Novel Conjugated Molecule Shows Preclinical Potential to Treat Sensorineural Hearing Loss
Key findings
- This study involved synthesis of an analog of neurotrophin-3, dubbed 1Aa, and creation of a novel small molecule that linked 1Aa to risedronate, a bisphosphonate previously shown to bind cochlear bone
- 1Aa promoted outgrowth of spiral ganglion neurons and regeneration of inner ear ribbon synapses in vitro
- 1Aa–risedronate retained the neurotrophic ability of 1Aa, both when freely available in culture and when pre-bound to hydroxyapatite, the primary mineral component of bone
- 1Aa and 1Aa–risedronate are attractive candidates for investigating regeneration of cochlear ribbon synapses in vivo
An emerging cause of sensorineural hearing loss is the loss of synapses, or connections, between spiral ganglion neurons (SGNs) and sensory hair cells within the inner ear. However, recent studies have shown that the bodies of these cells remain present for months in mice—and possibly for decades in humans—even after its connecting synapse has been lost.
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This suggests a window of time when delivering neurotrophic factors to the inner ear could promote survival of SGNs and re-wiring of sensory hair cells by surviving SGNs. The two major inner-ear neurotrophins are brain-derived neurotrophic factor (BDNF) and neurotrophin-3.
Researchers at Mass Eye and Ear previously described in Bioconjugate Chemistry a drug delivery system that may promote delivery of BDNF-related activity into the labyrinth. The bisphosphonate risedronate, which has high affinity for bone mineral, was conjugated to 7,8-dihydroxyflavone (DHF), an agonist of BDNF receptors. The resulting hybrid molecule bound bone mineral while maintaining neurotrophic activity. This approach may allow cochlear bone to become a depot for prolonged neurotrophic stimulation of SGNs.
Now, David H. Jung, MD, PhD, assistant professor in the Department of Otolaryngology at Mass Eye and Ear, Judith S. Kempfle, MD, research fellow in Otolaryngology–Head and Neck Surgery at Mass Eye and Ear, and colleagues have observed similar results with an analog of neurotrophin-3. Their data appears in Frontiers of Cellular Neuroscience.
Figure 1
Image of spiral ganglion neurons, courtesy of David H. Jung, MD, PhD.
SGN Neurite Outgrowth
The researchers treated murine postnatal SGNs with various molecules, finding that:
- 1Aa, a small-molecule agonist of neurotrophin-3 receptors, promoted SGN outgrowth to a level comparable to that of DHF
- Relative outgrowth with 1A–risedronate was comparable to the results with 1Aa
- When 1Aa–risedronate was pre-bound to hydroxyapatite nanoparticles, it produced stronger outgrowth than 1Aa alone or risedronate alone
Ribbon Synapse Regeneration
The team then isolated organ of Corti explants containing hair cells and SGNs from healthy mice, administered kainic acid in order to damage ribbon synapses and treated them with various molecules:
- Treatment with DHF, 1Aa or DHF + 1A resulted in statistically significant, similar increases in synaptic counts
- The number of synapses obtained after treatment with 1Aa–risedronate was comparable to that obtained after treatment with 1Aa
A Promising Platform
The use of bisphosphonate conjugates to target the cochlea may result in prolonged binding of drugs to the bony labyrinth and enable long-term stimulation of SGNs. Moreover, it might be possible to use this method to deliver other small molecules intended to work within the cochlea.
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