Oligonucleotide therapeutics for neurodegenerative diseases
by Victor Li and Yunlong Huang
In this review, we discuss recent advances in oligonucleotide technologies, including nanoparticle delivery, local administration, and C16-onjugation that work to extend the applicability of siRNAs and antisense oligonucleotides to nerve tissues. We discuss critical factors pivotal for the successful clinical translations of these modified or engineered oligonucleotides in the context of treating neurodegenerative diseases…
Oseltamivir (Tamiflu), a commonly prescribed antiviral drug, mitigates hearing loss in mice
by Emma J. Sailor-Longsworth,Richard D. Lutze, Matthew A. Ingersoll, Regina G. Kelmann, Kristina Ly, Duane Currier, Taosheng Chen, Jian Zuo, Tal Teitz
Noise exposure and chemotherapy treatments are leading causes of hearing loss, but currently there is only one FDA-approved drug fro a subgroup of cisplatin-treated cancer patients. Drug repurposing is a strategy for addressing unmet medical needs that can be quicker and more cost-effective than traditional drug development. Here, we performed unbiased cell-based screens of 1300 FDA-approved drugs and tested our top candidate oseltamivir phosphate (brand name Tamiflu), a common influenza antiviral drug, in established cisplatin- and noise-induced hearing loss animal models…
Piplartine attenuates aminoglycoside-induced TRPV1 activity and protects from hearing loss in mice
by Marisa Zallocchi, Sarath Vijayakumar, Jonathan Fleegel, Lyudmila Batalkina, Katyarina E. Brunette, Dhaval Shukal, Zhiyong Chen, Olivier Devuyst, Huizhan Liu, David Z. Z. He, Ali Sajid Imami, Abdul-Rizaq Ali Hamoud, Robert McCullumsmith, Martin Conda-Sheridan, Luana Janaína De Campos, Jian Zuo
Aminoglycoside therapy can result in permanent hearing loss in 40% to 60% of patients receiving treatment, and despite these high numbers, no drug for preventing or treating this type of hearing loss has yet been approved by the US Food and Drug Administration. We have previously conducted high-throughput
screenings of bioactive compounds, using zebrafish as our discovery platform, and identified piplartine as a potential therapeutic molecule. In the present study, we expanded this work and characterized piplartine’s physicochemical and therapeutic properties…
In silico transcriptome screens identify epidermal growth factor receptor inhibitors as therapeutics for noise-induced hearing lossand
by Sarath Vijayakumar, Joseph A. DiGuiseppi, Parinaz Jila Dabestani, William G. Ryan, Rene Vielman Quevedo, Yuju Li, Jack Diers, Shu Tu, Jonathan Fleegel, Cassidy Nguyen, Lauren M. Rhoda, Ali Sajid Imami, Abdul-Rizaq Ali Hamoud, Sándor Lovas, Robert E. McCullumsmith, Marisa Zallocchi, Jian Zuo
Noise-induced hearing loss (NIHL) is a common sensorineural hearing impairment that lacks U.S. Food and Drug Administration–approved drugs. To fill the gap in effective screening models, we used an in silico transcriptome-based drug screening approach, identifying 22 biological pathways and 64 potential small molecule treatments for NIHL. Two of these, afatinib and zorifertinib [epidermal growth factor receptor (EGFR) inhibitors], showed efficacy in zebrafish and mouse models…
Repurposing AZD5438 and Dabrafenib for Cisplatin-Induced Acute Kidney Injury
by Chithra K. Pushpan, Daniel F. Kresock, Matthew A. Ingersoll, Richard D. Lutze, Darby L. Keirns, William J. Hunter, Khalid Bashir, Tal Teitz
Cisplatin is an effective chemotherapy agent for a wide variety of solid tumors, but its use is dose-limited by serious side effects including acute kidney injury (AKI) and hearing loss. There are no FDA-approved drugs to treat both side effects. Recently, two anti-cancer oral drugs, AZD5438 and dabrafenib, were identified as protective against cisplatin-induced hearing loss in mice. We hypothesize that similar cell stress and death pathways are activated in kidney and inner ear cells when exposed to cisplatin, and tested whether these drugs alleviate cisplatin-induced AKI…
Dabrafenib protects from cisplatin-induced hearing loss in a clinically relevant mouse model
by Matthew A. Ingersoll*, Richard D. Lutze*, Chithra K. Pushpan, Regina G. Kelmann, Huizhan Liu, Mark T. May, William J. Hunter, David Z.Z. He, and Tal Teitz
*Equal contribution
The widely used chemotherapy cisplatin causes permanent hearing loss in 40-60% of cancer patients. One drug, sodium thiosulfate, is approved by the FDA for use in pediatric patients with localized solid tumors for preventing cisplatin-induced hearing loss, but more drugs…
ERK1/2 Inhibition Alleviates Noise-Induced Hearing Loss While Tempering Down the Immune Response
by Richard D. Lutze, Matthew A. Ingersoll, Alena Thotam, Anjali Joseph, Joshua Fernandes, Tal Teitz
Noise-induced hearing loss (NIHL) is a major cause of hearing impairment, yet no FDA-approved drugs exist to prevent it. Targeting the mitogen activated protein kinase (MAPK) cellular pathway has emerged as a promising approach to attenuate NIHL. Tizaterkib is an orally bioavailable, highly specific ERK1/2 inhibitor…
KSR1 knockout mouse model demonstrates MAPK pathway’s key role in cisplatin- and noise-induced hearing loss
by Matthew A. Ingersoll, Richard D. Lutze, Regina G. Kelmann, Daniel F. Kresock, Jordan D. Marsh, Rene V. Quevedo, Jian Zuo, and Tal Teitz
Hearing loss is a major disability in everyday life and therapeutic interventions to protect hearing would benefit a large portion of the world population. Here we found that mice devoid of the protein kinase suppressor of RAS 1 (KSR1) in their tissues (germline KO mice) exhibit resistance to both cisplatin- and noise-induced permanent hearing loss…
AZD5438-PROTAC: A selective CDK2 degrader that protects against cisplatin- and noise-induced hearing loss
by Santanu Hati*, Marisa Zallocchi*, Robert Hazlitt, Yuju Li, Sarath Vijayakumar, Jaeki Min, Zoran Rankovic, Sándor Lovas, Jian Zuo
*Equal contribution
Cyclin-dependent kinase 2 (CDK2) is a potential therapeutic target for the treatment of hearing loss and cancer. Previously, we identified AZD5438 and AT7519-7 as potent inhibitors of CDK2, however, they also targeted additional kinases,…
Genetic predisposition to tinnitus in the UK Biobank population
by Madeleine E. Urbanek & Jian Zuo
To better understand the underlying genes that may preclude tinnitus, we performed a genome-wide association study of the UK Biobank’s 49,960 whole exome sequencing participants to identify any loci strongly associated with tinnitus. We identified 17 suggestive single nucleotide polymorphisms (p < 1e−5) spanning 13 genes in two sex-separated cohorts reporting chronic, bothersome tinnitus…
In silico transcriptomics identifies FDA-approved drugs and biological pathways for protection against cisplatin-induced hearing loss
by Pezhman Salehi*, Marisa Zallocchi*, Sarath Vijayakumar, Madeleine Urbanek, Kimberlee P. Giffen, Yuju Li, Santanu Hati, Jian Zuo
*Equal contribution
Acquired hearing loss is a major health problem that affects 5-10% of the world population. However, there are no FDA-approved drugs for the treatment or prevention
of hearing loss. Employing the Connectivity Map (CMap) that contains >54,000 compounds, we performed an unbiased in silico screen using the transcriptomic profiles
of cisplatin-resistant and -sensitive cancer cell lines….
Characterization of quinoxaline derivatives for protection against iatrogenically induced hearing loss
by Marisa Zallocchi, Santanu Hati, Zhenhang Xu, William Hausman, Huizhan Liu, David Z He, Jian Zuo
Hair cell loss is the leading cause of hearing and balance disorders in humans. It can be caused by many factors, including noise, aging, and therapeutic agents. Previous studies have shown the therapeutic potential of quinoxaline against drug-induced ototoxicity. Here, we screened a library of 68 quinoxaline derivatives for protection against aminoglycoside-induced damage…
BRAF inhibition protects against hearing loss in mice
by Matthew A. Ingersoll, Emma A. Malloy, Lauryn E. Caster, Eva M. Holland, Zhenhang Xu, Marisa Zallocchi, Duane Currier, Huizhan Liu, David Z.Z. He, Jaeki Min, Taosheng Chen, Jian Zuo, Tal Teitz*
Hearing loss caused by noise, aging, antibiotics, and chemotherapy affects 10% of the world population, yet there are no Food and Drug Administration (FDA)-approved drugs to prevent it. Here, we screened 162 small-molecule …
Supplementary Materials for BRAF inhibition protects against hearing loss in mice
by Matthew A. Ingersoll, Emma A. Malloy, Lauryn E. Caster, Eva M. Holland, Zhenhang Xu, Marisa Zallocchi, Duane Currier, Huizhan Liu, David Z.Z. He, Jaeki Min, Taosheng Chen, Jian Zuo, Tal Teitz*
Figures S1 – S8 and Table S1
Aggressive Childhood Neuroblastomas do not express caspase-8
by Dr Tal Teitz and Dr Vincent Kidd
Neuroblastomas that overexpress N-Myc due to amplification of the MYCN oncogene are aggressive tumors that become very resistant to treatment by chemotherapy and irradiation. to identify tumor suppressor genes in this …
Development of Second-Generation CDK2 Inhibitors for the Prevention of Cisplatin-Induced Hearing Loss
by Robert A. Hazlitt Tal Teitz, Justine D. Bonga , Jie Fang , Shiyong Diao, Luigi Iconaru, Lei Yang , Asli N. Goktug , Duane G. Currier, Taosheng Chen, Zoran Rankovic, Jaeki Min, and Jian Zuo
There are currently no FDA-approved therapies to prevent the hearing loss associated with the usage of cisplatin in chemotherapeutic regimens. We recently demonstrated that the pharmacologic inhibition with kenpaullone…
Progress in the Development of Preventative Drugs for Cisplatin-Induced Hearing Loss
by Robert A. Hazlitt, Jaeki Min, and Jian Zuo
This review summarizes the clinical and preclinical studies of the most effective small molecule candidates currently in clinical trials, while also detailing their molecular mechanisms of action, to gain insight for future drug development in the field….
CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss
by Tal Teitz, Jie Fang, Asli N. Goktug, Justine D. Bonga, Shiyong Diao, Robert A. Hazlitt, Luigi Iconaru, Marie Morfouace, Duane Currier, Yinmei Zhou, Robyn A. Umans, Michael R. Taylor, Cheng Cheng, Jaeki Min, Burgess Freeman,, Junmin Peng, Martine F. Roussel, Richard Kriwacki,R. Kiplin Guy,Taosheng Chen, and Jian Zuo
Hearing loss caused by aging, noise, cisplatin toxicity, or other insults affects 360 million people worldwide, but there are no Food and Drug Administration–approved drugs to prevent or treat it. We screened 4,385…
Common variants in ACYP2 influence susceptibility to
cisplatin-induced hearing lossas
by Heng Xu, Giles W Robinson, Jie Huang, Joshua Yew-Suang Lim, Hui Zhang, Johnnie K Bass, Alberto Broniscer, Murali Chintagumpala, Ute Bartels, Sri Gururangan, Tim Hassall, Michael Fisher, Richard Cohn, Tetsuji Yamashita, Tal Teitz, Jian Zuo, Arzu Onar-Thomas, Amar Gajjar, Clinton F Stewart & Jun J Yang
Taking a genome-wide association study approach, we identified inherited genetic variations in ACYP2 associated with cisplatin-related ototoxicity (rs1872328: P = 3.9 × 10−8, hazard ratio = 4.5) in 238 children with newly diagnosed brain tumors, with independent replication in 68 similarly treated children. The ACYP2 risk variant strongly predisposed these patients to precipitous hearing loss and was related to ototoxicity severity. These results point to new biology underlying the ototoxic effects of platinum agents….