Abstract: The present disclosure provides myeloid cells, microglial progenitor cells, and microglia-like cells in which a mutant gene has been repaired or replaced, and methods of using such cells to treat disease. Mutations in CSF1R were corrected in human induced pluripotent stem cells. The resulting cells were differentiated into microglial progenitors and then transplanted into the brain of xenotransplantation-compatible CSF1R-AFIRE/AFIRE mice, thereby preventing or reversing phenotypes associated with leukodystrophy, including thalamic microbleeds, calcification, astrogliosis, axonal spheroids, synaptic loss, and accumulation of Tau phosphorylated at threonine residue 217.

Abstract: A reverse transcription (RT) assay to directly detect chemical adducts on RNA. A fluorescence quenching assay to detect RT polymerization was optimized and employed to detect N 1-alkylation of inosine, an important post-transcriptional modification, using a phenylacrylamide as a model compound. The methods and composition may be expanded to identify novel reagents that form adducts with RNA, regardless of the primary sequence, and further explored to understand the relationship between RT processivity and natural post-transcriptional modifications in RNA.

Abstract: Microglia/monocytes exist within a ‘niche’ which limits the total number of microglia/monocytes/macrophages that reside within a mammalian central nervous system (CNS). Therefore, methods are needed that can help therapeutically modify microglia, monocytes, and macrophages or the cells that give rise to them to compete with endogenous microglia and partially or completely occupy the CNS niche. The present disclosure features therapeutic microglia, monocytes, or macrophages that have a selective advantage in comparison to endogenous brain resident microglia in their response to CSF1R inhibitors. Specifically, therapeutic cells developed in the present disclosure do not die at a given dose of CSF1R inhibitor that is sufficient to kill endogenous microglia. The therapeutic cells described herein can be used to treat neurological diseases.

Abstract: Modified cells that express and present or secrete at least one therapeutic molecule that can treat or ameliorate a disease of interest such as but not limited to Alzheimer's disease. In the modified cells, expression of the therapeutic molecule is induced when the modified cells are proximate to or in contact with pathology related to the disease of interest. The present disclosure also relates to compositions and kits comprising the disclosed cells. The present disclosure also relates to methods of using the disclosed cells for treating disease.

Abstract: Microglia/monocytes exist within a ‘niche’ which limits the total number of microglia/monocytes/macrophages that reside within a mammalian central nervous system (CNS). Therefore, methods are needed that can help therapeutically modify microglia, monocytes, and macrophages or the cells that give rise to them to compete with endogenous microglia and partially or completely occupy the CNS niche. The present disclosure features therapeutic microglia, monocytes, or macrophages that have a selective advantage in comparison to endogenous brain resident microglia in their response to CSF1R inhibitors. Specifically, therapeutic cells developed in the present disclosure do not die at a given dose of CSF1R inhibitor that is sufficient to kill endogenous microglia. The therapeutic cells described herein can be used to treat neurological diseases.

Abstract: Efforts to use RNA-cleaving DIMA enzymes (DNAzymes) as gene silencing agents in therapeutic applications have stalled due to their low efficacy in clinical trials. Here the present invention reports a xeno-nucleic acid (XNA) modified version of the classic DNAzyme 10-23 that achieves multiple turnover activity under cellular conditions and resists nuclease digestion. The new reagent overcomes the problem of product inhibition limiting previous 10-23 designs using molecular chemotypes with DNA. FANA, and TNA backbone architectures that balance the effects of enhanced biological stability with RNA hybridization and divalent metal ion coordination. In cultured mammalian cells. X 10-23 facilitates persistent gene silencing by efficiently degrading exogenous and endogenous mRNA transcripts. Together, these results demonstrate that new molecular chemotypes can improve the activity and stability of DNAzymes, and may provide a new route for nucleic acid enzymes to reach the clinic.

Abstract: The present invention relates to the development of and use of genetically modified human differentiated cells coupled with xenotransplantation into animal models to identify injury and disease-specific RNA and/or protein biomarkers. Specifically, the present invention encompasses two complementary methods for biomarker discovery that enable the direct and selective labelling, isolation, and analysis of human-specific RNA and/or proteins from xenotransplantation (or chimeric) animal models. Both methods involve the treatment of animal models with an RNA analog and/or amino acid analog that enables the specific isolation and quantification of human RNAs and/or proteins for the identification of novel human biomarkers for a large array of human injuries and diseases.

Abstract: Microglia/monocytes exist within a ‘niche’ which limits the total number of microglia/monocytes/macrophages that reside within a mammalian central nervous system (CNS). Therefore, methods are needed that can help therapeutically modify microglia, monocytes, and macrophages or the cells that give rise to them to compete with endogenous microglia and partially or completely occupy the CNS niche. The present disclosure features therapeutic microglia, monocytes, or macrophages that have a selective advantage in comparison to endogenous brain resident microglia in their response to CSF1R inhibitors. Specifically, therapeutic cells developed in the present disclosure do not die at a given dose of CSF1R inhibitor that is sufficient to kill endogenous microglia. The therapeutic cells described herein can be used to treat neurological diseases.

Abstract: Microglia/monocytes exist within a ‘niche’ which limits the total number of microglia/monocytes/macrophages that reside within a mammalian central nervous system (CNS). Therefore, methods are needed that can help therapeutically modify microglia, monocytes, and macrophages or the cells that give rise to them to compete with endogenous microglia and partially or completely occupy the CNS niche. The present disclosure features therapeutic microglia, monocytes, or macrophages that have a selective advantage in comparison to endogenous brain resident microglia in their response to CSF1R inhibitors. Specifically, therapeutic cells developed in the present disclosure do not die at a given dose of CSF1R inhibitor that is sufficient to kill endogenous microglia. The therapeutic cells described herein can be used to treat neurological diseases.