These findings provide a proof-of-concept study for RNA editing tools as a therapeutic treatment for various semidominant forms of hearing loss and other diseases.įunding: This work was supported by the Chinese National Science and Technology major project R&D Program of China (2018YFC2000101 to H.Y.), the Strategic Priority Research Program of Chinese Academy of Science (XDB32060000 to H.Y.), the National Natural Science Foundation of China (31871502 to H.Y., 31901047 to H.Y., 31925016 to H.Y., 91957122 to H. We also observed increased survival rate of hair cells and decreased degeneration of hair bundle morphology in the treated compared to untreated control ears.
The treatment rescued auditory function, including auditory brainstem response and distortion product otoacoustic emission up to 3 months after AAV-mxABE- Myo6 injection in Myo6 C442Y/+ mice. Single adeno-associated virus (AAV)–mediated delivery of mxABE in the cochlea corrected the mutated Myo6 C442Y to Myo6 WT allele in homozygous Myo6 C442Y/C442Y mice and resulted in increased Myo6 WT allele in the injected cochlea of Myo6 C442Y/+ mice. We first screened several variants of Cas13-based RNA base editors and guide RNAs (gRNAs) targeting Myo6 C442Y in cultured cells and found that mini dCas13X.1-based adenosine base editor (mxABE), composed of truncated Cas13X.1 and the RNA editing enzyme adenosine deaminase acting on RNA 2 deaminase domain variant (ADAR2dd E488Q), exhibited both high efficiency of A > G conversion and low frequency of off-target edits. Here, we evaluated RNA correction therapy with Cas13-based RNA base editors in the myosin VI p.C442Y heterozygous mutation ( Myo6 C442Y/+) mouse model that recapitulated the phenotypes of human dominant-inherited deafness. However, the potential of these RNA tools to treat disease remains unknown. Additionally, I recommend setting up the external editor workflow for use. As a general rule of thumb, at least with me, is leave layer 1 as is (default base) and just add layers on top of it. It looks like you might have done something to Layer 1. Final fine details (pores etc) Export highest and lowest versions. If you are importing, it should create a new texture layer. Subdivide low poly in Zbrush and project high poly onto retopo mesh. Programmable RNA editing tools enable the reversible correction of mutant transcripts, reducing the potential risk associated with permanent genetic changes associated with the use of DNA editing tools. Decimate in Zbrush then retopo and unwrap in 3D Coat.
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