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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: • • • • • • • • 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