Researchers Develop LNP-mRNA Therapy to Enable In Vivo Gene Editing of Hematopoietic Stem Cells

Transplantation of gene-edited autologous hematopoietic stem cells has been shown to be a curative treatment for hematopoietic disorders, including β-thalassemia and sickle cell disease (SCD). While this approach has been successful in numerous clinical trials, eliminates the need for donor matching, and potentially prevents graft-versus-host disease (GvHD), it remains hampered by the difficulty in obtaining sufficient high-quality hematopoietic stem cells for ex vivo manipulation. Furthermore, prior to transplantation, myeloablative conditioning (typically chemotherapy) is required to eliminate the patient's own hematopoietic stem cells to create space in the bone marrow microenvironment for the gene-edited autologous hematopoietic stem cells. The complex process, high production costs, and significant side effects have severely limited clinical application and commercialization.

In recent years, researchers have begun exploring the use of viral vectors for in vivo gene therapy. However, this approach continues to face challenges such as immunogenicity, toxicity, production costs, and precise targeting, which have also limited its further clinical application.

Recently, researchers published an article titled "In vivo genome editing of human hematopoietic stem cells for the treatment of blood disorders using mRNA delivery" in the journal Nature Biomedical Engineering. This study successfully developed a lipid nanoparticle (LNP) delivery system that does not require antibody modification, enabling precise gene editing of human hematopoietic stem cells in vivo and efficiently activating fetal hemoglobin expression. This offers hope for a single-step cure without myeloablative therapy for inherited blood disorders, including thalassemia and sickle cell anemia.

Figure 1. Efficient base editing to induce HbF expression in CD34+ HSPCs from β-thalassemia patients and in immunodeficient mice. (Xu S, et al., 2025)

Modifying autologous stem cells ex vivo and then reintroducing them into the body offers a promising treatment option for hematologic diseases. However, current approaches involve complex procedures and chemotherapy pretreatment, resulting in limited access and severe side effects.

In this recent study, a research team successfully developed a novel lipid nanoparticle, LNP-168, by screening a library of ionizable lipids. LNP-168 enables efficient bone marrow targeting without the need for antibody conjugation. This nanoparticle can be used to deliver mRNA to hematopoietic stem cells (HSCs) in vivo, effectively base editing the promoter of the γ-globin gene (HBG1/2) in human HSCs and reactivating fetal hemoglobin expression in erythrocytes derived from these HSCs.

Using this optimized LNP-168 to deliver an adenine base editor (ABE8e/sgRNA mRNA) in mRNA format, efficient in vivo base editing of HBG1/2 in HSCs was achieved in a mouse model of transfusion-dependent β-thalassemia (TDT) transplanted with HSCs derived from patients. After editing, the proportions of various hematopoietic lineages were normal, the fetal hemoglobin content in erythroid cells was significantly increased, the pathological phenotype was significantly ameliorated, and red blood cell morphology returned to normal. Furthermore, the study demonstrated that the injected LNPs were rapidly cleared from the body, without inducing a strong immune response or causing organ damage. No significant off-target effects of the base editors were observed across the entire genome.

These findings demonstrate that LNP-mRNA-based in vivo gene editing can efficiently edit endogenous genes in human hematopoietic stem cells (HSCs). This non-viral delivery system eliminates the need to collect or mobilize HSCs, offering the potential for a powerful, one-time cure for blood disorders such as sickle cell disease and aplastic anemia.

Reference

Xu S, et al. In vivo genome editing of human haematopoietic stem cells for treatment of blood disorders using mRNA delivery. Nature Biomedical Engineering, 2025: 1-17.