Discovery of TrkC agonist antibodies for hearing loss

! Project Summary AbstractSensori neural hearing lossSNHLis caused by several factorsincluding excessive noisedrug toxin exposure and genetic lesionsTaken togetherhearing deficits represent the number one neurological disorder worldwideDespite numerous past and ongoing clinical studies there is currently no effective therapeutic treatment for hearing loss and its associated decline in quality of lifeAt the cellular level hearing loss involves damage or loss of sensory hair cells and or the afferent nerve fibers from the associated spiral ganglion neuronsSGNsIn many casesthe SGN cell bodies also degenerate over time and result in the inability to relay auditory signals to the brainThusthere is a need to develop safe and reliable pharmaceuticalsalong with reliable drug delivery technologies to prevent and restore inner ear functionNumerous studies over the past three decades have revealed that two members of the neurotrophin family of growth factor proteinsneurotrophinNTand brain derived neurotrophic factorBDNFare among the most critical trophic signals for development and maintenance of the SGNsThe weight of current experimental evidenceincluding animal efficacy studiessuggests that exogenous delivery of NTto the adult cochlea is a promising therapeutic avenue to mitigate or even reverse hearing lossFrom extensive pre clinical and clinical experience exploring the biology and therapeutic potential of the neurotrophinsit has been concluded thatfor largely biophysical reasonsthe NTproteina smallhighly basic moleculeis in itself a poor therapeutic entityTo circumvent limitations of neurotrophin proteinsZebra Biologicsin collaboration with the Scripps Research Institutehas developed proprietary technology to generate agonisti eactivatingantibodies to several classes of cell surface receptors using function based cellular assays that allow screening of very largecombinatorial antibody librariesZebra has now generated pools of candidate agonist antibodies to the NTreceptorTrkCZebra thus has the technical ability and experience to generate and bring into the clinic Trk agonist antibody therapies for neurodegenerative conditionsincluding hearing lossThe overall goal of this program is to identifyoptimizedeliver and develop TrkC agonist antibodies into effective pharmaceuticals to treat hearing losssubserving a critical unmet medical needWe propose submitting a PhaseSTTR grant application addressing the following SAsSASelectCharacterize and Optimize Fully Human TrkC Agonist AntibodiesTest agonist antibodies for intrinsic potenciesECmaximal responsesEmaxin the TrkC reporter cell line and compare to NTDetermine the canonical signaling properties of selected agonists SASelect Agonist Antibodies That Activate TrkC in Mouse NeuronsDetermine ECEmax and signaling properties of antibodiesselected in SAon cultured mouse SGNs !Narrative Sensori neural hearing lossSNHLis caused by several factorsincluding excessive noisedrug toxin exposure and genetic lesionscollectivelyhearing deficits represent the number one neurological disorder worldwide and represent a critical unmet medical needZebra Biologics has harnessed its innovative cell based agonist antibody discovery technology to generate agonists to the NTreceptorTrkCin order to restore and regenerate spiral ganglion neurons involved in auditory functionThe ultimate goal of this research program is to test TrkC agonist antibodies for efficacy in rodent models of hearing loss and to establish a rationale for eventual clinical trials of TrkC agonist antibodies for the treatment of SNHL