Deafness and balance defects are the most prevalent inherited sensory disorder in humans and is a major concern and a serious burden for Public Health. Today, clinical prevalence of deafness is approximately 1 in 700 newborn. About 80% of deafness cases, associated or note with balance defect, are attributed to a genetic cause. As of now, no curative therapeutic approaches exist to cure inner ear disorders. Gene therapy based on adeno-associated virus (AAV) has emerged as a promising treatment strategy. Because of their distinct tropism and high levels of transgene expression, AAV gene therapy is now being utilized for several inherited disorders in a number of pre-clinical, but so far none are related to hearing loss. Others and we have shown that AAV gene therapy partially restores hearing in DFNB1, DFNB59 and Ush1g mouse models. We also demonstrated that there is a linear correlation between hearing threshold rescue and the percentage of transduced sensory cells within the inner, suggesting that the normalization of thresholds may be possible with a higher cell transduction rate. These results highlight the great need for a vector system that effectively and specifically transduces the defective cells within the inner ear. Accomplishing specific expression of the therapeutic gene within a particular inner ear cell type is an important step toward clinical application of gene therapy for treating inner-ear disease.
The aim of the present proposal is the use of AAV viral gene therapy to restore hearing and balance in mice established as models for human deafness and vestibular defect. We plan to engineer and/or identify AAV vectors to target specifically the inner ear tissue. In addition, we will seek promoters to potentiate tissue-specific control of gene expression. The field has newly begun to explore such vectors for enhanced benefit and we will advance in this avenue to offer better gene delivery tailored for various forms of inner ear defect.
Our project has three inter-related experimental objectives and uses a fully integrated experimental approach, including, molecular engineering virology, molecular genetics, cell biology, electron microscopy and auditory hair cell physiology. 1) We will identify AAVs with tropism for inner ear cells that are the primary targets for gene therapy. 2) In parallel we will use a high-throughput molecular engineering approach called directed evolution, to identify AAV variants with the most efficient delivery to inner ear tissues. 3) The AAV variant with the highest efficacy for a given target cell will be used to deliver the therapeutic genes in mouse models for human deafness and/or balance defects. This includes three mouse models, DFNB1 due to mutations in the connexin-26 (Cx26) gene, DFNB16, recessive forms of a progressive human deafness caused by mutation in stereocilin gene, and Usher syndrome of type IB (USH1B), characterized by profound congenital deafness and vestibular dysfunction, involving mutated forms of the actin-based motor protein myosin VIIa genes. For each treated mouse model investigated, we will evaluate the improvement of all features of the hearing and balance phenotypes brought by the therapeutic gene delivery. Of note, two patents « PCT/EP2016/053613” related to these data have been conjointly filed by the Pasteur Institute, INSERM and CNRS. The co-applicant also has a patent related to the AAV engineering approach we wish to implement (U.S. Patent No.: 14/701,063).
We foretell that other patents will be examined and filed for the protection of the new approaches that we plan to develop within the framework of the present proposal. We anticipate the results from the studies undertaken to have a decisive impact on the development of therapeutic approaches for AAV gene therapy for deafness and balance defect.
The overall goal of this project is to develop AAV gene therapies for inner ear defects that will ultimately be translated the affected patients.
Monsieur Saaid Safieddine (INSERM)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Inserm U1120 INSERM
IDV INSTITUT DE LA VISION
Help of the ANR 516,477 euros
Beginning and duration of the scientific project: - 48 Months