Periodic Reporting for period 4 - OptoHear (Cochlear Optogenetics for Auditory Research and Prosthetics)
Berichtszeitraum: 2020-06-01 bis 2022-02-28
According to a report of the WHO, approximately 466 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 (CIs) represent the state-of-the-art approaches for partial restoration of auditory function and are likely to remain key means for alleviating sensorineural hearing impairment also during the coming decades.
CIs bypass cochlear dysfunction via direct electric stimulation of auditory neurons of the inner ear and are considered the most successful neuroprosthesis, used in more than 700,000 hearing impaired patients worldwide. Cis enable open speech comprehension in most users and have become a major tool in auditory research. However, the use of current Cis 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 CIs. 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 Cis suffer from poor frequency resolution of hearing and therefore show poor comprehension of speech in noisy environments and typically cannot follow musical melodies. The low frequency resolution limits the use of electric CIs in basic research, too. Increasing the frequency and intensity resolution of auditory coding is a central objective for improving the CI.
Optical stimulation of auditory neurons, which we established in the project “OptoHear”, is a novel approach that promises a dramatic increase of the frequency resolution of CIs, since light can be more easily confined in the cochlea and therefore less spread of excitation than in electrical implants can be achieved (Fig. 1). The increased frequency resolution provides unprecedented opportunities for auditory research and promises to overcome the major bottleneck of current CIs.
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, as well as thin-film flexible electronics on polymer substrates have become available.
“OptoHear” has established and used cochlear optogenetics as a research tool, validated its potential for research and hearing restoration, and prepared translation into the clinic by validating the safety and efficiency of auditory optogenetics in rodents. Further experiments in marmoset monkeys as a last step before first clinical trials are underway, which we hope to achieve starting 2026.
CIs bypass cochlear dysfunction via direct electric stimulation of auditory neurons of the inner ear and are considered the most successful neuroprosthesis, used in more than 700,000 hearing impaired patients worldwide. Cis enable open speech comprehension in most users and have become a major tool in auditory research. However, the use of current Cis 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 CIs. 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 Cis suffer from poor frequency resolution of hearing and therefore show poor comprehension of speech in noisy environments and typically cannot follow musical melodies. The low frequency resolution limits the use of electric CIs in basic research, too. Increasing the frequency and intensity resolution of auditory coding is a central objective for improving the CI.
Optical stimulation of auditory neurons, which we established in the project “OptoHear”, is a novel approach that promises a dramatic increase of the frequency resolution of CIs, since light can be more easily confined in the cochlea and therefore less spread of excitation than in electrical implants can be achieved (Fig. 1). The increased frequency resolution provides unprecedented opportunities for auditory research and promises to overcome the major bottleneck of current CIs.
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, as well as thin-film flexible electronics on polymer substrates have become available.
“OptoHear” has established and used cochlear optogenetics as a research tool, validated its potential for research and hearing restoration, and prepared translation into the clinic by validating the safety and efficiency of auditory optogenetics in rodents. Further experiments in marmoset monkeys as a last step before first clinical trials are underway, which we hope to achieve starting 2026.
The ERC AdG project “OptoHear” has brought significant progress towards the development of optical CIs. We measured optical parameters of cochlear tissue and prepared mathematical models of the inner ear, which allow us to further examine the spread of light within the cochlea. By this, we can predict the spectral resolution that we can achieve with a given type of optical implant already in silico (Fig. 2). Using mathematical models of optically excitable auditory neurons, we can now further determine requirements for and possibilities of optical CIs.
In parallel, we established auditory optogenetics in rodents by injections of viral vectors carrying Channelrhodopsin genes into the inner ear of mice, rats, and gerbils, thus rendering auditory neurons light sensitive. We have established postnatal injections into the inner ear as an efficient transfer process. 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, which we are now using in experiments with marmoset monkeys. Notably, we have managed to develop and identify Channelrhodopsin variants with such fast kinetics that we can achieve optically evoked firing rates that equal those obtained from physiological sound stimulation.
Utilizing optical stimulation of transfected animals by laser light via optical fibers and by µLEDs on optical CI 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, especially regarding the spectral resolution of activation (Fig. 3). This shows that optical Cis have the potential to evoke hearing percepts that go far beyond the quality found in electrical Cis and approach that of natural hearing. We hope to further improve on this by an alternative implant technology: Making use of waveguide arrays in combination with red laser diodes, we plan to achieve activation of neurons by red light which offers a reduced risk of phototoxicity and better tissue penetration.
During the course of “OptoHear”, we have founded the startup company OptoGenTech, which will further develop the optical CI technology to prepare for transition into the clinics. Following further experiments in marmoset monkeys, we hope to start the first in man clinical trial in 2026.
In parallel, we established auditory optogenetics in rodents by injections of viral vectors carrying Channelrhodopsin genes into the inner ear of mice, rats, and gerbils, thus rendering auditory neurons light sensitive. We have established postnatal injections into the inner ear as an efficient transfer process. 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, which we are now using in experiments with marmoset monkeys. Notably, we have managed to develop and identify Channelrhodopsin variants with such fast kinetics that we can achieve optically evoked firing rates that equal those obtained from physiological sound stimulation.
Utilizing optical stimulation of transfected animals by laser light via optical fibers and by µLEDs on optical CI 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, especially regarding the spectral resolution of activation (Fig. 3). This shows that optical Cis have the potential to evoke hearing percepts that go far beyond the quality found in electrical Cis and approach that of natural hearing. We hope to further improve on this by an alternative implant technology: Making use of waveguide arrays in combination with red laser diodes, we plan to achieve activation of neurons by red light which offers a reduced risk of phototoxicity and better tissue penetration.
During the course of “OptoHear”, we have founded the startup company OptoGenTech, which will further develop the optical CI technology to prepare for transition into the clinics. Following further experiments in marmoset monkeys, we hope to start the first in man clinical trial in 2026.
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 Cis 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 CIs. 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 for CI users. 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.