Gene Therapy · asia
Delivering CRISPR by Targeting CD34: Lipid Nanoparticles Edit Human Blood Stem Cells In Vivo in Mice
Researchers directed lipid nanoparticles bearing anti-CD34 antibodies to the bone marrow, achieving sustained reactivation of fetal hemoglobin and improved neutrophil production in two humanized mouse models. The findings overcome one barrier to in vivo delivery, but multiple challenges remain before the approach can replace ex vivo stem cell therapy.
Blood stem cell gene therapy typically requires first collecting a patient’s cells, editing and quality-testing them in the laboratory, and then reinfusing them after conditioning. If editing tools could be delivered directly to stem cells in the bone marrow in vivo, treatment could be substantially simplified. A study published in *Nature Biomedical Engineering* shows that lipid nanoparticles guided by CD34 antibodies can perform this task in mice engrafted with a human hematopoietic system.
The researchers first screened 15 lipid nanoparticles and selected a formulation called LNPDP, which they then conjugated with an antibody that recognizes CD34. CD34 is a common surface marker on human hematopoietic stem and progenitor cells. This targeting design enabled the particles to deliver messenger RNA and CRISPR/Cas editing payloads into the target cells, rather than relying solely on the tissue distribution of the lipid particles themselves.
In the first humanized mouse experiment, the researchers injected CD34/LNPDP into the femoral bone marrow to edit the erythroid-specific BCL11A enhancer in human hematopoietic stem cells. BCL11A suppresses fetal hemoglobin, and reducing its activity is an important strategy for treating sickle cell disease and β-thalassemia. Following treatment, red blood cells generated from these stem cells continued to express fetal hemoglobin, and the study found no evident disruption of overall hematopoietic function.
The team also redirected the editing target to the second exon of ELANE in a humanized neutropenia model carrying an ELANE mutation. Long-term observation showed that the treatment partially restored neutrophil development. This did not constitute complete correction of the disease, but it demonstrated that the same delivery platform can be adapted to different gene targets to address different types of blood disorders.
Publicly available data provide another basis for verifying the results. The researchers deposited 21 whole-RNA sequencing datasets from human CD34-positive hematopoietic stem and progenitor cells in the NCBI Gene Expression Omnibus. The datasets cover conditions including untreated cells, non-targeted lipid particles, IgG control particles, and CD34-targeted particles, and can be used to compare how delivery treatments affect cellular transcriptional states.
However, this remains a preclinical study in mice, and it used intrafemoral injection, which differs from intravenous administration that could be broadly implemented. The volume, immune environment, and stem cell distribution of human bone marrow are more complex. The off-target effects of editing, immune responses to the antibody and CRISPR components, the extent to which different hematopoietic cells are affected, and whether efficacy can be maintained for years must all be clarified in larger animals and formal clinical trials. This work demonstrates the feasibility of targeting human blood stem cells in vivo, but it has not yet shown that the approach is sufficiently safe and effective for use in patients.