Delivering Therapeutics to the Inner Ear

Just as the brain is protected by the blood-brain barrier, the sensory epithelia of the inner ear are protected by the blood-labyrinth barrier; principally by tight junction coupled endothelial cells of the inner ear vasculature, and epithelial cells lining the endolymphatic duct. These barriers perform three essential functions: (1) to screen out macromolecules, cells, bacteria, and toxins from entering the inner sanctum; (2) to selectively take up amino acids, sugars, lipids, and gases to nourish the tissues within; and (3) to remove toxins generated by respiration, metabolism and cellular debris. A functional blood-labyrinth barrier is required to maintain the electrophysiological environment that enables sensitive auditory and vestibular function.

These protective barriers pose significant challenges for exogenous therapeutic support for otoprotection or repair of inner ear structures from congenital disorders, infection, ototoxins and noise trauma more challenging. Yet specific therapeutics, such as aminoglycosides and cisplatin, delivered systemically readily cross the blood-labyrinth barrier to induce permanent vestibulotoxicity and cochleotoxicity. Recent advances in identifying compounds that protect the exquisite mechanosensory epithelia within the inner ear from ototoxicity and noise trauma in vitro mean that understanding the efficacious delivery of these otoprotective drugs in vivo is of paramount importance.
In this research topic, original research and review manuscripts are invited in three broad categories:

(i) Systemic delivery across the blood labyrinth barrier, including anatomy and physiology; paracellular, and transcellular mechanisms of transport, development of the barrier, expression and kinetics of drug-permeant ion channels and transporters for uptake and elimination, pharmacokinetics, modulation by comorbidities (e.g., aging, inflammation, injury, ischemia, neurodegenerative disease, noise trauma), genetic polymorphisms and dysfunction;

(ii) Local delivery to the inner ear, including round window application, and direct infusion into perilymph (e.g., via catheters in cochlear implants, intra-thecal delivery, fetal delivery, magnetic forces), distribution within, and elimination from, inner ear tissues; and

(iii) Pharmacotherapeutic-specific considerations for delivery into, and clearance from, the inner ear, including challenges related to delivery of gene therapies, nanotechnologies, biologics or small molecules, and strategies to address loss of therapeutics via cerebrospinal fluid (wash), systemic clearance and/or unwanted uptake by off-target cells.

Ultimately, all manuscripts should focus on the mechanism(s) that deliver the ototoxic agent or pharmacotherapy across the blood-labyrinth barrier and into the inner ear efficaciously. Secondarily, manuscripts can also discuss how delivery of these agents may affect the specific mechanism of ototoxicity or otoprotection. All manuscripts should also discuss available animal models for the topic under discussion, and gaps in knowledge for a specific methodology that need to be addressed.

All articles in this Research Topic are independent opinions of the authors and do not represent the official views of the Department of Veterans Affairs, National Institutes of Health or the United States Government. This Research Topic is sponsored by the US Department of Defense Hearing Center of Excellence (San Antonio, TX).

Topic Editor Benjamin Shapiro is President and co-founder of Otomagnetics. Topic Editor Sylvain Celanire is a co-Founder and Chief Executive Officer of PRAGMA Therapeutics. All other Topic Editors declare no competing commercial interests with regards to the Research Topic subject.