SPI is a pioneer in neurotologic drug development aimed at treating sensorineural diseases of the inner ear.
Our expertise in molecular biology, immunohistochemistry and electrophysiology have lead to the development of preclinical models of hearing loss and tinnitus that are translating into novel and successful clinical trials.
Otoprotection studies in animals by a number of independent laboratories have validated that the inner ear can be protected from the irreversible effects of noise damage by the systemic administration of pharmacologic agents or drugs. SPI-1005, a proprietary oral formulation of ebselen, is a small molecule mimic and inducer of glutathione peroxidase (GPx). GPx is the dominant catalytic antioxidant enzyme in the cochlea and is critical for auditory function.
Endogenous GPx reduces reactive oxygen and nitrogen species by first binding them to selenocysteine then reducing the selenic acid intermediate through a reduction with glutathione (GSH). SPI-1005 mimics the catalytic activity of GPx1 by utilizing a bound selenonitryl moiety at its active site and cycling with GSH or other thiols. Therefore, ebselen functions catalytically, and is redox sensitive. This efficient mechanism of action allows SPI-1005 to work at low oral doses, unlike antioxidants such as n-acetylcysteine. During the in vivo metabolism of SPI-1005, the selenium moiety is retained and is not bioavailable.
In addition to functioning as a GPx mimic and inducer, ebselen has been shown to reduce cytochrome-C release from mitochondria and nuclear damage during lipid peroxidation, and is effective in preventing neuronal apoptosis and reducing tissue inflammation associated with traumatic injury.
Our NIHL results with SPI-1005 (Lynch et al., 2004, 2005, Kil et al., 2007) have been replicated and extended by independent researchers (Pourbahkt et al., 2003, Yamasoba et al., 2005, Park et al., 2005).
Download (PDF)Several classes of therapeutic agents including cancer chemotherapy drugs and aminoglycoside antibiotics can cause side effects in the inner ear (ototoxicity). In particular, the platinum containing chemotherapies (cisplatin, carboplatin) are widely used in cancer treatment, but their ototoxicity can dramatically decrease the quality of life following treatment. The incidence of cisplatin or carboplatin-induced hearing loss is as high as 39-62% in adults and as high as 84-100% in children.
Clinical symptoms of ototoxicity are associated with hearing loss, tinnitus, dizziness and difficulty understanding speech. Ototoxicity from aminoglycoside treatment in cystic fibrosis (CF) patients and non-tuberculosis mycobacterium (NTM) patients is as high as 25 to 50%. Hearing loss due to ototoxic medications usually presents initially at the higher frequencies and subsequently progresses to the lower frequencies. Impaired hearing as a result of ototoxicity can be temporary, but usually is permanent and may be progressive.
Our product candidate, SPI-3005, has been shown to protect against chemotherapy induced hearing loss and neurotoxicity in several animal studies (Park 2009, Lynch et al., 2005a, Rybak 2000). Significant chemoprotection was achieved without interfering with the tumor activity of the cisplatin in rat and mouse tumor models (Lynch et al., 2005b, Baldew 1992, Baldew 1990).
Download (PDF)For individuals with severe to profound hearing loss, SPI is developing drugs aimed to regenerate cells within the cochlea and restore hearing. SPI has proprietary compounds that inhibit the cyclin dependent kinase inhibitor 1B (p27Kip1). Inhibition of p27Kip1 induces adult cells within the inner ear to become more stem-like.
For example, in the cochlea of deafened animals, supporting cells can be coaxed to re-enter the cell cycle, proliferate, and regenerate both a supporting cell and a sensory hair cell. This novel technology could be used to repopulate many different types of non-regenerating tissues and organs.
In mice deficient in p27Kip1, terminally differentiated cells within the organ of Corti are now capable of cellular regeneration (Kil 2011). Importantly, these newly dividing cells have the capacity to become replacement auditory hair cells, supporting cells, and neurons in adulthood (Osterle et al 2011).
Conditional p27 knock out mice are capable of hair cell regeneration in both the postnatal and adult period. These mice exhibit normal hearing as measured by evoked auditory brainstem responses, which indicates their appropriate connection to the brain (Walters et al 2014).
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