Base Editing for Genetic Disease: Changing DNA Bases Without Double-Strand Breaks
Background: Why precise gene editing is needed
Base editing is a gene-editing technique that changes specific base pairs without inducing DNA double-strand breaks. Conventional CRISPR-Cas9 cutting methods cut both DNA strands and rely on cellular repair processes, which can introduce unintended insertions or deletions. The efficiency of precise repair to the desired sequence is also limited. Base editing was developed to reduce these limitations.
This review, published in Journal of Cellular and Molecular Medicine, summarizes how base editing works, its therapeutic applications, and its remaining limitations. It does not report results from a new trial in patients; it covers multiple preclinical studies and examples of early clinical development.
Key findings: Base conversion that avoids double-strand breaks
Typical CRISPR-based base editors combine a Cas protein that locates target DNA with a deaminase responsible for chemically converting bases. Guide RNA directs the editor to the target site, where bases are changed within a defined window on an exposed DNA strand. Cytosine base editors (CBEs) convert C·G base pairs to T·A, while adenine base editors (ABEs) convert A·T base pairs to G·C.
CBEs first convert cytosine (C) to uracil (U), while ABEs convert adenine (A) to inosine (I). Cellular replication and repair processes then contribute to the final base-pair conversion. No externally supplied DNA repair template is required.
Not inducing DNA double-strand breaks does not mean that no DNA damage occurs. Some editors use Cas proteins with their cutting activity disabled, while others use a nickase that cuts only one strand. Off-target editing, which changes DNA or RNA outside the target, remains a concern, as does bystander editing, in which bases other than the intended one are changed within the editing window. Tools with higher editing activity are not necessarily more precise, and outcomes vary with the target sequence and cell type.
Implications and outlook: Entering clinical trials and demonstrating therapeutic benefit are separate steps
The review describes examples of clinical development of base-editing treatments for conditions including sickle cell disease, beta thalassemia, and hypercholesterolemia. It distinguishes ex vivo approaches, in which a patient’s cells are edited outside the body, from in vivo approaches, in which editing tools are delivered into the body. For example, the sickle cell disease treatment candidate BEAM-101 aims to increase fetal hemoglobin production by editing regions that regulate HBG1/2 gene expression in a patient’s hematopoietic stem cells. This differs from directly reverting a disease-causing variant to its original sequence.
Expanding therapeutic possibilities requires delivering editing tools to the intended tissues and reducing unintended changes. Entry into early clinical trials alone provides insufficient evidence to conclude that a treatment is safer than existing therapies or that a single edit can cure genetic diseases broadly. The durability of effects and long-term safety must be assessed for each disease and treatment candidate. The review’s clinical status table reflects information as of March 2026, while its text also includes earlier reports; these should be distinguished from current recruitment status or the latest treatment outcomes.
The principles and therapeutic applications of base editing are summarized based on the provided excerpt from the publicly available text of this review.
CRISPR-Cas9 systems revolutionized gene editing, but inherent drawbacks, namely DNA double-strand breaks (DSBs) and the difficulty of achieving precise repairs (due to low HDR efficiency), led researchers to invent new, more accurate gene editing tools. Base editing represents a significant leap forward, enabling targeted single-nucleotide conversions directly on the DNA without DSBs or donor templates. The core technology involves fusing catalytically dead or nickase Cas proteins to DNA deaminase enzymes. Cytosine base editors (CBEs) convert C•G to T•A pairs, while adenine base editors (ABEs) change A•T to G•C. These editors exploit the deaminase function within the R-loop structure formed by Cas binding and co-opt endogenous DNA repair mechanisms for precision. While offering improved efficiency and editing precision, base editing faces persistent challenges, such as off-target effects, bystander edits, delivery and ethical concerns. Continuous engineering efforts have refined these tools, enhancing accuracy, expanding targetability and reducing unwanted edits. The base editing arsenal has also broadened to include C-to-G base editors (CGBEs), dual A&C editors and versions targeting organelles. Successful preclinical studies demonstrating the correction of mutations responsible for the disease have paved the way for clinical trials, which are now testing therapies for conditions like sickle cell disease, β-thalassaemia and hypercholesterolemia using various delivery systems. This review explores CRISPR base editing's origins, mechanisms of action, potential therapies and current restrictions, pointing to its broadening impact on medical genetics.
Base editing offers an option that avoids DNA double-strand breaks for treatments requiring a specific base conversion. When hematopoietic stem cells collected from a patient are edited ex vivo, editing efficiency, unintended changes, and cell quality can be assessed before transplantation. Alongside approaches that directly correct a causal variant, regulatory-region editing to increase fetal hemoglobin production is also being developed for treatment. However, cell quality control does not guarantee a patient’s long-term safety or therapeutic benefit. During development, the proportion of intended changes must be assessed alongside off-target and bystander editing, and the durability of effects and adverse events must be monitored after transplantation.