Download Emerging Treatments for Noise-Induced Hearing Loss

Valencia, June 2016
Emerging Treatments for Noise-Induced
Hearing Loss
and Ototoxicity
Jochen Schacht, Ph.D.
Professor of Biological Chemistry
Department of Otolaryngology
Director Emeritus
Kresge Hearing Research Institute
University of Michigan Medical School
Let’s chat about:
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A few statistics
Treatment of noise-induced hearing loss
Pathology of acquired hearing loss
Potential mechanisms of hair cell loss
Protection in animal models
Protection in you and me
A changed scenario: Hidden hearing loss
Outlook
Hearing Disorders
15% of the population have trouble hearing.
A disabling hearing loss affects
2% of adults aged 45 to 50 y; 8% of 55 to 64 y;
25% of 65 to 74 y; 50% of people >75 years old.
Noise-induced hearing loss
• 3-5% of the population in most countries have a
noise-induced hearing loss.
• ~15% of Americans (20 to 69 years old) have high-frequency
hearing loss due to exposure to noise.
Source: https://www.nidcd.nih.gov/health/statistics/quick-statistics-hearing
An Age-old Problem
Dusty and dim are the eyes
of the miller,
Deaf are his ears with the moil
of the mill.
Robert Louis Stevenson (1850 – 1894)
A Child's Garden of Verses
Then and now, the most common occupational disease:
Millers and blacksmiths; boilermakers, industrial workers,
miners; then modern warfare:
Not Just an Old Problem
“ … a great thunderous noise,
large bells and artillery, and thus
one often sees gunners losing
their hearing because of the
great agitation of the air inside
the ear ...”
Ambroise Paré, 1510 - 1590
January 2010:
Hearing loss is the no. 1 diagnosis
for U.S. soldiers in combat
- and now we are even having fun ruining our ears ….
Treatment of Noise-Induced Hearing Loss
Today’s 20-year olds:
The Hearing-Loss
Generation
Human
Pathology
“…findet sich and der Stelle,
wo die Haarzellen und die
Deiters’schen Zellen liegen
sollen, eine Lücke”
“…. Schwund des
Nervenendapparates , der
Nervenfasern .. .. und
Verminderung der Ganglienzellen . ”
Water faucet
Hammer
Experimental
Pathology
H. Hössli, Z. Ohrenheilk. 1912
Steel drum
After impulse noise
Pathology of Acquired Hearing Loss
is remarkably similar between noise trauma,
ototoxicity, and age.
Permanent Loss of Hair Cells
Nerve Degeneration
Johnson and Hawkins, Ann Otol Rhinol Laryngol, 1972
Proposed Mechanisms of Auditory Trauma
1. Oxidative Stress (Oxidant Stress)
[reactive oxygen species, ROS; RNS;
motley free radicals]
2. Upregulation of homeostatic pathways
3. Expression of cell death pathways
For reviews, see
• Oishi, N. and Schacht, J. Emerging treatments for noise-induced hearing loss. Expert
Opin. Emerg. Drugs 16:235-245, 2011
• Böttger, E.C. and Schacht, J. The mitochondrion: A perpetrator of acquired hearing
loss. Hear. Res. 303:12-19, 2013.
• Yang, C.-H., Schrepfer, T. and Schacht, J. Age-related hearing impairment and the
triad of acquired hearing loss. Front. Cell. Neurosci. 9:276, 2015.
After Nemoto and Finkel, Nature 2004
Oxidant Stress
Noxious stimuli
- a necessary evil
Reactive Oxygen Species (ROS) are
products and byproducts of normal
metabolism and serve physiologically
important functions (e.g., NO)
NOS, Oxidases
ROS
Highly reactive:
May cause cell damage/death
Life is a balancing act
Cell death
Reactive Oxygen Species vs. Cellular Antioxidants
OXIDATIVE [REDOX] BALANCE
Signaling Pathways
CELL SURVIVAL
CELL DEATH
Noise/Drugs
Reactive Oxygen Species vs. Cellular Antioxidants
OXIDATIVE IMBALANCE
Redox-sensitive Signaling Pathways
CELL SURVIVAL
CELL DEATH
Oxidant Stress
Increases in the
Cochlea
after noise trauma
Control
Noise
4-HNE
Staining for lipid peroxidation products (4-HNE, one of the “fingerprints” of
oxidative stress) increases following noise overexposure.
Oxidant Stress
Increases in the
Cochlea
after drug treatment
Kanamycin
4-HNE (lipid peroxidation product) + Nuclei
CBA/J mouse, 700 mg kanamycin bid x 7 d
Noise/Drugs
Antioxidant supplementation
Reactive Oxygen Species vs. Cellular Antioxidants
OXIDATIVE BALANCE
Signaling Pathways
CELL SURVIVAL
CELL DEATH
Antioxidant Therapy
is [potentially] easy to administer:
Endogenous antioxidants
Natural preparations
Glutathione, vitamin E
Broccoli, Green tea
Antioxidants Protect
against drug-induced
hair cell death
Control
Gentamicin-induced damage
Surface preparation of the
cochlea after in-vivo treatment,
stained for actin
Gentamicin + Antioxidant
Threshold Shift [dB]
Antioxidants Protect Auditory Function
hydroxybenzoate
2,3-dihydroxybenzoate
Saline
Gentamicin
Gm
+ DFO
Gm
+ DHB
Permanent ABR threshold shifts after in-vivo treatment
Gm
+SA
FAQ #1
Oxidative damage and hair cell loss can be attenuated
in animals.
Can we translate inner ear protection
from animals to human?
Aminoglycoside-induced hearing loss can
serve as an example:
Aminoglycosides Today
Broad-spectrum, bactericidal &
non-allergenic antibiotics
• The most commonly used antibiotics world-wide
• 10% of all hospital admissions in the USA
• 10-50% incidence of hearing loss
in short-term treatment
• Up to 100% incidence of hearing loss
in tuberculosis
• Vestibulotoxicity - Nephrotoxicity
Aminoglycosides Today
Therapy of genetic disorders
~ 20% of genetic diseases (~1,800) are caused by premature RNA stop
codons leading to the synthesis of truncated and dysfunctional
proteins.
Present in 7-10% of patient populations with Duchenne muscular
dystrophy, cystic fibrosis, Rett syndrome, Usher syndrome, Hurler
syndrome, PKU, more.
Aminoglycosides can help override these stop codons and allow for the
synthesis of functional proteins, mitigating the effect of the disease.
Translational Success: Protection
75% reduction of the incidence of gentamicin-induced
hearing loss* after a 7- to 10-day clinical course
Gm + Placebo
Gm + Aspirin
14 / 106 patients
3 / 89 patients
13%
p = 0.013
3%
* >15 dB threshold increase at both 6 & 8 kHz
Double-blind, randomized, placebo-controlled
Sha, Qiu & Schacht. New England J. Med. 354:1856-1857, 2006
Antioxidants Also Protect Against
Noise Trauma
Threshold Shift (dB)
100
16 kHz
80
60
40
20
C
MK-801 (-)MK L-NAME NAC
MK+NAC
Permanent ABR threshold shifts 14 days after noise exposure
PD
Your Local Pharmacy to the Rescue
A variety of antioxidants and related compounds will
attenuate the effects of noise in animal models:
• N-acetyl cysteine, glutathione, d-methionine, ebselen,
resveratrol, coenzyme Q, ferulic acid, ascorbic acid.
Other agents have also been (more or less) successfully
tested in animals:
• A1 adenosine receptor antagonists, Ca-channel blockers, NMDA
receptor antagonists, inhibitors of apoptotic signaling.
The list is not exhaustive. A compilation of 28 drugs already tested by the year 2005 can be
found at Lynch ED, Kil J. Drug Discov Today 10:1291-1298, 2005.
FAQ #2
• Preventive therapies against noise-induced hearing
loss are successful in animal models but ...
• Prospective treatment is not always possible in
real-life situations
Can we rescue the ear after traumatic exposure?
Hair Cell Loss Spreads Post-Exposure
% Missing Hair Cells
Immediately after
Day 7 post
Day 1 post
Day 10 post
Day 3 post
Day 14 post
Distance from cochlear apex (mm)
Post-trauma Treatment Has Limits
4 kHz
Antioxidant cocktail
Control
Vehicle
Noise
-3
0
+1
+3
+5 days
Begin of treatment re: noise exposure
Therapeutic Intervention:
The Good News
Effective agents have been identified in animal
studies.
A “window of rescue” appears to exist.
A clinical trial on drug-induced hearing loss proves
the feasibility of antioxidant intervention in acquired
hearing loss.
Therapeutic Intervention:
Open Questions
• Experimental conditions often vary between studies
and real life: continuous vs. impulse noise.
• Type and severity of insult might determine the
mechanisms and progression of hearing loss.
• The ‘window of rescue’ might be variable.
• Species and strain differences might be confounding.
• Genetic factors contribute to noise sensitivity and
possibly to “rescue missions”.
Not all ears are created
equal
Humans are not inbred animals
Painting by
Andrea Montegna, 1497
Genetics Determines Susceptibility to Noise
Genetic variant (identified polymorphisms)
1. Glutathione S-transferase (M1, T1, P1)
2. Superoxide dismutase (IVS3-23T/G )
3. Superoxide dismutase (V16A)
4. Heat shock proteins
5. PCDH15 and MYH14
Genetic or physiological variant
6. Vitamin B12 deficiency
1. Lin CY, Wu JL, Shih TS, et al. Hear Res 2009;257:8-15
2. Chang NC, Ho CK, Wu MT, et al. Am J Otolaryngol 2009;30:396-400
3. Liu YM, Li XD, Guo X, et al. Dis Markers 2010;28:137-47
4. Chang NC, Ho CK, Lin HY, et al. Audiol Neurootol. 2010;16:168-74
5. Konings A, Van Laer L, Wiktorek-Smagur A, et al. Ann Hum Genet 2009;73:215-24
6. Shemesh Z, Attias J, Ornan M, et al. Am J Otolaryngol 1993;14:94-9.
Tests in Military or Industrial Settings
TTS models:
1. Magnesium: 20 subjects. Higher serum Mg in experimental group
correlated with some protection (r = 0.36).
Mg in placebo group not assayed.
2. ‘Supra-physiological’ vitamin B12: 20 subjects.
Protective effect at one frequency.
3. N-acetyl cysteine: 32 subjects. No effect. (Insufficient noise level?)
4. NAC: 53 subjects. No effect overall. Protection (1.2 vs. 3.1 dB)
in subgroup with null-genotypes in both GSTT1 and GSTM1
1. Attias J, Sapir S, Bresloff I, et al. Clin Otolaryngol. Allied Sci 2004;29:635-41
2. Quaranta A, Scaringi A, Bartoli R, et al. Int J Audiol. 2004;43:162-5
3. Kramer S, Dreisbach L, Lockwood J, et al. J Am Acad Audiol 2006;17:265-78
4. Lin CY, Wu JL, Shih TS, et al. Hear Res 2010;269:42-7
Open question: relationship between TTS and PTS
Compounds Tested in Military Settings
Potential PTS, Prospective:
1. Magnesium vs. placebo: 300 subjects. Prospective; basic military
training with ear plugs at shooting. Lower incidence of PTS in
Mg-group than placebo.
Note: regardless of treatment, PTS was lower in subjects with
higher serum Mg.
2. N-acetyl cysteine vs. placebo: 566 subjects. Prospective; weapons
training. No difference in overall hearing loss between groups.
Analysis of secondary outcomes suggested potential treatment
effect.
1. Attias J, Weisz G, Almog S, et al. Am J Otolaryngol 1994;15:26-32.
2. Kopke, R, Slade, MD, Jackson R, et al., Hear. Res. 2015; 323:40-50.
Compounds Tested After Noise Exposure
Potential PTS, Post-traumatic:
3. JNK-ligand AM-111: 11 subjects. Intratympanic; firecracker exposure.
Parallel-dose trial; no placebo. Recovery judged to have
exceeded expected spontaneous recovery.
Residual PTS after 30 days: 11 dB.
4. Prednisolone & piracetam: 52 subjects. IV; gunshots at military training.
Three groups with variably delayed onset of treatment of <1 h to
> 24 h. No placebo. Higher recovery rate (69%) and lower final
threshold shift with treatment within 1 hour.
3. Suckfuell M, Canis M, Strieth S, et al. Acta Otolaryngol 2007;127:938-42
4. Psillas G, Pavlidis P, Karvelis I, et al. Eur Arch Otorhinolaryngol 2008;265:1465-9
Currently Registered Clinical Trials
on Noise-induced Hearing Loss
The table is not necessarily comprehensive. It lists clinical trials currently registered on ClinicalTrials.gov,
a service of the U.S. National Institutes of Health. Search terms: hearing loss, interventional studies, noise
(accessed May 19, 2016).
A New Paradigm:
Synaptopathy
&
Hidden Hearing Loss
• Degeneration of synaptic connections between hair cells and spiral
ganglion nerve while hair cells remain intact and functional
“Hidden Hearing Loss”
Synapse counts and ABR threshold shift after TTScausing noise exposure;
Kujawa SG and Liberman MC. J. Neurosci. 29:14077-85, 2009.
Kujawa SG and Liberman MC. Hear. Res. 330:191-199, 2015.
Neurotrophin-3 Rescues Synaptic Connections
After Noise Trauma
Suzuki, Corfas, Liberman. Sci. Rep. 6:24907, 2016
Neurotrophins – The New Frontier?
Noise Trauma
(Acute synaptopathy)
NT-3
NT-3?
Aging
(Chronic synaptopathy)
Wan & Corfas, Hear. Res. 329:1-10, 2015
Inner
Hair Cell
Acoustic
Trauma
Ribeye
NT-3
Supporting
Cell
GluR2
Synapse Integrity
Auditory Function
Spiral Ganglion
Nerve Terminal
NT-3 delivery either before or after acoustic trauma promotes regeneration of
synapses and recovery of auditory function.
A Quick Detour to
Aminoglycosides
Protection
is a stop-gap measure
and does not address today’s urgent problems in
chemotherapy.
2,000,000 MDR infections and 30,000 deaths
in the USA every year
Today’s Drug Challenge
New broad-spectrum antibacterials against
MDR and XDR bacteria
Designer aminoglycosides to mitigate the effects of
genetic diseases
without ototoxicity!
Next-generation Antibacterial Aminoglycosides
with Erik Böttger, University of Zürich
Matt et al., Proc. Natl. Acad. Sci. US 109:10984-10989, 2012.
Duscha et al., mBio 5:e01827-14, 2014.
Designer Aminoglycosides as Stop-codon Suppressors
with Timor Baasov, Technion, Haifa
Nudelman et al., J. Med. Chem. 52:2836-2845, 2009
Xue et al., Am. J. Resp. Cell Mol. Biol., 50:805-816, 2014
A New Frontier
Gentamicin
New designer drug *
Permanent threshold shift after in-vivo treatment
* Highly effective against drug-resistant clinical isolates
In a Nutshell
Animal models suggest oxidative stress as a
major contributor to hair cell loss.
Antioxidant therapy is successful in animals.
Protection from aminoglycoside-induced hearing loss is
proof-of-principle of translation from experimental
animals to the clinic.
However, protection is not the therapy of choice for ototoxicity:
novel drugs are needed.
Synaptopathy has emerged as an early event in noise-induced,
ototoxic and age-related hearing loss.
Neurotrophins are potential rescue agents.
Today
Protect your hair cells
and their synapses
Beware of environmental noise pollution.
Avoid loud music: Turn your music player
down
Avoid the potential dangers of clinical drugs
Avoid aging