Periodic Reporting for period 1 - MY-O-SENSES (Pre-clinical development of a lentiviral gene therapy to treat hearing and balance loss in Usher 1B patients)
Período documentado: 2022-09-01 hasta 2024-02-29
The most prevalent genetic sensory defect, sensorineural hearing loss (SNHL), affects 360 million people and results in substantial financial and social consequences. Current treatment options are limited, achieving only temporary or partial relief and are restricted to a sub-group of patients. Therefore, novel treatment options are of high clinical need. Genetic mutations play a role in the majority of SNHL cases, which makes SNHL an ideal setting for innovative clinical gene therapy approaches.
Usher syndrome type 1B (USH1B) is an especially severe form of SNHL, with loss of vision and balance accompanying the profound deafness. The size of some genes, mutations of which are causative for USH1B, exceeds the cargo capacity of gene therapy vectors currently employed to treat inner ear disorders. In my ERC-funded consolidator project "iHEAR", we have provided the first ground-breaking evidence of efficient gene transfer into inner ear cell types using lentiviral vectors (LV). As these LV have the capacity to deliver large genetic payloads, we acquired initial data demonstrating functional improvement of balance and hearing defects in a knock-out mouse model following LV application. This MY(O)SENSES PoC proposal aimed to advance these valuable research results towards clinical application by completing pre-clinical development and securing the exploratory pathway to form the basis for a later first-in-human clinical LV gene therapy trial to treat USH1B patients. The results obtained in this PoC grant will, moreover, help to extend this concept to treat inherited and acquired hearing loss in patients. In particular, the The MY(O)SENSES gene therapy approach will be the first and only treatment to address debilitating vertigo and hearing loss, thus, addressing 2 major senses. This will have major impact with the potential to drastically improve patients’ life and benefit society.
Usher syndrome type 1B (USH1B) is an especially severe form of SNHL, with loss of vision and balance accompanying the profound deafness. The size of some genes, mutations of which are causative for USH1B, exceeds the cargo capacity of gene therapy vectors currently employed to treat inner ear disorders. In my ERC-funded consolidator project "iHEAR", we have provided the first ground-breaking evidence of efficient gene transfer into inner ear cell types using lentiviral vectors (LV). As these LV have the capacity to deliver large genetic payloads, we acquired initial data demonstrating functional improvement of balance and hearing defects in a knock-out mouse model following LV application. This MY(O)SENSES PoC proposal aimed to advance these valuable research results towards clinical application by completing pre-clinical development and securing the exploratory pathway to form the basis for a later first-in-human clinical LV gene therapy trial to treat USH1B patients. The results obtained in this PoC grant will, moreover, help to extend this concept to treat inherited and acquired hearing loss in patients. In particular, the The MY(O)SENSES gene therapy approach will be the first and only treatment to address debilitating vertigo and hearing loss, thus, addressing 2 major senses. This will have major impact with the potential to drastically improve patients’ life and benefit society.
A clinical vector has been created to express our cDNA of interest and vector titer and expression were found to be suitable to continue clinical translation exploration. Moreover, we have created a plasmid backbone (with Kanamycin resistance gene) that is applicable for later clinical translation and included modules that are compatible with clinical implementation and regulatory needs. We are in regular contact with different patient organizations to incorporate their needs and desires as well as getting an idea about the willingness to use such therapies (e.g. Usher Coalition and Save Sight Now). We have generated PoC data in a suitable mouse model for Usher syndrome (see publication in Molecular Therapy) that such a therapy can be efficacious and safe to treat hearing loss and balance disorders due to Myo7a mutations. No major technical difficulties were observed. Different vector doses were tested and could be delivered in vitro and in vivo. Importantly, no treatment-related structural damages were observed upon application of the therapy to the inner ear. Further plans for the later development and exploitation of this highly promising strategy were advanced and potential partners identified. In addition, we have reached out to our clinical cooperation partners to plan major steps for clinical implementation and clinical study design.
The Paul-Ehrlich-Institute (PEI) as Germany's regulatory authority for ATMPs was contacted for scientific advice and a respective meeting was arranged in the future.
The Paul-Ehrlich-Institute (PEI) as Germany's regulatory authority for ATMPs was contacted for scientific advice and a respective meeting was arranged in the future.
This strategy could be potentially curative for hearing loss and balance disorders in Usher patients and addresses an urgent medical need. This is the first demonstration of efficient gene therapy delivery to the inner ear via safety-improved lentiviral vectors. Patents were filed to secure IPR and freedom-to-operate and the overall lentiviral concept was adapted to acquired hearing loss, e.g. caused by ototoxic medications. We have included international partners to broaden the impact of this groundbreaking approach and have approached the regulatory agency for scientific advice and regulatory guidance. In addition, we have made contact with EU and North American investigators and patient groups. Also, we have identified a CDMO for clinical vector production and secured funds to cover the costs of vector production and accompanying preclinical research. Further preclinical work and funding acquisition will be needed to initiate and run a clinical trial to treat patients in need.
In summary, this project has generated PoC for the use of lentiviral vectors for hearing loss and balance disorders.
In summary, this project has generated PoC for the use of lentiviral vectors for hearing loss and balance disorders.