From the musical notes of a jazz bar piano to the intonation of a friend's laughter, our daily lives are enhanced by our ability to hear. Hearing enriches our sensory experience and connects us to the world. When this sense is impaired, our perception of the world changes, limiting our ability to engage and imposing upon our overall quality of life.
“Hearing loss has a tremendous effect on self-identity, completeness and confidence to thrive in one's environment,” explained Peter Steyger, PhD, director of Creighton University's Translational Hearing Center, which seeks to prevent and treat drug-induced hearing loss. Steyger has a personal connection to this mission, as he experienced childhood hearing loss following treatment with aminoglycoside for bacterial meningitis. “The loss is more profound when this occurs after infancy, particularly in adults, in those using spoken language. For individuals with progressive hearing loss, this loss continues to exert itself with each progression of hearing loss.”
Recent research efforts have accelerated to focus on preventive and restorative treatment methods to address hearing loss. These endeavors seek to tackle this public health issue by delving into the inner ear—specifically the hair cells of the cochlea. The synergistic collaboration between hearing health care professionals and scientists, along with new technologies, has led to further advancements in inner ear drug delivery systems. These developments hold an exciting promise in redefining the clinical treatment options for auditory and vestibular disorders, and thus the diagnosis of a hearing loss.
MEDICATIONS FOR THE INNER EAR
Across the globe, 466 million people—34 million of whom are children—have disabling hearing loss.1 With the increase in environmental factors and lack of hearing loss treatment options, this number is estimated to rise to 900 million (or one in 10 people) by 2050.1 Despite these numbers, no FDA-approved drug is available for the treatment or prevention of inner ear disorders.
The pharmaceutical industry quickly recognized the dire need for new hearing loss treatment options, which has led to a surge in new hearing loss companies.
“The lack of previous clinical experience in the inner ear field represents a big challenge for companies developing drugs in this space,” noted Hugo Peris, founder and CEO of Spiral Therapeutics, a San Francisco-based clinical-stage pharmaceutical company developing inner ear therapies. “[However], the fact that no drug has been approved to treat any inner ear conditions is also an opportunity.”
To date, approximately 43 pharmaceutical companies are developing inner ear therapies and drug delivery systems.2 The lead indications of these companies range from ototoxicity from medications such as cisplatin to Meniere's disease. The therapeutic approaches include otoprotection, hair cell regeneration, and gene therapy.2 Products in the pipeline are in various phases of development (pre-clinical and clinical trials), with a timeline trajectory of reaching the clinical market within the next few years.
“The revolution that we are about to witness in the treatment of hearing loss is extremely exciting. It has been a long time since a specific therapeutic area was so ripe and in so much need for disruption as the inner ear is today,” noted Peris.
In tandem with drug formulation, a highly influential factor impacts the progress in ushering inner ear therapies to the market: the drug delivery system specifically, determining the appropriate delivery system that will most safely and effectively transport the medication in the desired manner, while also prioritizing patient comfort. For inner ear drugs, this task is not as simple as transdermal delivery for a flu shot or oral drug delivery for cough syrup.
DRUG DELIVERY TO THE INNER EAR
Three administrative routes are employed in inner ear drug delivery: intratympanic, intracochlear, and systemic. Intratympanic administration involves syringe injection to the tympanic membrane (TM), delivering the drug across the middle ear to be absorbed through the round window membrane (RWM) and into the cochlea. The form of the drugs used for this method range from drug solutions, drug suspensions, and injectable gels.3
Intracochlear administration requires directly transferring the drug into the cochlea, which provides greater precision for drug targeting but is a high-risk procedure. This route can be utilized through an injection, a reciprocating perfusion system or osmotic mini-pump for perfusion, or a cochlear implant device.3
These local administration routes—intratympanic and intracochlear—are preferred, as they bypass blood-labyrinth barrier (BLB) issues that are usually encountered via systemic administration.
“Many challenges remain, particularly in understanding the physiology and regulation of the blood-labyrinth barrier that protects the inner ear in the same manner as the blood brain barrier,” said Steyger. “It is for this reason that many currently efficacious drugs are delivered by one of several local or middle ear delivery mechanisms, to circumvent the blood-labyrinth barrier.”
However, systemic delivery continues to be the more desired route for future therapeutic application in clinical settings because it poses a low risk of developing complications and provides better patient comfort. As such, additional research efforts are needed to develop new systemic administration methods for inner ear therapies.
“Systemic delivery of therapeutics that target the inner ear is a preferred goal for ease of clinical administration” explained Steyger. “Understanding which systemically administered therapeutics readily enter the inner ear to exert beneficial effects is grossly under-researched at present.”
Improvements in drug targeting and retention in the cochlea, gene and stem cell therapy for hair cell regeneration, and new methods to address drug delivery barriers have propelled progress in improving inner ear drug delivery systems.
“Great strides are being made and others are in progress, especially for local drug delivery via the middle ear,” said Steyger. “This can occur via implantable mini-pump delivery directly into the cochlear fluids and gels placed on the round window that slowly release drugs (akin to middle ear injections) into cochlear perilymph.”
Improvements with Drug Targeting and Retention
One breakthrough in intratympanic administration is the development of a thermosensitive gel that solidifies at body temperature within the middle ear and, ideally, stays on the RWM to be absorbed into the cochlea.4 This minimizes drug drainage through the Eustachian tube and prolongs the drug release time. Another drug delivery system being explored uses a fast film forming agent (FFA) for microphere injection, which has shown promise in localizing and enabling drug-loaded microspheres to remain on the RWM for more than a month.5 An implantable bioabsorbable stent is another device being researched, with the potential to extend drug delivery for upwards of two weeks.6
For intracochlear delivery, researchers have been looking into cochlea-implantable devices as less-invasive options than injections. For example, one microfluidics-based intracochlear drug delivery device is implanted into the scala tympani.7 The device operates with a reservoir that transfers drugs through a hole in the cochlea's basal turn into the perilymph. A more recent development is a micro-fabricated device that operates with a reciprocating micropump and drug reservoir.8 This implantable device disperses the drug while preserving vital inner pressurization to maintain continuous drug delivery into the cochlea.
Several options are also being explored to use a cochlear implant for inner ear drug delivery, one of which involves a cochlear implant with an electrode connected to a polymeric matrix with drug solution that enables continuous drug release for potentially years.9
In terms of direct injection into the cochlea, superparamagnetic nanoparticles (MNP) have shown to be effective drug carriers that can optimize drug targeting and controlled release.
To enhance drug permation, researchers at Columbia University developed a specialized multi-serrated syringe that enables microperforation of the RWM. The syringe is highly desirable as it allows for more uniform and precise perforation of the RWM for improved drug diffusion, with minimal trauma to the membrane.10
Improving Gene and Stem Cell Delivery
Both gene and stem cell therapies hold momentous promise in transforming the clinical treatment of hearing loss. For example, the recent discovery of CRISPR-Cas9 to prevent genetic hearing loss by protecting hair cells from Tmc1 gene damage has garnered great attention.11 However, its effectiveness is dependent on the drug delivery method. One such method is adeno-associated viral (AAV) vectors, which have proven to produce high transduction of hair cells in numerous pre-clinical studies.12 For stem cell delivery, bio-hybrid cochlear implants with specially prepared electrodes containing progenitor cells show potential in being used for intracochlear cell-based drug delivery to regenerate hair cells.13
New Routes for Drug Administration
For vestibular disorders (e.g., Meniere's disease), trans-oval window administration may be the most effective distribution method due to the oval window's route to the vestibule. One method in development is a trans-oval window implant, a silicon-based implant placed on the stapes to transport drugs to the oval window for absorption.14 In addition, miniature implants called ear cubes have been designed for drug delivery directly into the cochlea through the oval window. The silicone-based implants consist of a cylinder situated in a hole through the oval window and a connecting cuboid placed in the middle ear, which holds the inner ear drug.15
To continue such progress in inner ear drug delivery, collaboration will be key, particularly in translating lab bench results into treatment options available in the patient clinical setting.
“The biggest steps forward will occur as groups of researchers collaborate together to tackle the multi-faceted challenges posed by the small target of the inner ear, which is supremely protected by the blood-labyrinth barrier,” said Steyger. “These types of consortia and working groups are now beginning to develop, for example, the Hearing Restoration Project at the Hearing Health Foundation and the International Society of Inner Ear Therapeutics.”
CHALLENGES OF INNER EAR DRUG DELIVERY SYSTEMS
Significant challenges must be overcome in order to develop effective inner ear delivery systems. A primary difficulty is not knowing the exact drug formulation for which the delivery system is being designed—a hurdle that must be balanced in conjunction with inner drug formulation activities. Another is in converting findings from preclinical studies, which employ animal models, into relevant application for human patients.
“The challenge is in translating positive results of preclinical settings into the clinic. The inner ear is an extremely complicated and sensitive organ that is hidden in the skull and presents great differences in size among different species,” said Peris. “What has worked in a rat can't be expected to correlate fully in humans in pharmacokinetic terms.”
Local delivery methods also have several drawbacks. For example, transtympanic and transcochlear administration both require perforation of the TM or both the TM and RWM, a procedure that leads to temporary—and sometimes permanent—hearing loss.
As such, Steyger further emphasized systemic delivery as the ultimate delivery route and the need for efficacious drug formulation and dosage to make this route more viable in the clinic.
“The primary challenge for systemic delivery to the inner ear is achieving a therapeutic dose in the inner ear after crossing the blood-labyrinth barrier without causing unwanted side-effects systemically (the converse or opposite of ototoxicity, where a systemic therapeutic dose causes toxicity in the inner ear, for example by aminoglycosides or select chemotherapy agents),” Steyger explained.
PARADIGM SHIFT FOR PROFESSIONALS
Treatment options for hearing loss will undoubtedly undergo a paradigm shift in the coming years as pharmaceutical treatment options become available.
“In the next decade, I envision the approval of multiple therapeutic approaches to hearing loss, ranging from prevention to treatment, and including small molecules, biologics, stem cells, and gene therapies,” said Peris. “Prevention seems to be the logical first step, and one that might become first-line for acute events of hearing loss that can be predicted (ototoxicity) or are identified rapidly after they happened (acoustic trauma, idiopathic sudden and rapid hearing loss).”
As genetic causes account for 50 to 60 percent of cases of hearing loss among children, expansion of gene therapy capabilities hold the potential to reduce this number and even end genetic hearing loss altogether.16 In addition, gene and stem cell therapy hold the key to treating hearing loss from various inner ear disorders through hair cell regeneration.
“Gene therapies will make a big difference for people with congenital or hereditary hearing loss. Other regenerative therapies might work for people with severe to profound hearing loss where first-line therapies had failed or the opportunity window to treat with otoprotectants has already passed,” Peris noted.
Certain inner ear drug therapies are expected to reach patients sooner than others.
“There are still a number of hurdles with gene therapy, but otoprotectants have undergone promising clinical trials, especially with ototoxicity, and are more likely to find their way into clinical practice in the near future,” said Charles Pudrith, AuD, PhD, assistant professor of audiology at Northern Illinois University.
“Otoprotectants are smaller chemicals than the viral vectors of gene therapy and are more likely to be affective when delivered orally,” Pudrith said. “Depending on the required dosage, these treatments may be available over the counter. If so, audiologist could recommend them in the same way that they recommend ear wax removal kits.” Pudrith also predicts that with otoprotectants, “it is possible that these would be sold over the counter. This means that audiologists could recommend them in the same way they may recommend ear wax removal kits.”
The role of hearing health care professionals will also transform, particularly to oversee the efficacy of new inner ear medications. This task will require heightened pharmacology knowledge and training for competency in this role.
“Initially, hearing health care professionals will be essential for validating the efficacy and widespread utility of new ototherapeutics in which format they are administered—locally or systemically—and establishing the impact [of these therapies] in maintaining or restoring healthy auditory performance,” said Steyger.
He also anticipates an increased collaboration with health care professionals in other fields, such as oncology, to provide a more comprehensive team effort towards hearing loss prevention and treatment.
“Subsequently, once these protocols are validated, I foresee that hearing health care professionals will incorporate these strategies into specialty healthcare, particularly in pulmonology for the care of those with cystic fibrosis, neonatology for newborns treated with aminoglycosides, and oncology for those treated with chemotherapeutics,” Steyger added.
Regarding direct patient care practices, the plethora of options afforded by the availability of inner ear therapies will also impact the role of the audiologist and their daily practice. Specifically, audiologists will be at the forefront in referring patients to ENTs for pharmaceutical treatment.
According to Pudrith, “Audiologists identify patients who may benefit from medical treatment and make the appropriate referrals. The development of new therapies may have a drastic effect on their referral practices, depending on the delivery route and the efficacy of the new drugs.”
It is hoped that the breadth of options will positively influence patient expectations by providing greater confidence in the efficacy of their treatment plan. Whereas, instead of the expected amplification device, a potentially more permanent, convenient, and effective option is available. Subsequently, it is anticipated that the expansion of inner ear therapies will encourage patients to more proactively and confidently seek hearing health care. As Pudrith explained, “(p)atients may be more willing to seek treatment for hearing loss if there were pharmaceutical treatment options.”
Advancements in inner ear drug delivery systems will surely pave the way for the day when the diagnosis of hearing loss can be easily prevented or treated with medication. With the swift progress ensuing and interprofessional synergistic effort, Steyger predicted that “our sense of hearing will reach the same general level of importance and recognition as vision in our everyday lives.”
“Indeed, to paraphrase Helen Keller,” said Steyger, “hearing loss separates people from (other) people, and that communicative connection is a foundational principle of our rich human experience.”
Thoughts on something you read here? Write to us at [email protected]
2. Schilder, A.G.M. (2019). Hearing Protection, Restoration, and Regeneration: An Overview of Emerging Therapeutics for Inner Ear and Central Hearing Disorders. Otology & Neurotology.
3. Hao, J. & Li, K. (2019). Inner ear drug delivery: Recent advances, challenges, and perspective. Eur J Pharm Sci.
4. Feng, L., Ward, J.A., Li, S.K., Tolia, G., Hao, J., Choo, D.I. (2014). Assessment of PLGA-PEG-PLGA copolymer hydrogel for sustained drug delivery in the ear. Curr. Drug Deliv.
, 11, pp. 279-286.
5. Dormer, N.H., Nelson-Brantley, J., Staecker, H., & Berkland, C.J. (2018). Evaluation of a transtympanic delivery system in mus musculus for extended release steroids. Eur. J. Pharm. Sci.
6. Lavigne, P., Lavigne, F., & Saliba, I. (2016). Sustained inner ear steroid delivery via bioabsorbable stent: a tolerability and feasibility study on guinea pigs. Otolaryngol. Head Neck Surg.
, 155. pp. 649-65.
7. Sewell, W.F., Borenstein, J.T., Chen, Z., Fiering, J., Handzel, O., Holmboe, M., Kim, E.S., Kujawa, S.G., McKenna, M.J., Mescher, M.M., Murphy, B., Swan, E.E., Peppi, M., & Tao, S. (2009). Development of a microfluidics-based intracochlear drug delivery device. Audiol. Neurotol.
, pp. 411-422.
8. Tandon, V., Kang, W.S., Robbins, T.A., Spencer, A.J., Kim, E.S.,.McKenna, M.J., Kujawa, S.G., Fiering, J., Pararas, E.E., Mescher, M.J., Sewell, W.F.,.Borenstein, J.T. (2016). Microfabricated reciprocating micropump for intracochlear drug delivery with integrated drug/fluid storage and electronically controlled dosing Lab Chip, 16, pp. 829-846.
9. Krenzlin, S., Vincent, C., Munzke, L., Gnansia, D., Siepmann, J., & Siepmann, F. (2012) Predictability of drug release from cochlear implants. J. Control. Release
, 159, pp. 60-68.
10. Stevens, J.P., Watanabe, H., Kysar, J.W., & Lalwani, A.K. (2016). Serrated needle design facilitates precise round window membrane perforation. J. Biomed. Mater. Res. A.
11. Gao X, Tao Y, et al. Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents. Nature.
2018;553 (7687) :217-221.
12. Landegger, L.D., Pan, B., Askew, C., Wassmer, S.J., Gluck, S.D., Galvin, A., Taylor, R., Forge, A., Stankovic, K.M., Holt, J.R., Vandenberghe, L.H. (2017). AAV vector enables safe and efficient gene transfer to the mammalian inner ear. Nat. Biotechnol.
, 35, pp. 280-284.
13. Roemer, A., Kohl, U., Majdani, O., Kloss, S., Falk, C., Haumann, S., Lenarz, T., Kral, A., & Warnecke, A. (2016). Biohybrid cochlear implants in human neurosensory restoration. Stem Cell Res. Ther.
, 7, p. 148.
14. Sircoglou, J., Gehrke, M., Tardivel, M., Siepmann, F., Siepmann, J., & Vincent, C. (2015).
15. Gehrke, M., Sircoglou, J., Gnansia, D. Tourrel, G., Willart, J.F., Danede, F., Lacante, E., Vincent, C., Siepmann, F., & Siepmann, J. (2016). Ear cubes for local controlled drug delivery to the inner ear. Int. J. Pharm.
, 509, pp. 85-94.
16. Data and Statistics About Hearing Loss in Children. https://www.cdc.gov/ncbddd/hearingloss/data.html