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From Screen to Trial: Evidence-Based Decisions for Drug-Induced Hearing Loss

April 2018 This headline is not about a blockbuster movie or a courtroom drama. Rather, it refers to the latest step in a scientific quest to identify a safe and effective compound to prevent drug-induced hearing loss. This form of acquired hearing loss affects many patients with life-threatening infections (e.g., tuberculosis, respiratory infections) and epithelial cancers. These conditions can be treated with life-saving aminoglycoside antibiotics and platinum-based drugs, yet these ototoxic drugs have debilitating consequences on auditory performance and vestibular function. The inner ear sensory cells embedded within the bony otic capsule are the primary target of these drugs, and once killed, these sensory cells are not spontaneously replaced in mammals and humans. Protecting these vital sensory cells from drug-induced cytotoxicity will provide enormous individual and socioeconomic benefits. Many candidate compounds to protect inner ear sensory cells from ototoxicity have been and are currently being tested. The recent work by Chowdhury, et al., is among the first to describe how a candidate otoprotective compound was rationally optimized to reach investigational new drug (IND) status by the U.S. Food and Drug Administration (FDA), thereby providing a direction for others to follow (J Med Chem. 2018 Jan 11;61(1):84). The senior authors previously described a (then) novel screening strategy using zebrafish lateral line neuromast hair cells to identify potential ototoxic compounds and genetic modifiers of ototoxicity (J Assoc Res Otolaryngol. 2008 Jun; 9(2):178; PLoS Genet. 2008 Feb 29;4(2):e1000020). The beauty of their unbiased approach resided in the ability to rapidly screen a large number of single-variable conditions for surviving larval neuromast hair cells that had taken up a fluorescent marker. Thus, the doseresponse curve for hair cell survival (the HC50) in numerous compounds could be determined within days, rather than over many months, with a relatively low degree of variability. These studies also identified two candidates that not only protected neuromast hair cells but also mammalian vestibular hair cells in vitro from aminoglycoside-induced cytotoxicity. One compound, PROTO1 (Fig. 1a), the basis of the work of Chowdhury and colleagues, was selected for optimization (J Med Chem. 2018). The recent work by Chowdhury, et al., is among the first to describe how a candidate otoprotective compound was rationally optimized to reach investigational new drug status.