DNA Repair, Gene Editing & Gene Therapy

Species survival is closely related to genome stability, which is monitored and maintained by DNA repair pathways. However, cells can initiate error-prone DNA repair under various physiological and pathological conditions. Thus, the fidelity of DNA repair influences aging, evolution, and certain diseases.

Genome editing is a type of genetic engineering in which DNA is inserted, deleted, or replaced in the genome of a living organism using engineered nucleases. Utilizing genome editing tools to genetically manipulate the genome of cells and living organisms has broad applications in life sciences research, biotechnology and agricultural technology development, and, most importantly, pharmaceutical and clinical innovation.

Our lab revealed the molecular mechanism by which the cytidine deaminase APOBEC induces mutations during CRISPR/Cas9-mediated gene editing has been elucidated. Building on this mechanistic study, multiple novel base editing systems have been developed, including: an enhanced Cas9 base editor (eBE) with high efficiency; a Cpf1 base editor (dCpf1-BE) capable of effective editing in genomic A/T-rich regions; a universal Cas9 base editor (hA3A-BE) demonstrating high efficiency in G/C-rich and hypermethylated regions; a Cas12a base editor (BEACON) with minimal activation of DNA damage response pathways; an enhanced mitochondrial adenine base editor (eTALED); and a high-precision RNA adenine base editor (RtABE). To address off-target risks in clinical applications, a high-precision base editor (transformer BE, tBE) was developed using cytidine deaminase inhibitory proteins. Employing tBE, we achieved the world's first clinical application of base editing for β-thalassemia treatment. To date, this approach has successfully treated patients with β-hemoglobinopathies across multiple countries (including China, Laos, Malaysia, Nigeria and Pakistan). The related drug candidate CS-101 received IND approval for Phase I clinical trials from China's National Medical Products Administration (NMPA) in 2024. Recognized as a groundbreaking advancement in β-hemoglobinopathy treatment, it was featured in the European Hematology Association Congress (EHA2024) Scientific Report.

Our lab focuses on DNA repair-induced mutagenesis, the development and application of new gene editing systems, and gene editing therapy. We are particularly interested in: (1) DNA repair-induced mutagenesis in gene editing, carcinogenesis, and aging; (2) the development of new gene editing tools; and (3) gene editing therapy for human diseases.