Small But Mighty New Gene Editor
Published:24 Dec.2023 Source:University of Tokyo
A new CRISPR-based gene-editing tool has been developed which could lead to better treatments for patients with genetic disorders. The tool is an enzyme, AsCas12f, which has been modified to offer the same effectiveness but at one-third the size of the Cas9 enzyme commonly used for gene editing. By now you have probably heard of CRISPR, the gene-editing tool which enables researchers to replace and alter segments of DNA. The potential of CRISPR to improve our lives is so phenomenal that in 2020, researchers Jennifer Doudna and Emmanuelle Charpentier, who developed the most precise version of the tool named CRISPR-Cas9, were awarded the Nobel Prize in chemistry.
Even Cas9 has limitations. The common way to deliver genetic material into a host cell is to use a modified virus as a carrier. Adeno-associated viruses (AAVs) are not harmful to patients but have a size limit. Cas9 is at the very limit of this size restriction, so there has been a demand for a smaller Cas protein that can be efficiently packaged into AAV and serve as a genome-editing tool. The researchers selected an enzyme called AsCas12f, from the bacteria Axidibacillus sulfuroxidans. The advantage of this enzyme is that it is one of the most compact Cas enzymes found to date and less than one-third the size of Cas9.
Based on insights gained from the structural analysis of AsCas12f, researchers selected and combined these enhanced-activity amino acid mutations to create a modified AsCas12f. This engineered AsCas12f has more than 10 times the genome-editing activity compared to the usual AsCas12f type and is comparable to Cas9, while maintaining a much smaller size. The team discovered numerous potentially effective combinations for engineering an improved AsCas12f gene-editing system, so the researchers acknowledge the possibility that the selected mutations may not have been the most optimal of all the available mixes. As a next step, computational modeling or machine learning could be used to sift through the combinations and predict which might offer even better improvements.