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Methods and compositions for reconstitution of small glial cells

A cell, homozygous technology, applied in nervous system cells, other methods of inserting foreign genetic materials, drug combinations, etc., can solve the problems of fast and slow progress of nervous system diseases

Pending Publication Date: 2022-03-25
CHILDRENS MEDICAL CENT CORP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the slow engraftment and expansion of transplanted HSPCs and their progeny compared with the rapid progression of neurological diseases, this approach has not been widely used in the treatment of neurological and metabolic diseases.

Method used

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  • Methods and compositions for reconstitution of small glial cells
  • Methods and compositions for reconstitution of small glial cells
  • Methods and compositions for reconstitution of small glial cells

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0133] Example 1: CX3CR1 + / GFP Transplantation of hematopoietic cells leads to rapid microglial remodeling

[0134] From 8-week-old CD45.2 wild-type or CD45.2 CX3CR1 + / GFPIsolation of bone marrow cells from mice. After red blood cells were lysed, 2.0x10 6 Four cells were transplanted intravenously (IV) into eight-week-old CD45.1 wild-type recipients pretreated with busulfan (25 mg / kg for four days). Transplanted mice were clinically monitored and sacrificed 45, 90 and 180 days post-transplantation ( Figure 1A ). No deaths occurred. Upon sacrifice following perfusion, bone marrow and brain were harvested to monitor engraftment of transplanted cells by flow cytometry. Brain cells were isolated after papain digestion and Percoll density gradient Fenix.

[0135] Transplanted CX3CR1 was observed in recipient bone marrow + / GFP Similar sustained engraftment of cells and wild-type cells ( Figure 1B ). Compared with mice receiving wild-type cells, in mice receiving CX3CR1 ...

Embodiment 2

[0137] Example 2: CX3CR1 + / GFP Hematopoietic stem progenitor cells (HSPCs) have a competitive advantage after transplantation

[0138] Better Characterization of CX3CR1 + / GFP To phenotype the cells and assess whether they had a qualitative (and quantitative) advantage over wild-type, competitive transplantation experiments were performed. Eight-week-old CD45.2 wild-type or CD45.2 CX3CR1 + / GFP HSPCs were isolated from mice, labeled with lentiviral vectors encoding different fluorescent markers (PGK.mCherry and PGK blue fluorescent protein (BFP), respectively), and co-transplanted with CD45.1busulfan at a 1:1 ratio Among bone marrow recipients ( Figure 3A ).

[0139] Transplantation was performed in separate experiments using intravenous (IV) and intracerebroventricular (ICV) administration. In an IV setting, transplant a total of 1.0x10 per mouse 6 HSPC. In the ICV environment, a total of 0.3x10 per mouse transplantation 6 HSPC. Mice receiving HSPCs administered by IC...

Embodiment 3

[0143] Example 3: CX3CR1 + / GFP HSPCs generate more mature microglia-like cells than wild-type HSPCs after transplantation

[0144] To demonstrate that CX3CR1 haploinsufficiency might also be associated with faster maturation of suppressed cells and / or their progeny, particularly in the brain, the morphology and Expression of microglia-associated genes.

[0145] Different parameters reported in the literature, which are valuable criteria for describing microglial morphology (Verdonk et al. 2016), were evaluated. These parameters include the total length of the branches (Sum length); the complexity index (CI), defined as the ratio of the number of segments per cell to the number of primary branches, where segments are the length of the process between two base points; coverage The area of ​​surroundings (COA), which defines the total 2D surface covered by a cell's branches and is described as the area of ​​the polygon formed by connecting the ends of its processes, in μm 2 e...

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Abstract

The present disclosure features CX3CR1 hemizygous and / or homozygous deficient cells and methods of using such cells for the treatment of metabolic or nervous system disorders. The disclosed methods include methods for preparing and modifying CX3CR1 hemizygous and / or homozygous deficient cells, such as hematopoietic stem progenitor cells. Other disclosed methods include methods of treating a subject suffering from or susceptible to a metabolic disease or a neurological disease, comprising administering to the subject a composition comprising hemizygous and / or homozygous deficient CX3CR1 cells. The CX3CR1 hemizygous and / or homozygous deficient cells may be modified to have a nucleic acid molecule encoding a therapeutic polypeptide or polynucleotide.

Description

technical field [0001] Cross References to Related Applications [0002] This application claims priority to US Application No. 62 / 883,428, filed August 6, 2019, the entire contents of which are hereby incorporated by reference in their entirety. Background technique [0003] Recent findings suggest that hematopoietic stem and progenitor cells (HSPCs) can promote the renewal of the resident brain myeloid cell population following a conditioning regimen. In the context of metabolic and neurological diseases, the implanted cells may serve as vehicles to deliver neuroprotective agents to the brain of the affected patient. However, due to the slow engraftment and expansion of transplanted HSPCs and their progeny compared with the rapid progression of neurological diseases, this approach has not been widely used in the treatment of neurological and metabolic diseases. Therefore, improved methods of HSPC transplantation are needed. This disclosure addresses this need and other ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/715C12N15/10C12N15/90
CPCC12N15/90C07K14/7158C12N2506/11C12N5/0622A61K35/30A61K38/00A61K31/255A61P25/00C12N2510/00A61K2300/00A61K35/28
Inventor A·比菲A·蒙特佩洛索
Owner CHILDRENS MEDICAL CENT CORP
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