Otosclerosis is a disease of the otic capsule that is among the most common causes of acquired hearing loss. During the last fifteen years, our laboratory has focused on elucidating the molecular pathology of otosclerosis with the long-term goal of developing better forms of therapy. These studies have led us to a new and innovative treatment strategy: the inner ear delivery of bisphosphonates via a drug-eluting polymer. We have begun to develop and test a drug formulation for use in humans, and have developed an animal model to test it. Since most patients with otosclerosis receive stapes prosthesis, we will integrate the polymer into the prosthesis for intracochlear delivery. We will also integrate the polymer into a wafer for delivery via the round window membrane. The otic capsule is unique in that it normally exhibits little or no bone remodeling. Otosclerosis is characterized by an abnormal remodeling of the otic capsule. Some bisphosphonate compounds are potent inhibitors of bone remodeling, but potentially serious side effects can occur with systemic administration in humans such as inhibition of all skeletal remodeling and osteonecrosis of the jaw. Intracochlear and intratympanic administration should bypass these systemic problems and ensure that the drugs reach cochlear tissues and the otic capsule in the form and concentration desired. We have identified an animal model, the OPG-/- (knockout) mouse, which exhibits foci of active remodeling within the otic capsule, similar to otosclerosis. These mice also develop progressive hearing loss, similar to cases of advanced otosclerosis. We have shown that bisphosphonates are highly effective in halting the pathologic remodeling and hearing loss in OPG-/- mice. We will now investigate effects of direct intracochlear and intratympanic delivery of risedronate, a potent bisphosphonate. We have chosen risedronate because of its high potency and availability of a fluorescein conjugated form of the drug that allows its quantification and localization. These experiments will guide the development of a bisphosphonate formulation for inner ear delivery in humans. If successful, these studies will lead quickly to clinical trials in humans with progressive sensorineural hearing loss from cochlear otosclerosis using a bisphosphonate-eluting stapes prosthesis, an intratympanic bisphosphonate formulation, or both. The development of this technology will also be valuable for other inner ear disorders that may benefit from direct drug delivery.

Public Health Relevance

If successful, these studies will lead directly to clinical trials in humans with progressive sensorineural hearing loss from cochlear otosclerosis using a bisphosphonate-eluting stapes prosthesis, an intratympanic bisphosphonate formulation, or both, using safe and well-established techniques of middle ear surgery. The development of this technology will also be valuable for other inner ear disorders that may benefit from direct drug delivery.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC009837-05
Application #
8607841
Study Section
Special Emphasis Panel (ZDC1-SRB-R (33))
Program Officer
Watson, Bracie
Project Start
2010-03-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$343,414
Indirect Cost
$76,633
Name
Massachusetts Eye and Ear Infirmary
Department
Type
DUNS #
073825945
City
Boston
State
MA
Country
United States
Zip Code
02114
Jung, David H; Kang, Woo Seok; McKenna, Michael J et al. (2016) Response to "Drug Diffusion to the Apex of the Human Cochlea?". Otol Neurotol 37:1463-4
Sun, Shuting; Błażewska, Katarzyna M; Kadina, Anastasia P et al. (2016) Fluorescent Bisphosphonate and Carboxyphosphonate Probes: A Versatile Imaging Toolkit for Applications in Bone Biology and Biomedicine. Bioconjug Chem 27:329-40
Kang, Woo Seok; Nguyen, Kim; McKenna, Charles E et al. (2016) Intracochlear Drug Delivery Through the Oval Window in Fresh Cadaveric Human Temporal Bones. Otol Neurotol 37:218-22
Kang, Woo Seok; Nguyen, Kim; McKenna, Charles E et al. (2016) Measurement of Ototoxicity Following Intracochlear Bisphosphonate Delivery. Otol Neurotol 37:621-6
Kang, Woo Seok; Sun, Shuting; Nguyen, Kim et al. (2015) Non-Ototoxic Local Delivery of Bisphosphonate to the Mammalian Cochlea. Otol Neurotol 36:953-60
Cheong, Simon; Sun, Shuting; Kang, Benjamin et al. (2014) Bisphosphonate uptake in areas of tooth extraction or periapical disease. J Oral Maxillofac Surg 72:2461-8
Hokugo, Akishige; Sun, Shuting; Park, Sil et al. (2013) Equilibrium-dependent bisphosphonate interaction with crystalline bone mineral explains anti-resorptive pharmacokinetics and prevalence of osteonecrosis of the jaw in rats. Bone 53:59-68
Quesnel, Alicia M; Seton, Margaret; Merchant, Saumil N et al. (2012) Third-generation bisphosphonates for treatment of sensorineural hearing loss in otosclerosis. Otol Neurotol 33:1308-14
Sun, Shuting; Błażewska, Katarzyna M; Kashemirov, Boris A et al. (2011) Synthesis and characterization of novel fluorescent nitrogen-containing bisphosphonate imaging probes for bone active drugs. Phosphorus Sulfur Silicon Relat Elem 186:970-971
Sun, Shuting; McKenna, Charles E (2011) Farnesyl pyrophosphate synthase modulators: a patent review (2006 - 2010). Expert Opin Ther Pat 21:1433-51

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