Prolonged Delivery of Bone Binding BDNF Analogue Ris-DHF Supports Partial Hearing Recovery after Noise Damage

By June 7, 2019

Kempfle, J.S.1,2; Hamadani, C.1; Amador, C.3; Kashemirov, B.3; Zhang, A.1; McKenna, C.3; Jung, D.H.1
1 Department of Otology and Laryngology, Harvard Medical School; Eaton-Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston, USA;
2 Universitätsklinik für Hals- Nasen- Ohren- Heilkunde Tübingen, Tübingen Hearing Research Center, Germany;
3 Department of Chemistry, University of Southern California, Los Angeles, USA.

Recent work has identified primary synaptopathy as “hidden” cause for sensorineural hearing loss: Noise exposure results in SGN neurite retraction and loss of ribbon synapses between intact HCs and SGNs, while cell bodies of SGNs and HCs persist. Regeneration approaches with exogenous neurotrophins, such as brain-derived neurotrophic factor (BDNF)  have been successful in promoting neurite outgrowth and re-forming of ribbon synapses to reverse synaptopathy and improve hearing. We have previously developed a small hybrid molecule approach by linking the bone affine bisphosphonate Risedronate (Ris) to DHF, a small BDNF analogue. In an in vitro model of cochlear synaptopathy, we demonstrated that Ris-DHF led to prolonged local delivery to SGNs which resulted in improved neurite outgrowth and cochlear synaptogenesis.

We now used our well-established in vivo mouse model of primary synaptopathy, and treated animals 24 hours after noise exposure with Ris, DHF, Ris-DHF, or artificial perilymph via round window application. Four weeks after surgery, ABRs were measured again, and immunohistochemistry of the organ of Corti was used to correlate functional responses.

Damage was most noticeable in the 32 kHz range. Application of Ris-DHF resulted in partial recovery of suprathreshold wave 1 in the ABR at 32 kHz 4 weeks after noise damage, which was confirmed by increased synaptogenesis in whole mount preparations.

We now show for the first time that small hybrid molecule Ris-DHF maintains longterm neurotrophic activity in vivo, when bound to cochlear bone, and leads to increased synaptogenesis and partial functional recovery of hearing after noise damage.