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Cochlear Optogenetics for Auditory Research and Prosthetics

Periodic Reporting for period 3 - OptoHear (Cochlear Optogenetics for Auditory Research and Prosthetics)

Reporting period: 2018-12-01 to 2020-05-31

According to a report of the WHO, approximately 360 million people – 5% of the world’s population – suffer from disabling hearing impairment, commonly causing social isolation, depression, and reduction in professional capabilities. Therefore, understanding how hearing works and combating hearing impairment is of great importance. So far, despite major research efforts a causal treatment based on pharmacology, gene therapy, or stem cells is not yet available for its most common form: sensorineural hearing impairment. Hearing aids and/or cochlear implants represent the state-of-the-art approaches for partial restoration of auditory function and they are likely to remain key means for alleviating sensorineural hearing impairment also during the coming decades.
The cochlear implant bypasses cochlear dysfunction via direct electric stimulation of auditory neurons of the inner ear and is considered the most successful neuroprosthesis, used in more than 500,000 hearing impaired patients. Cochlear implants enable open speech comprehension in most users. Moreover, cochlear implants have become a major tool in auditory research. However, the use of current cochlear implants has limitations arising from the wide spread of current around each electrode contact which leads to channel-crosstalk and limits the number of useful frequency channels to typically less than ten in clinical cochlear implants. Since the coding of sound frequency in the inner ear is tied to the location of the excited neuron and thus to the spatial spread of excitation within the ear, users of electrical cochlear implants suffer from poor frequency resolution of hearing and therefore show poor comprehension of speech in noisy environments and typically cannot appreciate music. The low frequency resolution limits the use of electric cochlear implants in basic research, too. Increasing the frequency and intensity resolution of auditory coding is a central objective for improving the cochlear implant.
Optical stimulation of auditory neurons, which we establish in the project “OptoHear” funded by the European Research Council, is a novel approach that promises a dramatic increase of the frequency resolution of cochlear implants, since light can be more easily confined in the cochlea and therefore less spread of excitation than in electrical implants can be achieved. The increased frequency resolution provides unprecedented opportunities for auditory research and promises to overcome the major bottleneck of current cochlear implants. In addition, activation of smaller populations of neurons can also enhance the dynamic range of coding e.g. by varying recruitment of neighboring channels.
The application of optogenetics to the cochlea, pioneered by our research team, uses virus-mediated expression of Channelrhodopsins, light-gated ion channels that can be used to activate neurons, to render neurons sensitive to light. This method, coined “optogenetics” has revolutionized the life sciences and is in rapid development with various applications and advances such as the engineering of improved Channelrhodopsin variants and vectors, some of which also serve as vectors in clinical trials on gene therapy. Important technological advances enable tailored optical stimulation. Thin-film light emitting diodes (LEDs) reach high power efficiency, can be miniaturized (µLEDs) and prepared for shaping the beam of the emitted light. Flexible waveguide arrays, vertical cavity self-mixing laser diodes (VCSELs), as well as thin-film flexible electronics on polymer substrates have become available.
The goal of “OptoHear” is to lay the ground for the development of optical cochlear implants for auditory research and future clinical translation. For this, we work on identifying the best-suited viral vectors and Channelrhodopsins, optimize their expression in auditory neurons of rodents and non-human primates (marmosets), and probe the safety and reliability of their expression. In parallel, we establish multichannel optical stimulation in these animals, characterize neuronal responses to cochlear optogenetics along the auditory pathway by physiological and behavioral approaches, and employ cochlear optogenetics for fundamental auditory research.
“OptoHear” will establish and use cochlear optogenetics as a research tool, validate its potential for research and hearing restoration, and prepare translation into the clinic by finally validating the safety and efficiency of auditory optogenetics in marmoset monkeys as a last step before first clinical trials.
During the first funding period of “OptoHear” we have made significant progress towards the development of optical cochlear implants. We have measured optical parameters of cochlear tissue and are building mathematical models of the inner ear to further examine the spread of light within the cochlea and are working with mathematical models of optically excitably auditory neurons to further determine the requirements for and possibilities of optical cochlear implants.
In parallel, having established auditory optogenetics in rodents by injections of viral vectors carrying Channelrhodopsin genes into the inner ear of mice and gerbils, thus rendering auditory neurons of the spiral ganglion light-sensitive, we have characterized the expression efficiency, stability, and safety as well as the excitability and performance of different viral vectors and Channelrhodopsin variants, greatly improved their efficiency, and identified the best candidates for further progress towards experiments with marmoset monkeys.
Utilizing optical stimulation of transfected animals by laser light via optical fibers and by µLEDs on optical cochlear implant prototypes, we have successfully activated the auditory system, measured the responses of auditory neurons to the optical stimuli and provided proof of the creation of an auditory percept in behavioral experiments. Analysis of the optically evoked activity of auditory neurons underlines the ability of auditory optogenetics to evoke responses comparable to natural auditory activity in these cells. This shows that optical cochlear implants have the potential to evoke hearing percepts that go far beyond the quality found in electrical cochlear implants and approach that of natural hearing.
Our work so far has greatly advanced auditory optogenetics and also boosted the development of optogenetics in the neurosciences in general. Establishing cutting-edge genetic technology in the auditory system and developing new optical stimulation technologies we and our partners have opened new possibilities for neuronal stimulation in the inner ear and beyond. These results not only allow new approaches for basic auditory research but also pave the way for a new type of neuroprosthesis. Optical cochlear implants promise greatly increased quality of life to a substantial percentage of the human population suffering from hearing impairment by improving the quality of sound coding compared to electrical cochlear implants. We hope that our developments will result in a more natural hearing percept and thus improved understanding of speech, especially in noise, and better appreciation of music. Additionally, the technologies developed in this project can be transferred into other applications and may help utilizing the huge potential of optogenetics in the development of new types of prostheses and treatments.