Credit score: JCI Perception (2025). DOI: 10.1172/jci.perception.185193
An R75W mutation within the hole junction β2 (GJB2) gene causes extreme fragmentation of hole junction plaques, connecting adjoining cells and resulting in syndromic listening to loss. In a brand new experimental examine, scientists from Juntendo College in collaboration with researchers from the College of Tokyo have developed an adeno-associated virus (AAV) vector-mediated genome enhancing method to restore the R75W mutation.
Their findings, now printed in JCI Perception, may contribute to the event of progressive gene therapies to deal with hereditary listening to loss.
Congenital listening to loss refers to impaired auditory operate that happens resulting from genetic causes. GJB2 is the gene liable for roughly half of all instances of hereditary listening to loss. Connexin 26 (CX26), which is encoded by GJB2, helps within the formation of intercellular hole junctions—channels that enable for the motion of ions and chemical messenger molecules between adjoining cells, the place it regulates auditory operate.
GJB2 mutations typically result in fragmentation of hole junctions and hole junction plaques (GJPs) that are composed of CX26. Whereas the inheritance of a recessive GJB2 mutation containing two copies of the faulty gene will be functionally cured by way of GJB2 gene substitute, a GJB2 dominant-negative mutation the place the mutant protein inhibits the traditional functioning of the wild-type protein necessitates a gene enhancing method.
Researchers from Japan have efficiently developed a gene remedy to restore R75W, a dominant-negative mutation of GJB2 that causes syndromic listening to loss. The analysis staff included Affiliate Professor Dr. Kazusaku Kamiya and Assistant Professor Dr. Takao Ukaji within the Division of Otorhinolaryngology, Juntendo College School of Medication, Japan, and Dr. Osamu Nureki from the Division of Organic Sciences, Graduate Faculty of Science, the College of Tokyo, Japan.
“The overwhelming majority of mutations causing hereditary hearing loss involve the GJB2 gene. However, treatments that can restore hearing in patients with genetic deafness are lacking,” says Dr. Kamiya. “Our research can contribute to the development of gene therapy to tackle the increasing incidence of hereditary hearing loss patients.”
First, the researchers developed an AAV (AAV-Sia6e) that may ship genome enhancing instruments to a variety of internal ear cells that kind hole junctions. AAV is a helpful vector for delivering genes; nonetheless, the dimensions of the gene that may be carried is proscribed.
Subsequently, Dr. Kamiya and his staff constructed a base enhancing device (SaCas9-NNG-ABE8e) that was miniaturized to a measurement that may be carried by AAV utilizing SaCas9-NNG, which has a smaller measurement and better genome enhancing effectivity than typical Cas9. Subsequent, they loaded this base enhancing device onto AAV-Sia6e, which has excessive an infection tropism for internal ear cells and developed an all-in-one AAV vector for internal ear genome enhancing.
Genome enhancing by way of the all-in-one AAV vector confirmed appreciable effectivity and specificity. It confirmed on-target T to C conversion in human cells, expressing the GJB2 R75W mutation, repaired the R75W mutation, and shaped a transparent GJP. Moreover, after the bottom enhancing process, the physiological operate of hole junction cell-cell communication was restored.
Lastly, to validate their outcomes, the researchers carried out AAV-mediated genome enhancing in a transgenic mouse mannequin with the GJB2 R75W mutation. Interior sulcus cells of the cochlea, which had been contaminated with the all-in-one AAV vector, shaped distinct GJPs with pentagonal or hexagonal buildings organized round cells that had been much like these noticed in wild-type cells.
“By using an all-in-one AAV vector with high infectivity for the inner ear, we expect to improve the therapeutic effect, simplify the development process, and reduce costs. Furthermore, the ABE-based gene editing approach is expected to be less toxic and safer than the conventional CRISPR-Cas9 technology. The AAV genome editing therapy we developed can also be applied to the treatment of other genes that cause hearing loss,” concludes Dr. Kamiya.
Taken collectively, these findings spotlight the immense therapeutic potential of the AAV-mediated genome enhancing method for treating hereditary listening to loss.
Extra info:
Takao Ukaji et al, AAV-mediated base enhancing restores cochlear hole junction in GJB2 dominant-negative mutation-associated syndromic listening to loss mannequin, JCI Perception (2025). DOI: 10.1172/jci.perception.185193
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Gene enhancing with adeno-associated virus vector presents hope for hereditary deafness (2025, March 27)
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