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 30% 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 (about 15,000 per cochlea) and these have to last a lifetime.
The very low number of auditory hair cells present in the cochlea
is one of the major reasons hearing loss is so common. Once the
cells in a particular area of the cochlea are lost, hearing at that
frequency is also lost. There is little in the way of compensatory
hearing offered by neighboring hair cells as they are tuned to respond
to a particular frequency. It is the irreversible injury or loss
of auditory hair cells, supporting cells, and neurons 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:
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 book chapter, co-authored by Dr. Kil.
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 is focused on the development
of drugs to prevent hearing loss and restore hearing in our three
product pipelines: Otoprotection, Chemoprotection, and Regeneration.
Otoprotection studies in animals by a number of established academic
labs 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 hearing health. GPx reduces reactive
oxygen species (ROS) by the binding of free radicals to its Selenium
moiety. By reacting with glutathione, GPx limits free radical toxicity,
exhibiting strong activity against peroxynitrite (ONOO-). In addition,
ebselen has been shown to reduce cytochrome-C release from mitochondria
and nuclear damage during lipid peroxidation, attenuating neuronal
apoptosis associated with oxidative stress.
Our published 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., 2006).
SPI-1005 has been evaluated in Phase I studies and found to have
a favorable toxicity and pharmacokinetic profile. SPI-1005 is in
Ph-II clinical trials at
the University of Florida.
Several classes of therapeutic agents including cancer chemotherapy
drugs and aminoglycoside antibiotics can cause oxidative stress
in the inner ear resulting in irreversible cell death. In particular,
the platinum containing chemotherapies (cisplatin, carboplatin)
are well noted and studied for their ototoxicity.
Hearing loss due to ototoxic medications is sensorineural and usually
presents initially at the high frequencies and subsequently progresses
to the lower frequencies. Impaired hearing as a result of ototoxicity
can be temporary, but usually is permanent. The incidence of cisplatin
or carboplatin-induced hearing loss ranges up to 62% in early clinical
reports and as high as 84-100% in pediatric patients. Clinical symptoms
of ototoxicity are associated with hearing loss, tinnitus, and difficulty
Our lead product candidate, SPI-3005, ebselen has been shown to
protect against chemotherapy induced hearing loss and neurotoxicity
in several animal studies (Lynch et al., 2005a). Significant chemoprotection
was achieved without interfering with the tumor activity of the
cisplatin in rat and mouse tumor models (Lynch et al., 2005b). Sound
Pharmaceuticals has recently received FDA notification of allowance
to proceed with Phase II clinical testing of a proprietary oral
formulation of ebselen, in cancer patients receiving cisplatin or
carboplatin as part of their chemotherapy. SPI expects to develop
its proprietary formulations into oral and injectable drugs to protect
against drug induced hearing loss.
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, supporting cells, and neurons.
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, the other by Dr. Neil Segil at the
House Ear Institute in Los Angeles, CA.
disruption of p27Kip1 allows cell proliferation in the postnatal
and adult organ of Corti
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).
The Cyclin Dependent Kinase
Inhibitor p27Kip1 Maintains Terminal Differentiation in the Mouse
Organ of Corti
Hair cell regeneration in
the organ of Corti of p27 -/- and +/- mice.
Viewed as a whole mount (a) or cross section (b)
shows Outer Hair Cells and Inner Hair Cells and the intervening
tunnel of Corti (*). (c, e, g)
Proliferating cells were identified using antibody detection of
the DNA proliferation marker Bromo-deoxyUridine (BrdU). (c)
p27-/- has BrdU+ cells, while (e) p27+/- and (g)
p27+/+ show no proliferation. (d, f,
h) Treated with amikacin an aminoglycoside antibiotic
that kills hair cells and then stained for the presence of BrdU.
(d) p27-/- has multiple BrdU+ cells including three
BrdU+ Dieter’s cells (arrow heads) and one BrdU+ Inner Hair
Cell (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+ Outer Hair
Cells (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).
SPI has developed and is now optimizing RNAi based antagonists of
p27 in a proprietary formulation that is capable of inducing hair
cell regeneration within the damaged mammalian cochlea. Our current
focus is to continue to optimize the delivery and proliferative
effect of formulated p27 RNAi.