PAM-flexible adenine base editing rescues hearing loss in a humanized MPZL2 mouse model harboring an East Asian founder mutation
Brief intro:
- Author: Yilai Shu, Shao Wei Hu, Sohyang Jeong, Luoying Jiang, Hansol Koo, Zijing Wang, Won Hoon Choi, Biyun Zhu, Heeyoung Seok, Yi Zhou, Min Gu Kim, Dan Mu, Huixia Guo, Ziyi Zhou, Sung Ho Jung, Yingting Zhang, Ho Byung Chae, Liheng Chen, Sung-Yeon Lee, Luo Guo, Myung-Whan Suh, Yang Xiao, Moo Kyun Park, Honghai Tang, Jae-Jin Song, Xi Chen, Ai Chen, Jun Ho Lee, Sangsu Bae, ORCID, Sang-Yeon Lee
- Journal: Research Square
- Publication Date: 2024 Nov 24
Abstract
Hearing loss is one of the most prevalent sensory disorders, but no commercial biological treatments are currently available. Here, we identified an East Asia-specific founder mutation, the homozygous c.220C>T mutation in MPZL2, that contributes to a significant proportion of hereditary deafness cases in our cohort study. We found that the disease-causing mutation could be targetable by adenine base editors (ABEs) that enable A·T-to-G·C base corrections without DNA double-strand breaks. To demonstrate this, we developed a humanized mouse model (hMPZL2Q74X/Q74X) that recapitulates human MPZL2 deafness and leads to progressive hearing loss. A PAM-flexible ABE variant with reduced bystander and off-target effects (ABE8eWQ-SpRY:sgRNA3) was packaged in dual adeno-associated viruses (AAVs) and injected into the inner ear of hMPZL2Q74X/Q74X mice and effectively corrected the mutation. This treatment significantly restored hearing function, improved inner ear structural integrity, and reversed altered gene expression. Base editing may hold therapeutic potential for hereditary deafness, including most cases of MPZL2 deafness.
About PackGene
PackGene Biotech is a world-leading CRO and CDMO, excelling in AAV vectors, mRNA, plasmid DNA, and lentiviral vector solutions. Our comprehensive offerings span from vector design and construction to AAV, lentivirus, and mRNA services. With a sharp focus on early-stage drug discovery, preclinical development, and cell and gene therapy trials, we deliver cost-effective, dependable, and scalable production solutions. Leveraging our groundbreaking π-alpha 293 AAV high-yield platform, we amplify AAV production by up to 10-fold, yielding up to 1e+17vg per batch to meet diverse commercial and clinical project needs. Moreover, our tailored mRNA and LNP products and services cater to every stage of drug and vaccine development, from research to GMP production, providing a seamless, end-to-end solution.
