Autologous, Gene-Modified Hematopoietic Stem and Progenitor Cells Repopulate the Central Nervous System with Distinct Clonal Variants

Abstract

Summary Myeloid-differentiated hematopoietic stem cells (HSCs) have contributed to a number of novel treatment approaches for lysosomal storage diseases of the central nervous system (CNS), and may also be applied to patients infected with HIV. We quantified hematopoietic stem and progenitor cell (HSPC) trafficking to 20 tissues including lymph nodes, spleen, liver, gastrointestinal tract, CNS, and reproductive tissues. We observed efficient marking of multiple macrophage subsets, including CNS-associated myeloid cells, suggesting that HSPC-derived macrophages are a viable approach to target gene-modified cells to tissues. Gene-marked cells in the CNS were unique from gene-marked cells at any other physiological sites including peripheral blood. This novel finding suggests that these cells were derived from HSPCs, migrated to the brain, were compartmentalized, established myeloid progeny, and could be targeted for lifelong delivery of therapeutic molecules. Our findings have highly relevant implications for the development of novel therapies for genetic and infectious diseases of the CNS.

Stem cell–derived CAR T cells traffic to HIV reservoirs in macaques

“…In the cerebellum, CAR staining frequencies were below the threshold in all 4 macaques, indicating minimal to no trafficking of gene-modified cells to this site. In agreement with our previous studies, these findings strongly suggest that HSC-derived progeny engraft and persist long-term in the brain ( 43 ).…”

“…Therefore, the HSC-derived CD4CAR + cell types we observed in the CNS remain to be fully characterized. Nevertheless, our findings in the CNS are consistent with previous studies from our group and others ( 43 , 64 ), demonstrating that HSC-derived therapies enable trafficking of cell-based therapies to the brain, and in close proximity to potential CNS-associated viral reservoirs ( 65 ).…”

“…An alternative model holds that myeloablative and lymphodepleting conditioning with TBI, which was used to promote HSC engraftment in this study, leads to disruption and regeneration of various tissue sites and sequestration of HSCs and their progeny. For example, disruption of the blood brain barrier (BBB) permits influx of HSPCs, which become compartmentalized following BBB repair ( 43 ). Trafficking and reconstitution of hematopoietic cell subsets following TBI is likely to be a generalized phenomenon that is independent of a given gene modification strategy (i.e., CD4CAR).…”

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

“…We also observed that HSPC-derived MLCs were durably engrafted within the brain over a year post-transplantation and that these cells bore many of the transcriptional hallmarks of microglia, which strongly suggest they have the capacity to selfrenew much like endogenous microglia. This is consistent with long-term follow-up of HSPC-GT in nonhuman primates, where HSPC-derived myeloid cells in the brain were observed ten years posttransplantation 15 . It is similarly consistent with the durable phenotypic rescue in most patients enrolled in clinical trials for MLD and CALD 48 .…”

“…2h). Of note, we observed a general lack of correlation of biodistribution metrics (VCN, mRNA, protein) in peripheral tissues versus brain, consistent with previous clinical and preclinical reports 15,20,29 that engraftment in these two compartments are independent events that occur from separate cell populations derived from the drug product (Supp. Fig.…”