Bisphosphonate-Linked TrkB Agonist: Cochlea-Targeted Delivery of a Neurotrophic Agent as a Strategy for the Treatment of Hearing Loss

Bioconjugate Chemistry
Judith S KempfleCharles E McKenna

Abstract

Hearing loss affects more than two-thirds of the elderly population, and more than 17% of all adults in the U.S. Sensorineural hearing loss related to noise exposure or aging is associated with loss of inner ear sensory hair cells (HCs), cochlear spiral ganglion neurons (SGNs), and ribbon synapses between HCs and SGNs, stimulating intense interest in therapies to regenerate synaptic function. 7,8-Dihydroxyflavone (DHF) is a selective and potent agonist of tropomyosin receptor kinase B (TrkB) and protects the neuron from apoptosis. Despite evidence that TrkB agonists can promote survival of SGNs, local delivery of drugs such as DHF to the inner ear remains a challenge. We previously demonstrated in an animal model that a fluorescently labeled bisphosphonate, 6-FAM-Zol, administered to the round window membrane penetrated the membrane and diffused throughout the cochlea. Given their affinity for bone mineral, including cochlear bone, bisphosphonates offer an intriguing modality for targeted delivery of neurotrophic agents to the SGNs to promote survival, neurite outgrowth, and, potentially, regeneration of synapses between HCs and SGNs. The design and synthesis of a bisphosphonate conjugate of DHF (Ris-DHF) is presented, with a p...Continue Reading

References

Jan 1, 1993·The Annals of Otology, Rhinology, and Laryngology·H F Schuknecht, M R Gacek
Oct 23, 1997·Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-Head and Neck Surgery·J B Nadol
May 5, 1999·Journal of Anatomy·G Terenghi
Oct 8, 2004·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Konstantina StankovicGabriel Corfas
Feb 17, 2006·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Sharon G Kujawa, M Charles Liberman
Sep 25, 2008·Journal of Biomedical Materials Research. Part a·Alison J EvansRachael T Richardson
Oct 14, 2008·Advanced Drug Delivery Reviews·Erin E Leary SwanJeffrey T Borenstein
Nov 27, 2008·Bioconjugate Chemistry·Boris A KashemirovCharles E McKenna
Nov 13, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Sharon G Kujawa, M Charles Liberman
Nov 20, 2009·Audiology & Neuro-otology·Alec N Salt, Stefan K Plontke
Jan 30, 2010·Experimental Neurology·Seiji B ShibataYehoash Raphael
Feb 6, 2010·Proceedings of the National Academy of Sciences of the United States of America·Sung-Wuk JangKeqiang Ye
Feb 6, 2010·Journal of Visualized Experiments : JoVE·Mark ParkerAlbert S B Edge
Apr 28, 2010·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Anke J RoelofsMichael J Rogers
Mar 2, 2011·The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences·Frank R LinLuigi Ferrucci
Apr 21, 2011·The Journal of Clinical Investigation·Maxime CazorlaDidier Rognan
May 27, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Qiong Wang, Steven H Green
Jan 10, 2012·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Anke J RoelofsFraser P Coxon
Apr 3, 2012·Hearing Research·Dyan RamekersSjaak F L Klis
Apr 5, 2012·European Journal of Medicinal Chemistry·Haopeng SunQidong You
Aug 21, 2012·Journal of Molecular Biology·T BertrandM Mathieu
Sep 1, 2012·Otology & Neurotology : Official Publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology·Alicia M QuesnelMichael J McKenna
Aug 9, 2013·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Qing YuXi Lin
Aug 24, 2013·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Yevgeniya SergeyenkoSharon G Kujawa
Mar 7, 2014·Frontiers in Systems Neuroscience·Hari M BharadwajBarbara G Shinn-Cunningham
May 21, 2014·Otology & Neurotology : Official Publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology·Stefan K PlontkeAlec N Salt
Mar 3, 2015·Scientific Reports·Cameron L BudenzYehoash Raphael
Mar 21, 2015·Nature Reviews. Drug Discovery·Ulrich Müller, Peter G Barr-Gillespie
May 23, 2015·Otology & Neurotology : Official Publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology·Woo Seok KangDavid H Jung
Sep 12, 2015·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Dyan RamekersWilko Grolman
Sep 16, 2016·Otology & Neurotology : Official Publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology·David J SlyStephen J O'Leary
Nov 20, 2016·Expert Opinion on Therapeutic Patents·Kim NguyenCharles E McKenna

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Citations

Sep 12, 2020·Critical Reviews in Food Science and Nutrition·Marco EmiliFiorenza Stagni
Nov 20, 2019·Drug Delivery and Translational Research·James G NaplesDaqing Li
Aug 9, 2020·Frontiers in Molecular Neuroscience·Richard SeistKonstantina M Stankovic
Feb 2, 2021·Journal of Medicinal Chemistry·Jéssica S BarbosaSusana Santos Braga
Sep 3, 2020·British Journal of Pharmacology·Shuting SunFrank H Ebetino
Aug 3, 2021·Frontiers in Cellular Neuroscience·Judith S KempfleDavid H Jung

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