High-throughput analysis of hematopoietic stem cell engraftment after intravenous and intracerebroventricular dosing

• Published in: Molecular therapy Vol. 30; no. 10; pp. 3209 - 3225
• Main Authors: Plasschaert, Robert N., DeAndrade, Mark P., Hull, Fritz, Nguyen, Quoc, Peterson, Tara, Yan, Aimin, Loperfido, Mariana, Baricordi, Cristina, Barbarossa, Luigi, Yoon, John K., Dogan, Yildirim, Unnisa, Zeenath, Schindler, Jeffrey W., van Til, Niek P., Biasco, Luca, Mason, Chris
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 05.10.2022; American Society of Gene & Cell Therapy
• Subjects: autologous transplant; frontotemporal dementia; gene therapy; hematopoiesis; hematopoietic stem cells; lentiviral vector; microglia; neurodegenerative disease; Original; Parkinson’s disease; single cell analysis; hematopoiesis; neurodegenerative disease; single cell analysis; autologous transplant; gene therapy; frontotemporal dementia; hematopoietic stem cells; microglia; lentiviral vector; Parkinson’s disease
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2022.05.022

Hematopoietic stem/progenitor cell gene therapy (HSPC-GT) has shown clear neurological benefit in rare diseases, which is achieved through the engraftment of genetically modified microglia-like cells (MLCs) in the brain. Still, the engraftment dynamics and the nature of engineered MLCs, as well as their potential use in common neurogenerative diseases, have remained largely unexplored. Here, we comprehensively characterized how different routes of administration affect the biodistribution of genetically engineered MLCs and other HSPC derivatives in mice. We generated a high-resolution single-cell transcriptional map of MLCs and discovered that they could clearly be distinguished from macrophages as well as from resident microglia by the expression of a specific gene signature that is reflective of their HSPC ontogeny and irrespective of their long-term engraftment history. Lastly, using murine models of Parkinson’s disease and frontotemporal dementia, we demonstrated that MLCs can deliver therapeutically relevant levels of transgenic protein to the brain, thereby opening avenues for the clinical translation of HSPC-GT to the treatment of major neurological diseases. [Display omitted] Administration of genetically modified hematopoietic stem cells has lasting clinical benefit for certain rare neurological diseases. This study characterizes engrafted cells in the brain after this process using two routes of administration in mice and shows the method’s ability to provide potentially therapeutic transgene in two models of neurodegenerative disease.