Researchers from Wuhan University have developed a novel and compact version of a key CRISPR gene-editing protein that can be efficiently packaged within a non-pathogenic virus for targeted delivery to cells.
The CRISPR-Cas system has revolutionized the field of gene editing. While the widely used Cas9 and Cas12a proteins have their own strengths and limitations, one major challenge has been the size constraint imposed by the adeno-associated virus (AAV), a popular vector for gene therapy.
Addressing this challenge, the research team identified a relatively small version of Cas12a, termed EbCas12a, found naturally in a species of the Erysipelotrichia class of bacteria. Through a strategic amino acid substitution, they boosted its gene-editing efficiency, creating a modified protein called enEbCas12a.
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In laboratory tests on mammalian cells, enEbCas12a demonstrated gene-editing efficiency comparable to two other highly accurate Cas12a proteins. In addition, its compact size allowed it to be packaged within the AAV for targeted gene therapy applications.
To validate its potential, the researchers modified enEbCas12a to target a specific cholesterol-associated gene, packaged it within the AAV, and administered it to mice with high cholesterol levels. One month later, the treated mice exhibited a significant reduction in blood cholesterol levels compared to untreated mice.
"The novel compact enEbCas12a, along with its crRNA, can be packaged into an all-in-one AAV system for convenient gene editing in vitro and in vivo with high-fidelity, which can be very beneficial for future clinical applications and more tool developments including all-in-one AAV-based multi-gene editing, base editing, primer editing," explained Hongijan Wang, first author of the paper published in PLOS Biology.
While further research is necessary to assess its potential for addressing human diseases, this study represents a significant step forward in the development of viral gene therapy using CRISPR technology.