Recently, the team led by Professor Yilai Shu from the Affiliated Eye, Ear, Nose and Throat Hospital of Fudan University in China published a research paper titled "A base editor for the long-term restoration of auditory function in mice with recessive profound deafness" in the journal Nature Biomedical Engineering. The study used adenine base editor (ABE)-mediated gene editing therapy to effectively repair the Otof pathogenic mutation in the deaf mouse model and restore the expression level of otoferlin in 88% of the inner hair cells of the inner ear. At the same time, it improved the synaptic exocytosis function of the inner hair cells of the inner ear and restored hearing to a level close to the wild type for up to 1.5 years without obvious off-target effects. It is reported that this is the longest-observed effective result in the field of gene therapy for deafness in animal models to date.
In recent years, base editors have shown great potential in the treatment of various genetic diseases such as hypercholesterolemia, phenylketonuria, tyrosinemia, progeria, Duchenne muscular dystrophy, Leber congenital amaurosis, sickle cell disease and β-thalassemia. It is worth noting that base editing therapy has begun to enter early clinical trials for the treatment of heterozygous familial hypercholesterolemia caused by PCSK9 gene mutations and for the treatment of acute lymphoblastic leukemia.
Base editors, such as adenine base editors (ABE) and cytosine base editors (CBE), can accurately convert A·T to G·C and C·G to T·A, respectively, without causing DNA double-strand breaks, and are considered safer than CRISPR-Cas9-based gene editing technology.
In June 2020, Professor Liu Ruqian, the pioneer of base editing technology, and others published a paper in the journal Science Translational Medicine. The hearing of mice with complete deafness caused by recessive mutations in the Tmc1 gene was partially restored by delivering cytosine base editors (CBEs) via dual AAV vectors. This is the first time that humans have used gene editing technology to address genetic diseases caused by recessive genetic mutations. However, only partial hearing restoration was achieved in the treated mice, and this effect weakened within 6 weeks. This emphasizes the need to further optimize long-term therapeutic efficacy in clinical translation.
In this latest study, the research team described the development and assessment of combinations of six optimized ABEs and a single guide RNA (sgRNA) for their ability to directly correct the de novo Otof c.2482C>T, p.Q828X nonsense A·T mutation to wild-type (WT) G·C base pairs. The research team then packaged the most promising ABE (consisting of deaminase ABE7.10max and Cas9 variant SpCas9-NG)-sgRNA combination into the dual-vector adeno-associated virus (AAV) serotype PHP.eB (this AAV serotype has high efficiency in hair cell transduction) and injected it into the OtofQ828X/Q828X mouse model 1-3 days after birth through the inner ear.
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| AAV00118Z | AAV PHP.S-Null | Inquiry |
| AAV00295Z | AAV PHP.B-GFP | Inquiry |
| AAV00296Z | AAV PHP.B-mCherry | Inquiry |
| AAV00297Z | AAV PHP.B-Cre | Inquiry |
| AAV00298Z | AAV PHP.B-Cre-GFP | Inquiry |
| AAV00299Z | AAV PHP.B-CAG-GFP | Inquiry |
| AAV00300Z | AAV PHP.B-CAG-mCherry | Inquiry |
| AAV00301Z | AAV PHP.B-Syn-GFP | Inquiry |
| AAV00302Z | AAV PHP.eB-CMV-GFP | Inquiry |
| AAV00303Z | scAAV PHP.eB-CMV-GFP | Inquiry |
| AAV00304Z | AAV PHP.eB-CMV-Cre | Inquiry |
| AAV00305Z | AAV PHP.eB-CAG-GFP | Inquiry |
| AAV00306Z | AAV PHP.eB-CAG-Cre | Inquiry |
The results showed that this ABE-mediated gene editing therapy effectively repaired the Otof pathogenic mutation and restored the expression level of otoferlin in 88% of the inner ear hair cells. At the same time, it improved the synaptic exocytosis function of the inner ear hair cells and restored hearing to near wild-type levels for up to 1.5 years without obvious off-target effects.
Figure 1. Dual AAV base editor treatment restored otoferlin expression in deaf OtofQ828X/Q828X mice. (Cui C, et al., 2024)
In addition, even if the OtofQ828X/Q828X mouse model is treated at 13-14 days old, their hearing function can be significantly restored. The research team also developed an ABE treatment strategy targeting the human OTOF c.2485C>T (p.Q829X) site, restoring the hearing of the humanized OtofQ828X/Q828X mouse model to a level comparable to that of wild-type mice.
These findings suggest that adenine base editors (ABEs) can be used to rescue hearing function in cases of auditory synaptic diseases, thus providing a potential precision treatment strategy for hereditary hearing loss.
Reference
Cui C, et al. A base editor for the long-term restoration of auditory function in mice with recessive profound deafness. Nature Biomedical Engineering, 2024: 1-17.