The human genome consists of around 3 billion base pairs with 99.6% genetic similarity between individuals. Researchers from the University of California San Diego have developed efficient genome editing tools called multiplexed orthogonal base editors (MOBEs) that can install multiple point mutations simultaneously across the genome. These mutations are crucial for understanding complex health issues like heart disease and neurodegenerative diseases such as schizophrenia.
The research focused on comparing genomes that differ at a single letter change in the DNA, known as bases. By studying single nucleotide variants (SNVs) or single point mutations, researchers can identify harmful and harmless variants that may contribute to disease development. The challenge lies in the vast number of possible genetic variations, making it difficult to identify combinations responsible for diseases like heart disease.
The traditional gene-editing tool CRISPR-Cas9 utilizes a guide RNA to locate and edit specific genomic locations by cutting both strands of DNA, causing potential toxic effects on cells. Editing multiple genes in CRISPR-Cas9 increases the risk of random insertions and deletions. In contrast, base-editing erases and replaces one letter at a time, offering a slower but safer alternative. The MOBE system developed by Komor’s lab enables efficient and simultaneous editing of multiple sites in the genome with minimal unwanted changes.
MOBEs use aptamers, small RNA loops that bind to specific proteins, to recruit base-modifying enzymes to specific genomic locations. This enables simultaneous editing of multiple sites with high efficiency and reduced crosstalk, compared to using base editors independently. The MOBE system was tested in case studies involving real diseases like Kallmann syndrome, demonstrating its potential to efficiently edit cell lines of polygenic diseases and model genetic diseases to develop effective therapies.
The research team plans to make the MOBE plasmids accessible to other researchers through AddGene, allowing for widespread use of the technology in disease modeling and therapeutic development. The innovative MOBE system, which has been granted a provisional patent, offers a promising approach to studying genetic variants and their role in complex diseases. The study was funded in part by the National Institutes of Health and the Research Corporation for Science Advancement, highlighting the importance of further research in genome editing and disease modeling.
Overall, the development of multiplexed orthogonal base editors (MOBEs) represents a significant advancement in genome editing technology, enabling researchers to efficiently install multiple point mutations simultaneously across the genome. Through the use of aptamers and base-modifying enzymes, the MOBE system offers a novel approach to studying genetic variants and their impact on complex diseases. The research holds promise for advancing our understanding of genetic diseases and developing effective therapies based on targeted genome editing.