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Engineering Brain Parasites for Intracellular Delivery of Therapeutic Proteins

View ORCID ProfileShahar Bracha, Karoliina Hassi, Paul D. Ross, Stuart Cobb, Lilach Sheiner, Oded Rechavi
doi: https://doi.org/10.1101/481192
Shahar Bracha
1Department of Neurobiology, Wise Faculty of Life Sciences & Sagol School for Neuroscience, Tel Aviv University, Tel Aviv, Israel
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  • ORCID record for Shahar Bracha
  • For correspondence: Shaharbra@gmail.com Lilach.Sheiner@glasgow.ac.uk Odedrechavi@gmail.com
Karoliina Hassi
2Wellcome Centre For Molecular Parasitology, Institute of Infection, Immunity & Inflammation, College of Medical, Veterinary & Life Sciences, University of Glasgow, UK
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Paul D. Ross
3Institute of Neuroscience and Psychology, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, UK
4Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK
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Stuart Cobb
3Institute of Neuroscience and Psychology, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, UK
4Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK
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Lilach Sheiner
2Wellcome Centre For Molecular Parasitology, Institute of Infection, Immunity & Inflammation, College of Medical, Veterinary & Life Sciences, University of Glasgow, UK
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  • For correspondence: Shaharbra@gmail.com Lilach.Sheiner@glasgow.ac.uk Odedrechavi@gmail.com
Oded Rechavi
1Department of Neurobiology, Wise Faculty of Life Sciences & Sagol School for Neuroscience, Tel Aviv University, Tel Aviv, Israel
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  • For correspondence: Shaharbra@gmail.com Lilach.Sheiner@glasgow.ac.uk Odedrechavi@gmail.com
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Abstract

Protein therapy has the potential to alleviate many neurological diseases; however, delivery mechanisms for the central nervous system (CNS) are limited, and intracellular delivery poses additional hurdles. To address these challenges, we harnessed the protist parasite Toxoplasma gondii, which can migrate into the CNS and secrete proteins into cells. Using a fusion protein approach, we engineered T. gondii to secrete therapeutic proteins for human neurological disorders. We tested two secretion systems, generated fusion proteins that localized to T. gondii’s secretory organelles and assessed their intracellular targeting in various mammalian cells including neurons. We show that T. gondii expressing GRA16 fused to the Rett syndrome protein MeCP2 deliver a fusion protein that mimics the endogenous MeCP2, binding heterochromatic DNA in neurons. This demonstrates the potential of T. gondii as a therapeutic protein vector, which could provide either transient or chronic, in situ synthesis and delivery of intracellular proteins to the CNS.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted December 03, 2018.
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Engineering Brain Parasites for Intracellular Delivery of Therapeutic Proteins
Shahar Bracha, Karoliina Hassi, Paul D. Ross, Stuart Cobb, Lilach Sheiner, Oded Rechavi
bioRxiv 481192; doi: https://doi.org/10.1101/481192
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Engineering Brain Parasites for Intracellular Delivery of Therapeutic Proteins
Shahar Bracha, Karoliina Hassi, Paul D. Ross, Stuart Cobb, Lilach Sheiner, Oded Rechavi
bioRxiv 481192; doi: https://doi.org/10.1101/481192

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