eiF2B Activators to Treat Noise-Induced Hearing Loss - Abstract
The overall goal of Jacaranda Biosciences, Inc. (JBI) is to develop compounds that will treat a broad
range of hearing loss indications, a sorely unmet need. In this initial SBIR project, we will use our
expertise in medicinal chemistry, cell biology and hearing physiology to functionally test and
chemically optimize a series of novel compounds that modulate the unfolded protein response (UPR).
These compounds, made and IP protected by JBI, will be used to demonstrate initial efficacy to
prevent noise-induced hearing loss in our mouse model.
Noise-induced hearing loss (NIHL) is a profound public health problem, affecting over 40 million
Americans and causing the loss of 4 million disability-adjusted life years worldwide from occupational
exposure annually. HL is also a significant risk factor for dementia, underscoring the expanded
morbidity of this disorder. 27% of NIHL is from acute sound exposure, whereas 23% occurs from sub-
acute or chronic exposure to sound, suggesting that interventions that target the mechanisms that
underlie acute or sub-acute HL can make an immediate and transformative clinical impact for this
large and inadequately treated patient population.
Through our novel work in genetic and noise-induced animal models of hearing loss, we have
discovered that homeostatic regulation of the UPR in the endoplasmic reticulum (ER) of cochlear hair
cells is essential to prevent dysregulated over-activation of the UPR and subsequent hair cell death
and hearing loss. Moreover, we have shown in published data that regulating the UPR through
treatment with publicly available eiF2B activators and CHOP inhibitors (UPR pathway proteins) can
prevent hair cell death and hearing loss in both noise-induced and genetic HL models. To take
advantage of these insights, we will develop and optimize a proprietary series of novel eiF2B
activators for eventual treatment in a large patient population. Our Aims are to (1) optimize the
efficacy and physicochemical properties of our IP-protected, novel compounds; (2) Test whether the
optimized compounds can lessen apoptosis and UPR over-activation in our cell-based models; and
(3) determine whether these compounds prevent hearing loss and cochlear injury in our established
animal model of acoustic overstimulation.
