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Genetically engineered microglia-like cells have therapeutic potential for neurodegenerative disease

Robert N. Plasschaert, Mark P. DeAndrade, Fritz Hull, Quoc Nguyen, Tara Peterson, Aimin Yan, Mariana Loperfido, Cristina Baricordi, Luigi Barbarossa, John K. Yoon, Yildirim Dogan, Zeenath Unnisa, Jeffrey W. Schindler, Niek P. van Til, Luca Biasco, Chris Mason
doi: https://doi.org/10.1101/2021.09.16.460703
Robert N. Plasschaert
1AVROBIO, Inc., Cambridge, MA, USA
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Mark P. DeAndrade
1AVROBIO, Inc., Cambridge, MA, USA
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Fritz Hull
1AVROBIO, Inc., Cambridge, MA, USA
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Quoc Nguyen
1AVROBIO, Inc., Cambridge, MA, USA
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Tara Peterson
1AVROBIO, Inc., Cambridge, MA, USA
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Aimin Yan
1AVROBIO, Inc., Cambridge, MA, USA
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Mariana Loperfido
1AVROBIO, Inc., Cambridge, MA, USA
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Cristina Baricordi
1AVROBIO, Inc., Cambridge, MA, USA
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Luigi Barbarossa
1AVROBIO, Inc., Cambridge, MA, USA
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John K. Yoon
1AVROBIO, Inc., Cambridge, MA, USA
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Yildirim Dogan
1AVROBIO, Inc., Cambridge, MA, USA
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Zeenath Unnisa
1AVROBIO, Inc., Cambridge, MA, USA
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Jeffrey W. Schindler
1AVROBIO, Inc., Cambridge, MA, USA
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Niek P. van Til
1AVROBIO, Inc., Cambridge, MA, USA
2Child Neurology, Emma Children’s Hospital, Amsterdam University Medical Centers, Vrije Universiteit and Amsterdam Neuroscience, Amsterdam, the Netherlands
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Luca Biasco
1AVROBIO, Inc., Cambridge, MA, USA
3Great Ormond Street Institute of Child Health, University College London
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Chris Mason
1AVROBIO, Inc., Cambridge, MA, USA
4Advanced Center for Biochemical Engineering, University College London
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  • For correspondence: chris.mason@ucl.ac.uk
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ABSTRACT

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 Statement

All authors are current employees of AVROBIO, Inc.

Footnotes

  • l.biasco{at}ucl.ac.uk

    chris.mason{at}ucl.ac.uk

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted September 18, 2021.
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Genetically engineered microglia-like cells have therapeutic potential for neurodegenerative disease
Robert N. Plasschaert, Mark P. DeAndrade, Fritz Hull, Quoc Nguyen, Tara Peterson, Aimin Yan, Mariana Loperfido, Cristina Baricordi, Luigi Barbarossa, John K. Yoon, Yildirim Dogan, Zeenath Unnisa, Jeffrey W. Schindler, Niek P. van Til, Luca Biasco, Chris Mason
bioRxiv 2021.09.16.460703; doi: https://doi.org/10.1101/2021.09.16.460703
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Genetically engineered microglia-like cells have therapeutic potential for neurodegenerative disease
Robert N. Plasschaert, Mark P. DeAndrade, Fritz Hull, Quoc Nguyen, Tara Peterson, Aimin Yan, Mariana Loperfido, Cristina Baricordi, Luigi Barbarossa, John K. Yoon, Yildirim Dogan, Zeenath Unnisa, Jeffrey W. Schindler, Niek P. van Til, Luca Biasco, Chris Mason
bioRxiv 2021.09.16.460703; doi: https://doi.org/10.1101/2021.09.16.460703

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