PT - JOURNAL ARTICLE AU - Robert N. Plasschaert AU - Mark P. DeAndrade AU - Fritz Hull AU - Quoc Nguyen AU - Tara Peterson AU - Aimin Yan AU - Mariana Loperfido AU - Cristina Baricordi AU - Luigi Barbarossa AU - John K. Yoon AU - Yildirim Dogan AU - Zeenath Unnisa AU - Jeffrey W. Schindler AU - Niek P. van Til AU - Luca Biasco AU - Chris Mason TI - Genetically engineered microglia-like cells have therapeutic potential for neurodegenerative disease AID - 10.1101/2021.09.16.460703 DP - 2021 Jan 01 TA - bioRxiv PG - 2021.09.16.460703 4099 - http://biorxiv.org/content/early/2021/09/18/2021.09.16.460703.short 4100 - http://biorxiv.org/content/early/2021/09/18/2021.09.16.460703.full AB - Hematopoietic stem/progenitor cell gene therapy (HSPC-GT) results in the engraftment of genetically modified microglia-like cells (MLCs) in the brain. While HSPC-GT has shown a clear neurological benefit in the clinic for specific rare diseases, the nature of MLC engraftment in the brain and the functional characteristics of MLCs remain contentious. Here we comprehensively characterized how different routes of administration affect the engraftment and biodistribution of genetically engineered HSPC-derivatives in mice. Using high-throughput single-cell profiling, we show that MLCs bear a transcriptional signature similar to resident microglia rather than invading macrophages. However, MLCs could clearly be distinguished from resident microglia by expression of a specific set of genes. Finally, in murine models of Parkinson’s disease and frontotemporal dementia, we demonstrate that MLCs can provide therapeutically relevant levels of protein to the brain, thereby potentially opening avenues of HSPC-GT to address the underlying disease etiology of these and other similar disorders.Competing Interest StatementAll authors are current employees of AVROBIO, Inc.