Restoration of DFNB83 deafness
Our technology restores hearing with a virus-mediated delivery of CaBP2 for a gene-therapy of DFNB93. A one-vector system for CaBP2 (Ca+2 binding protein 2) is delivered directly into the cochlea. In a CaBP2 knock-out mouse model we showed transduction of inner hair cells and restoration of hearing.
Ca2+ binding proteins (CaBP) influence inner hair cell (IHC) presynaptic Ca2+ signal and sound encoding. CaBPs prevent calmodulin (CaM)-mediated Ca2+ channel inactivation. Efficient IHC transmitter release requires very fast Ca2+ channel activation. Different CaBPs do have different main functions.
Mutations in CaBP2 cause hearing impairment DVNB93. Absence of CaBP2 in IHCs leads to hearing impairment in knock-out mice. Its absence causes a disruption in temporal precision of sound encoding. Hearing impairment DFNB93 is a human autosomal-recessive deafness. Patients suffer from a moderate-to-severe prelingual hearing impairment. Pharmacological drugs can not be used to restore hearing. Gene therapy promises restoration of hearing (i.e. introduction of intact copies of the defective gene in the affected cell population in the ear). Each monogenic hearing disease requires an individual therapeutical construct.
AAV virus-mediated one-vector delivery of CaBP2 (Ca+2 binding protein 2) into the cochlea. Successfully in vivo tested showing a transduction of inner hair cells of the cochlea and recovery of hearing in CaBP2 knock-out mice.
IN VIVO PROOF OF CONCEPT
Postnatal injection of "wild-type" AAV2/1-Cabp2-P2A-EGFP. Construct was injected into scala tympani of the right ear of CaBP2LacZ/LacZ or control mice via the round window at p5-7. Hearing in the injected right ear was compared to hearing in the left non-injected ear. Four weeks after injection hearing was tested by auditory brainstem recordings (ABRs). The animals were then sacrificed; cochleae was isolated and used in patch-clamp experiments.
1) Recovery & improvement of hearing in CaBP2 knock-out mice. Improvement of hearing in CaBP2 knock-out mice upon postnatal injection of AAV2/1-CaBP2-P2A-EGFP. Figure shows measured ABR thresholds upon tone bursts or clicks (source: patent application).
2) Decreased inactivation of IHC Ca2+ currents in CaBP2 knock-out mice upon postnatal injection of AAV2/1-CaBP2-P2A-EGFP
Gene therapy of deafness DFNB93 for restoration of hearing.
Preclinical in vivo tests achieved.
We filed PCT international IP rights in the name of the Georg-August-Universität Göttingen, Universitätsmedizin, and are looking for a licensing partner, who develops and markets a product.
Dr. Martin Andresen