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NIH grant 2I01RD001347-13A2: Basic mechanisms in hearing loss of cochlear origin.
Institute: {'code': 'VA', 'abbreviation': 'VA', 'name': 'Veterans Affairs', 'admin_org_id': '12500964', 'admin_funding_url': ''}. PI: Allen F. Ryan. Award: $.
Start: 2026-10-01T00:00:00.
VA PROJECT SUMMARY/ABSTRACT
Significance to the VA: Hearing loss (HL) is a significant burden to Veterans and the VA. Current
treatments for HL, hearing aids or cochlear implants, are effective but do not restore normal hearing. A
method to prevent hearing loss or its progression would be valuable. Since mechanisms of HL have now
been identified, delivery inhibitory drugs into the cochlea without breaching the integrity of its fluid spaces
and risking damage to sensory dells and neurons would be highly desirable. Our discovery of peptide-
mediated delivery of cargo into the intact inner ear would fill this clinical gap.
Innovation and Impact: Several methods to deliver drugs to the cochlea have been investigated, but
none have led to a clinical treatment. Thus, developing a method for rapid and noninvasive therapeutic
delivery to the inner ear would be highly advantageous. Using phage display screening of 2.9 billion
peptides, we discovered a novel mechanism that can rapidly and efficiently deliver large cargo (~ 1 μm in
size, sufficient for large drug packages or large gene therapy vectors) across the round window
membrane (RWM) that separates the middle and inner ears. This innovative discovery promises a
noninvasive, safe method for delivery of therapeutics to the inner ear.
Specific Aims:
Specific Aim 1. To optimize peptide-mediated active transport across the intact RWM
1a. Utilize NGS phage display to identify and compare all IE delivery peptides in the library.
1b. Assess transport rates and identify optimal IE delivery peptides, assess binding to human RWM.
Specific Aim 2. Evaluate the use of peptides for IE delivery of therapeutic cargo.
2a. Test peptide-mediated delivery of a drug into the cochlea.
2b. Enhance RWM dwell time and evaluate phage and drug levels along the scala tympani.
Hypotheses.
1. Phage display identifies peptides that target RWM to actively move large (~1 um) cargo into IE.
2. NGS phage display will identify and rank by copy number all peptides supporting RWM transport.
3. Trans-RWM can deliver pharmacologically relevant quantities of drugs into perilymph.
4. Longer RWM dwell times ] will enhance delivery levels and spread along the cochlea.
Methodology: Next-generation sequencing (NGS) phage display will be used to discover optimal
peptides that non-invasively cross the round window membrane carrying large cargo into the inner ear.
Individual peptide levels of phage and peptides without phage in inner ear fluid will be evaluated after
RWM application to identify transport rates and saturation levels. Peptide phage binding to the human
RWM will be assessed in vitro. Delivery of a drug linked to peptide phage into the inner ear will be
measured. Spread of peptide phage along the length of the cochlea will be measured by apical fluid
sampling after long-term delivery to the RWM.
Path to translation/Implementation: To develop our discovery it will be necessary to identify the
optimal delivery peptides and to characterize the rate and saturability of delivery. It will also be required
to determine whether the method of delivery is safe, does not disturb hearing, and can deliver large drug
packages. In addition, it will be desirable increase the time for delivery by stabilizing drugs in the inner
ear, and to determine the extent along the length of the cochlea to which drugs can be delivered.
Translation to human should be explored. If successful, this project has the potential to revolutionize
treatment of inner ear disorders.document fetched 2026-10-24 02:46