The mission to achieve in vivo genome editing of hematopoietic stem cells (HSCs) in humans has taken another step forward. 

A new study in Nature Biomedical Engineering reports efficient base editing of the γ-globin gene (HBG1/2) promoter in transfusion-dependent β-thalassemia (TDT) patient-derived HSCs that had engrafted in humanized mice to reactivate fetal hemoglobin (HbF) in derived erythroid cells. The base editor messenger RNA (mRNA) was delivered using a new method called antibody-free targeted lipid nanoparticles (LNPs) from the Chinese company YolTech, eliminating the need for HSC collection. If translated to the clinic, this strategy could provide a less invasive, potentially one-time treatment for inherited blood disorders.

Moving on from your ex

The approval of Casgevy—the first FDA-authorized CRISPR-based therapeutic—ignited interest in ex vivo autologous HSC gene therapy for blood disorders such as β-thalassemia and sickle cell disease. This method, which modifies a patient’s own HSCs outside the body before reinfusion, avoids the risks of donor mismatch and graft-versus-host disease. However, it remains a complex and resource-intensive process, requiring the collection of high-quality stem cells and pre-conditioning with chemotherapy or radiation to clear space in the bone marrow. These steps can limit accessibility and introduce serious side effects, making the approach less viable for broad patient populations.

Researchers are now exploring in vivo HSC gene-editing strategies that bypass some of these hurdles. Current adenovirus-based delivery systems have shown promise but face significant drawbacks, including immune reactions, high rates of pre-existing immunity, and limited tissue targeting. LNP delivery offers a potential alternative, enabling transient expression of gene-editing machinery with low immunogenicity, repeat dosing, and simpler manufacturing. Advances in targeted delivery—such as CD117 antibody–conjugated LNPs—have demonstrated the ability to deliver RNA directly to HSCs in mice with a single injection. While early studies in animal models, including nonhuman primates, show efficient in vivo editing, only a handful of experiments have tested these strategies in humanized mouse models, leaving the therapeutic potential for patients an open and active area of investigation.

Targeting human HSCs in mice

To optimize the utilization of high-performance base editor ABE8e, researchers screened hundreds of guide RNAs (sgRNAs) targeting the γ-globin (HBG) promoter to pinpoint sequences that most strongly reactivated HbF. Among the top candidates, “sgRNA-25” stood out, creating a new DNA binding site for transcription factors such as SP1 and KLF1. This alteration increased HBG expression without disrupting normal red blood cell development.

When tested in CD34+ hematopoietic stem and progenitor cells (HSPCs) from both healthy donors and β-thalassemia patients, ABE8e/sgRNA-25 editing led to substantial rises in γ-globin levels—nearly doubling HbF content and improving the balance of α- and β-like globin chains. In patient-derived cells, these changes also enhanced the maturation of red blood cells, reversing disease-related defects. In mouse transplantation experiments, edited human HSPCs retained their ability to engraft, self-renew, and generate multiple blood lineages, while maintaining elevated HbF production months after transplantation.

To move toward an in vivo therapy, the team engineered multiple libraries of ionizable lipids, ultimately identifying “Lipid-168” as a highly efficient bone marrow–targeted carrier. Adding microRNA-122 target sequences to the ABE8e mRNA reduced unintended liver editing while preserving bone marrow efficiency.

In humanized mouse models transplanted with β-thalassemia patient HSPCs, intravenous infusion with Lipid-168 containing ABE8e/sgRNA-25 edited over 40% of target sites in the HBG promoter, significantly raising γ-globin expression and restoring healthy red blood cell morphology. Protein analysis revealed that Lipid-168’s bone marrow targeting may stem from its distinct “protein corona,” rich in albumin, fibronectin, and fibrinogen rather than liver-homing apolipoprotein E. Safety studies showed rapid clearance of the mRNA payload, minimal immune activation, no liver damage, and negligible off-target DNA editing. Importantly, the base editing approach avoided the large genomic deletions sometimes caused by traditional CRISPR nucleases, further improving HbF induction.

Fledgling clinical field

These results demonstrate that rationally designed LNPs can deliver precision gene editors directly to human HSPCs in vivo, enabling long-lasting HbF reactivation without ex vivo manipulation. That the targeted cells were human-derived is what sets this study apart from previous studies that have demonstrated efficient genome editing in mice livers, lungs, and bone marrow using LNPs without inducing off-target mutations or notable safety concerns in animals.

The report follows a series of significant news announcements from YolTech regarding the initiation of the first in vivo CRISPR therapy trial for blood diseases in both the United States and China. On June 6, 2025, YolTech Therapeutics announced FDA clearance of the Investigational New Drug (IND) Application for YOLT-101, an in vivo base editing therapy to treat Heterozygous Familial Hypercholesterolemia (HeFH). The company also announced clearance from the National Medical Products Administration (NMPA), China’s FDA equivalent, on July 14, 2025.

In addition to YolTech, several biotech companies have advanced in vivo CRISPR genome editing into nonhuman primate (NHP) studies, a key step toward human use. Editas Medicine achieved CEP290 gene editing in NHP retinas via AAV, while Mammoth Biosciences used AAV to deliver its compact “NanoCas” CRISPR to skeletal muscle. Intellia Therapeutics demonstrated durable liver editing with LNPs lasting over 15 months, and Precision BioSciences used its ARCUS nuclease in models of metabolic and viral diseases. NeuBase Therapeutics’ LNP-delivered Stealth Editors™ proved non-immunogenic and redosable. These findings show rapid progress toward safe, efficient, and repeatable CRISPR therapies across multiple organs.

Coupled with recent clinical progress from YolTech and others, these findings highlight the growing potential for safe, efficient, and durable in vivo CRISPR therapies to transform treatment for inherited blood disorders and beyond.