), a lysosomal enzyme involved in the breakdown and recycling of glycosaminoglycans (GAGs). Although an enzyme replacement therapy is available, the efficacy for the treatment of neuropathic symptoms is limited. To facilitate drug discovery and model disease pathophysiology, we have generated neural stem cells (NSCs) from MPS I patient-derived iPSCs. NSCs exhibited characteristic disease phenotypes with deficiency of alpha-L-iduronidase (IDUA), accumulation of glycosaminoglycans (GAGs) and enlargement of lysosomes, correlating with the severity of clinical symptoms. Transcriptome profiling of NSCs revealed differential expression of 429 genes that changed more extensively in the more severe Hurler syndrome subgroup compared to the Hurler-Scheie (median severe) and Scheie (less severe) subgroups. Clustering and pathway analyses demonstrated high concordance of the severity of neurological defects with marked dysregulation of GAG biosynthesis and degradation, lysosomal function and extracellular matrix. Gene Ontology (GO) analysis identified a dramatic upregulation of autophagy pathway, especially in the Hurler syndrome. Thus, GAG accumulation in the patient cells disrupts lysosomal homeostasis affecting multiple related cellular pathways which compensates for IDUA deficiency. These dysregulated process likely lead to enhanced autophagy and more severe disease states. Our studies provide useful tools for clinical biomarker development and potential targets for drug development.

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Single, off-the-shelf treatment of Neuropathic Mucopolysaccharidoses with iPSC-derived microglia [scRNA-seq]

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Project description:Mucopolysaccharidoses (MPS) I, II, and VI are a group of rare, lysosomal storage diseases in which certain enzymes are missing that are normally required for breaking down specific complex carbohydrates. Deficiencies in these enzymes result in the build-up of toxic substances in various tissues and cause damage to the body's organs. In the past, children diagnosed with MPS I, II, or VI frequently died in early to late childhood. Recent advances in treatments including hematopoietic cell transplantation (HCT) and enzyme replacement therapy (ERT) have been helping children with these disorders live into adulthood. The long term-course of the disease is now unknown. Unfortunately, severe skeletal disease persists for most individuals despite current therapies. This is a longitudinal study of 50 children and adults with MPS I, II, and VI. Study participants will be evaluated every year for up to 3 years. The purpose of this study is to document the progression of skeletal disease and identify biomarkers that either predict disease severity or could be used as therapeutic targets. This information is needed to: <ul> <li>determine long-term benefits and limitations of current treatments including HCT or ERT</li> <li>direct development of further treatment options</li> <li>improve clinical care for children affected by the disorder</li> </ul>

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Single, off-the-shelf treatment of Neuropathic Mucopolysaccharidoses with iPSC-derived microglia [bulk RNA-seq]

Project description:Single, off-the-shelf treatment of Neuropathic Mucopolysaccharidoses with iPSC-derived microglia [bulk RNA-seq]

| PRJNA924312 | ENA

RNA-Seq profiling of brain in Mucopolysaccharidosis type II mouse model

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