A research team funded by the National Institutes of Health (NIH) has developed an improved CRISPR gene-editing system capable of being delivered directly inside the human body, marking a significant breakthrough in the field of genetic medicine.

The study centres on a naturally occurring enzyme known as Al3Cas12f, which is small enough to be packaged into adeno-associated virus (AAV) vectors—one of the most widely used delivery systems in gene therapy. Scientists further engineered the enzyme into an enhanced variant, Al3Cas12f RKK, significantly boosting its gene-editing efficiency in human cells.

This advancement addresses a long-standing challenge in CRISPR technology, where commonly used gene-editing proteins are too large to fit into targeted delivery systems. As a result, most existing applications have been limited to editing cells outside the body before reintroducing them, such as in blood or bone marrow therapies.

Using advanced imaging and machine learning tools, researchers at the University of Texas at Austin examined the enzyme’s structure and discovered that it forms a highly stable and tightly connected complex. This structural advantage allows the enzyme to function more effectively within human cells compared to similar systems.

The engineered variant, Al3Cas12f RKK, demonstrated a dramatic improvement in performance, increasing gene-editing efficiency from below 10 percent to over 80 percent across multiple targets and reaching up to 90 percent efficiency in certain genomic regions. The system was tested in human cell lines originally derived from a leukaemia patient, targeting genes linked to conditions such as cancer, atherosclerosis and amyotrophic lateral sclerosis.

Researchers say the findings could pave the way for more practical and scalable in-body gene therapies. The next phase of the study will focus on testing the enzyme within AAV delivery systems to evaluate its clinical potential.

The research was supported by the National Institute of General Medical Sciences, a part of the NIH that funds foundational biomedical research to advance understanding of disease mechanisms and therapeutic development.