Therapeutics to prevent aminoglycoside-induced hearing loss

Project Summary Ting Therapeutics LLC is a pharmaceutical company developing drugs to prevent and treat hearing loss. Aminoglycosides are one of the most widely used drugs to treat Gram-negative bacterial infections. However, aminoglycoside therapy causes hearing loss in 40-60% of the patients. To date, no drugs have been approved by the Food and Drug Administration for protection from aminoglycoside-induced hearing loss (AGIHL). Most candidate compounds currently in pre-clinical and clinical trials are related to antioxidants, vitamins, and glutathione metabolism, such as ebselen or N-acetylcysteine. We have performed high throughput screens for otoprotectants against AGIHL in zebrafish and identified TT003, known as piperlongumine, a natural product extracted from the pepper Piper Longum. TT003 attenuates hearing loss in adult mice treated with kanamycin (700 mg/kg twice a day for 14 days) when delivered intraperitoneally (IP) at 40 mg/kg/day for 17 consecutive days. Interestingly, TT003 seems to be protective against excitotoxicity in a zebrafish model that mimics glutamate overexposure. In this SBIR Phase II, we will perform Investigational New Drug-enabling experiments to test TT003’s effect on aminoglycoside’s bacteria killing efficacy in vivo and to conduct efficacy studies to define an optimal dosing regimen and therapeutic index in an animal model that mimic the pathophysiological environment of patients with Gram-negative bacterial infections. The long-term goal is for TT003 to become a standard otoprotective drug of aminoglycoside-based therapies. For this purpose, we will identify TT003’s no- observed adverse effect level and demonstrate TT003’s efficacy in a mouse model of inflammation that mimics the physiological environment of cystic fibrosis patients (Aim 1). We will determine pharmacokinetics and pharmacodynamics profiles in blood and perilymph, as well as efficacy, in a guinea pig model for aminoglycoside- induced hearing loss (Aim 2). This Aim will be performed under contract with an independent and reputable Contract Research Organization, Turner Scientific LLC. Finally, we will test drug-drug interactions in vivo to verify that TT003 does not interfere with aminoglycoside’s anti-bacterial activity in mouse model for acute Pseudomonas aeruginosa infections (Aim 3). By successfully completing these studies, Ting Therapeutics will obtain critical data necessary for the initiation of Investigational New Drug enabling complaint preclinical studies and subsequent clinical trials. Ting Therapeutics has filed a Patent Cooperation Treaty (PCT) for both the US and international rights. The completion of this proposal will allow Ting Therapeutics to initiate conversations with pharmaceutical companies and venture investments for the commercialization of TT003.