Core Viewpoint - The article discusses advancements in base editing technology, specifically focusing on a new method to minimize bystander editing while maintaining high editing efficiency, which addresses significant challenges in genome editing applications [1][2][9]. Group 1: Research Findings - The research team from Harvard University developed a multi-faceted approach to enhance base editing precision by optimizing gRNA and deaminases, thereby minimizing bystander editing [2][5]. - A library of approximately 60,000 different 3' extended sgRNAs was designed and tested to improve the precision of adenine base editors (ABE), leading to the identification of promising agRNA candidates [6]. - The V28C variant, evolved through phage-assisted non-continuous evolution (PANCE), demonstrated a significant increase in editing efficiency at target sites while substantially reducing bystander editing, achieving precision two to three times greater than ABE8e with a 20% efficiency improvement [6][7]. Group 2: Methodologies - The study integrated three complementary technologies: engineering gRNA to reduce bystander editing, using PANCE to evolve more precise base editors, and employing protein language models (PLM) for rational design of optimized deaminases [5][9]. - The M151E mutation, identified through PLM, significantly narrowed the editing window and improved target site editing efficiency [7]. Group 3: Clinical Applications - The performance of the evolved base editors was validated in two clinically relevant scenarios, showing high efficiency and precision in editing cardiovascular disease-related target PCSK9 and early-onset Parkinson's disease-related mutation SNCA E46K [7].

Core Viewpoint - The article discusses the potential of base editing technology as a new strategy for treating trinucleotide repeat (TNR) diseases, specifically Huntington's disease and Friedreich's ataxia, by interrupting pathogenic repeat sequences [3][8]. Group 1: TNR Diseases Overview - TNR diseases are caused by the expansion of trinucleotide repeat sequences in the genome, leading to neurodegenerative disorders, with no approved treatments currently available [2][6]. - CAG repeat expansions in the HTT gene are linked to Huntington's disease, while GAA repeat expansions in the FXN gene cause Friedreich's ataxia [2][6]. - The severity and progression of TNR diseases are primarily determined by the length of the repeat sequences at birth, with longer repeats correlating to worse prognosis [7]. Group 2: Base Editing Technology - Base editing is a precise genome editing technique developed by Professor Liu Ruqian, allowing targeted single-base changes in DNA within living cells [8]. - The technology utilizes cytosine base editors (CBE) and adenine base editors (ABE) to introduce interruptions in CAG and GAA repeat sequences, respectively, mimicking naturally occurring stable alleles [8][12]. - The recent study demonstrated that base editing can effectively reduce somatic repeat expansions in patient-derived cells and mouse models of Huntington's disease and Friedreich's ataxia [3][13]. Group 3: Research Findings - The research team successfully delivered optimized base editors using AAV9 to treat Huntington's disease Q111 mice and YG8s hereditary ataxia mice, achieving significant reductions in TNR expansions in the central nervous system [12][13]. - Introducing interruptions in pathogenic TNR sequences may alleviate key neurological features of TNR diseases, providing a promising avenue for future therapies [13].