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Treatment of neurologic disorders by brain-wide microglia replacement using a non-conditioning strategy

ABSTRACT: Treatment of neurologic disorders by brain-wide microglia replacement using a non-conditioning strategy

PROVIDER: PRJNA1135958 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29829558_1.fastq.gz	Fastqsanger.gz
	SRR29829558_2.fastq.gz	Fastqsanger.gz
	SRR29829559_1.fastq.gz	Fastqsanger.gz
	SRR29829559_2.fastq.gz	Fastqsanger.gz
	SRR29829560_1.fastq.gz	Fastqsanger.gz

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Treatment of neurologic disorders by brain-wide microglia replacement using a non-conditioning strategy

Project description:Genetic evidence indicates that microglial dysfunctions contribute to the development and progression of various neurologic diseases, emphasizing microglia replacement as a promising therapeutic strategy. However, traditional bone marrow transplantation (BMT) aimed at replenishing brain microglia faces challenges due to low efficiency and potential brain injury from preconditioning with irradiation or chemotherapy. Moreover, the BM-derived cells that migrate to the brain fail to replicate the characteristics of resident microglia. Here, we present a simple yet highly effective microglia transplantation strategy devoid of any conditioning, termed "Tri-Cyclic Microglial Depletion for Transplantation" (TCMDT). This approach leverages three cycles of microglial depletion using the CSF1R inhibitor PLX3397, creating a critical window for the efficient engraftment of exogenous microglia. Notably, transplanting primary cultured microglia via the TCMDT strategy achieves their full restoration to the identity and functions of native microglia. To evaluate the therapeutic potential, we applied our strategy to a Sandhoff disease mouse model, a form of neurodegenerative lysosomal storage disorder (LSD) caused by Hexb deficiency. The results revealed that our strategy facilitated the efficient replacement of deficient microglia, leading to a notable decrease in neurodegeneration and an enhancement in motor performance. Similarly, in an Alzheimer's disease (AD) mouse model carrying the Trem2 R47H mutation, our transplantation strategy corrected microglial dysfunction and alleviated AD-related pathology. Overall, our study presents a practical approach for microglia replacement that is simple, efficient, and safe, offering significant therapeutic potential for treating microglia-associated disorders.

2025-03-06 | GSE272257 | GEO

Development of a ß-Globin Gene Replacement Strategy as a Therapeutic Approach for ß-Hemoglobinopathies

Project description:β-hemoglobinopathies are the most common genetic disorders worldwide. In sickle cell disease (SCD) a single mutation (E6V) in the b-globin (HBB) gene results in dysfunctional hemoglobin protein, while in β-thalassemia, over 300 mutations distributed across the HBB gene are known to reduce the production of β-globin and cause severe anemia. A genetic engineering approach that replaces the whole HBB gene is an ideal strategy to rescue HBB expression for most genotypes but is technically challenging as the insert cannot be homologous to the endogenous gene and codon-optimized, intron-less sequences may not reconstitute adequate HBB levels. Here, we developed a novel approach for a “one-size-fits-all" HBB gene repair strategy using CRISPR-Cas9 which successfully addresses these problems. First, our DNA donor design avoids sequence homology through a diverged HBB coding sequence and second, incorporates heterologous introns from the fetal g-globin gene, further reducing homology to endogenous HBB while mimicking its intron composition. Screening DNA donors with various heterologous globin introns, polyadenylation signals and truncated sequences, identified a heterologous intron DNA donor that highly expresses β-globin and rescued β-globin expression in two in vitro hemoglobinopathy models in hematopoietic stem and progenitor cells (HSPCs). Furthermore, healthy donor HSPCs modified with this HBB gene replacement approach showed successful engraftment in immunodeficient mice at 16 weeks. In summary, we developed a universal HBB gene replacement strategy that results in physiological b-globin production, offering a potential differentiated approach for treating patients with β-thalassemia, SCD or compound heterozygous individuals.

2024-04-01 | GSE229212 | GEO

Conditioning-1

Project description:Conditioning-1

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The Glycosylation Design Space for Recombinant Lysosomal Replacement Enzymes Produced in CHO Cells

Project description:Lysosomal storage diseases are rare life-threatening disorders caused by deficiency of a lysosomal enzyme, and delivery of a recombinant replacement enzyme is the primary therapy for several of these diseases. The structures of N-glycans on recombinant replacement enzymes are important for their therapeutic efficacy, biodistribution and circulation time. Here we use alpha-galactosidase A (GLA) and beta-glucoscerebrosidase (GBA) as representative replacement enzymes, and present a panel of genetically engineered CHO cells that enable production of lysosomal replacement enzymes with different N-glycan features. We also tested several GLA variants with distinct glycoforms in a Fabry mouse model and present evidence that GLA glycoforms capped with alpha 2-3 linked sialic acids may represent a new strategy to overcome the most critical problems of rapid clearance in liver and poor biodistribution found with current ERTs.

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Efficient strategies for microglia replacement in the central nervous system

Project description:Microglia are important immune cells in the central nervous system (CNS). Dysfunctions of gene-deficient microglia contribute to the development and progression of multiple CNS diseases. Microglia replacement by nonself cells has been proposed to treat microglia associated disorders. However, most of attempts are failed due to low replacement efficiencies, such as with the traditional bone marrow transplantation approach. In this study, we develop three efficient strategies for microglia replacement: microglia replacement by bone marrow transplantation (mrBMT), microglia replacement by peripheral blood (mrPB) and microglia replacement by microglia transplantation (mrMT). mrBMT and mrPB allow microglia-like cells to efficiently replace resident microglia in the whole CNS. On the other hand, mrMT achieves microglia replacement in brain regions of interest. In summary, the present study offers effective tactics for microglia replacement with diverse application scenarios, which potentially opens up a window on treating microglia-associated CNS disorders.

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Project description:Aim of the study is to ascertain whether a different strategy of fluids administration can be responsible of differences in terms of acid/base disorders (Stewart approach), pro-inflammatory and inflammatory mediators. Hence two groups of patients will be treated either with not-balanced solutions (Normal Saline) or balanced solutions

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Project description:LC-MS of yeast strain that maintained high viability during bottle conditioning compared to strain that had poor viability during bottle conditioning.

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Development of a ß-Globin Gene Replacement Strategy as a Therapeutic Approach for ß-Hemoglobinopathies

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