Background
Hearing loss is the third leading chronic disorder and exceeds the number of persons with either diabetes or visual loss combined. Unfortunately, the existing strategies for hearing loss reduction are inadequate. In the U.S., the incidence of hearing loss is increasing and affects over 10-15% of the general population. The onset begins in children and young adults and can be induced by loud sounds, drugs, or infections. In addition, hearing loss is often progressive leading to greater disability year after year. We are born with a relatively small number of auditory hair cells and once lost, they are never replaced. It is the irreversible injury or loss of auditory hair cells that cause the majority of hearing loss.

The following table indicates maximal Sound Pressure Levels (SPLs), durations and sources of sound before the inner ear is at risk of permanent hearing loss:

SPL	Duration	Source	Industry
140 dB	< 1 min	firearms, jet planes	military
130 dB	> 1 min	jackhammers	construction/mining
120 dB	> 5 min	amplified car stereo	recreational
110 db	> 15 min	rock concerts, planes	musicians
100 dB	> 1 hr	woodshops, chainsaws	logging
90 dB	> 4 hr	motorcycles, lawnmowers	recreational
85 dB	> 8 hr	interior plane cabins	aviation

Biology of hair cell death
Irreversible hair cell death is elicited by metabolic or biochemical changes in the hair cells that involve reactive oxygen species or ROS. This process is illustrated in the following figure which appeared in a recent book chapter, co-authored by Dr. Kil and Dr. R.D. Kopke, Director of the Naval Medical Center San Diego’s Spatial Orientation Center.

Noise and drug-induced hair cell injury and death. A. Shows the formation of damaging ROS such superoxide (O2- ) and hydroxyl anion (OH-). B. Shows some of the internal antioxidant mechanisms that hair cells employ to control ROS induced damage including reduced glutathione and antioxidant enzymes. C. ROS can irreversibly damage cell membranes, mitochondria, nuclear DNA and proteins and signal the cell to die through apoptosis.

SPI will focus on the development of three pre-clinical product pipelines that have lead candidate products in pre-clinical testing using live animal models.

Otoprotection
Otoprotection studies in animals indicates that the inner ear can be protected from the irreversible effects of noise damage by the systemic administration of pharmacologic agents or drugs. We have already demonstrated efficacy in live animal models of hearing loss. In addition, two of our current drug leads are already approved for human use in other diseases and are considered to be well tolerated or exhibit adequate safety.

SPI expects to develop its patented formulations into oral drugs that will prevent noise and age induced hearing loss.

Chemoprotection
Chemoprotection from platinum based anti-tumor agents such as cisplatin will be our first goal. Unlike "rescue" agents (e.g. growth factors) that are administered after chemotherapy toxicities have occurred, chemoprotectants are given prior to or concurrent with chemotherapy. Chemoprotectants have the added potential benefit of preventing irreversible side effects such as hearing loss. SPI expects to develop its proprietary formulations (patents pending) into oral and injectable drugs to protect against drug induced hearing loss.

Regeneration
For those patients who already have substantial hearing loss, SPI is developing drugs aimed to restore hearing. SPI is currently optimizing compounds that antagonize specific cell cycle proteins resulting in new cell division or proliferation. In mice deficient in p27Kip1, a growth inhibitory protein, normally non-dividing epithelial cells within the inner ear are now able to divide. More importantly, these newly dividing cells have the capacity to become replacement auditory hair cells.

National Institute's Director of Deafness and other Communication Disorders commends our novel efforts in sensorineural regeneration to the US Congress...
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Validation of p27Kip1 as a target for inducing supporting cell proliferation and hair cell regeneration in the organ of Corti was further substantiated by two independent research teams. One lead by Dr. Kil while at the University of Washington and Otogene, the other by Dr. Neil Segil at the House Ear Institute in Los Angeles, CA.

Hair cell regeneration in the organ of Corti of p27 -/- and +/- mice. Viewed as a whole mount (A) or cross section (B) shows OHCs and IHCs and the intervening tunnel of Corti (*). (C, E, G) Proliferating cells were identified using BrdU immunoperoxidase. (C) p27-/- has BrdU+ cells, while (E) p27+/- and (G) p27+/+ show absolutely no proliferation. (D, F, H) Treated with amikacin an aminoglycoside antibiotic that kills hair cells and then stained with BrdU immunoperoxidase. (D) p27-/- has multiple BrdU+ cells including three BrdU+ Dieter’s cells (arrow heads) and one BrdU+ IHC (arrow). (F) p27+/- has BrdU+ cells after amikacin treatment indicating that ototoxic drugs induce cell proliferation and regeneration when p27 is decreased. Note two BrdU+ OHCs (arrows) and a single BrdU-positive supporting cell (arrowhead). (H) p27+/+ is completely devoid of BrdU+ cells following amikacin treatment. Note two dead OHCs (arrows) and three BrdU- supporting cells (arrowheads).

See the paper describing the cochlear phenotype in the p27 knockout as published in the Proceedings of the National Academy of Sciences:

Gene disruption of p27Kip1 allows cell proliferation in the postnatal and adult organ of Corti