High Dose Hematopoietic Stem Cell Transplantation Leads to Rapid Neural and Peripheral Disease Cross-Correction Via Robust Hematopoietic and Microglia Recovery

Abstract

Background Allogeneic hematopoietic stem cell transplant (HSCT) is a curative approach to halt disease progression of select inherited metabolic disorders (IMDs). For IMDs that affect the central nervous system (CNS), donor-derived cells, like microglia, cross-correct defects via production of normal enzyme. The typical cell dose used in HSCT can be sub-optimal and, in gene therapy applications, copy number has been shown to be variable. We developed MGTA-456, a high dose cell therapy that led to rapid neutrophil recovery and 100% engraftment in patients with malignant and non-malignant diseases (Wagner et al Blood 2017; Orchard et al AAN 2019). The impact of cell dose on disease correction, however, is unknown. Here, we show that fast and robust hematopoietic and microglia recovery via high cell dose therapies, like MGTA-456, leads to rapid and complete disease resolution of Hurler syndrome through hematopoietic engraftment in the CNS. Results At 1-16 weeks post-HSCT, transplant of increasing doses of total bone marrow cells following myeloablative busulfan conditioning led to a dose-dependent increase microglial engraftment (26-fold for 10 × 106 cells vs 0.3 × 106 cells, p Relative to low cell dose therapies, transplant of MGTA-456, a high cell dose therapy with two normal IDUA gene copies, led to robust, long-term immune recovery (n=88 animals), 60-fold greater microglial engraftment as early as 2 weeks post-HSCT (Figure D, p 600-fold higher IDUA enzyme levels (Figure E, p Conclusions We show that high dose HSCT leads to improved disease correction, including normalization of behavioral outcomes, via robust engraftment. High dose cell therapies, like MGTA-456, may rapidly and durably resolve peripheral and neurologic disease in patients with IMDs and other neurodegenerative diseases caused by defective microglia.