Novel Small-Molecule TrkB and TrkC Agonists for Cochlear Synaptic Regeneration
Abstract
It is estimated that more than 30 million Americans over the age of 12 years have hearing loss in both ears and an estimated 48 million have hearing loss in at least one ear. Hearing loss is commonly associated with difficulty hearing in noise, and noise exposure exacerbates these symptoms. Strikingly, the two most prevalent military Service-connected disabilities are related to hearing. In this regard, the most recent data from the Veterans Benefits Administration, Department of Veterans Affairs, indicate that there are 1.1 million Veterans with service-connected disability due to hearing loss. Irrespective of military service, presbycusis, or age-related hearing loss, affects nearly two-thirds of adults 70 years of age and older and has been classically associated with degeneration of cochlear cells, including hair cells (HCs) and spiral ganglion neurons (SGNs). Emerging evidence suggests that the synaptic connections between HCs and SGNs are the most sensitive element to noise damage and aging in the cochlea. Low spontaneous rate, high-threshold fibers appear to be more sensitive to noise damage than high spontaneous rate, low-threshold fibers. The hearing loss resulting from the loss of cochlear synapses has therefore been referred to as hidden as threshold measures are relatively insensitive in its detection. In the context of human hearing loss, these findings may imply that hearing thresholds remain relatively unchanged following synaptic loss but that other symptoms, including difficulty hearing in noise, are manifested. The cell bodies of HCs and SGNs persist long after synaptic degradation, for months in mice and possibly decades in humans. Regeneration of synapses between HCs and SGNs might therefore represent a paradigm shift in the treatment of these difficult symptoms. Medical devices are available to help patients cope with more severe forms of hearing loss, including hearing aids and, in profound cases, cochlear implants. However, treatments for difficulty hearing in noise in the large number of patients who are not candidates for hearing aids or cochlear implants do not currently exist and represent a tremendous unmet medical need. The goal of this proposal is therefore to define a small molecule approach to regenerate cochlear afferent synapses and thereby create a novel method to improve hearing in these patients, for whom no satisfactory therapy currently exists. Neurotrophins, including brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3), are expressed by cochlear HCs and supporting cells and act via their respective tropomyosin receptor kinase receptors (Trks), TrkB and TrkC, on the surface of SGNs. DHF and 1Aa are small molecule agonists of TrkB and TrkC, respectively. Our approach is to improve delivery of DHF and 1Aa through conjugation with bisphosphonates (BPs), which bind strongly to cochlear bone. We have shown that a hybrid BP-DHF derivative can increase pre- and post-synaptic marker juxtaposition in vitro and improve suprathreshold Wave 1 amplitudes in vivo following noise damage. As steps toward our goal of generating a novel treatment for cochlear synaptopathy, we propose the following experiments. First, we will chemically synthesize the BP-DHF, 1Aa, and BP-1Aa and compare their individual and any synergistic activity to regenerate cochlear synapses both in vitro and in vivo. Next, we will determine the most effective treatment using our mouse model of noise damage and synaptic regeneration, specifically defining the ability of our small BP-linked molecule drugs to regenerate cochlear synapses in the context of both noise-exposed and aged, non-noise-exposed mice. Finally, we will confirm these findings in a non-human primate model of cochlear synapse loss following noise damage. Demonstration of efficacy in a non-human primate model will provide strong evidence for the translational potential of our approach, as a key milestone before advancing to further evaluation
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910188
Entities
People
- David Jung
Organizations
- Massachusetts Eye and Ear Infirmary
- United States Army