Emerging approaches for restoration of hearing and vision

Physiological Reviews, Journal Year: 2020, Volume and Issue: unknown

Published: March 19, 2020

Impairments of vision and hearing are highly prevalent conditions limiting the quality life presenting a major socioeconomic burden. For long, retinal cochlear disorders have remained intractable for causal therapies, with sensory rehabilitation limited to glasses, aids, electrical or implants. Recently, application gene therapy optogenetics eye ear has generated hope fundamental improvement restoration. To date, one restoration been approved undergoing clinical trials will broaden its including replacement, genome editing, regenerative approaches. Moreover, optogenetics, i.e. controlling activity cells by light, offers more general alternative strategy. Over little than decade, optogenetic approaches developed applied better understand function biological systems, while protein engineers identified designed new opsin variants desired physiological features. Considering potential applications spotlight is on systems. Multiple efforts undertaken restore lost hampered in ear. Optogenetic stimulation promises overcome shortcomings stimulation, namely poor spatial resolution cellular specificity, accordingly deliver detailed information. This review aims at providing comprehensive reference current therapeutic research relevant vision. We introduce gene-therapeutic discuss biotechnological optoelectronic aspects

Language: Английский

---

Viral rhodopsins 1 are an unique family of light-gated cation channels

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Nov. 11, 2020

Phytoplankton is the base of marine food chain as well oxygen and carbon cycles thus plays a global role in climate ecology. Nucleocytoplasmic Large DNA Viruses that infect phytoplankton organisms regulate dynamics encompass genes rhodopsins two distinct families. Here, we present functional structural characterization proteins viral rhodopsin group 1, OLPVR1 VirChR1. Functional analysis VirChR1 shows it highly selective, Na+/K+-conducting channel and, contrast to known cation channelrhodopsins, impermeable Ca2+ ions. We show that, upon illumination, able drive neural firing. The 1.4 Å resolution structure reveals remarkable differences from channelrhodopsins unique ion-conducting pathway. Thus, 1 represent unique, large light-gated channels (viral VirChR1s). In nature, VirChR1s likely mediate phototaxis algae enhancing host anabolic processes support virus reproduction, therefore, might play major dynamics. Moreover, have potential for optogenetics they lack possibly noxious permeability.

Language: Английский

---

AAV-S: A versatile capsid variant for transduction of mouse and primate inner ear

Molecular Therapy — Methods & Clinical Development, Journal Year: 2021, Volume and Issue: 21, P. 382 - 398

Published: March 30, 2021

Gene therapy strategies using adeno-associated virus (AAV) vectors to treat hereditary deafnesses have shown remarkable efficacy in some mouse models of hearing loss. Even so, there are few AAV capsids that transduce both inner and outer hair cells-the cells express most deafness genes-and fewer still efficiently primates. with robust transduction primate cochlea will be needed for clinical trials. Here, we test a capsid previously isolated from random library, AAV-S, non-human ear. In mice cynomolgus macaques, AAV-S mediates highly efficient reporter gene expression variety cochlear cells, including fibrocytes, supporting cells. model Usher syndrome type 3A, encoding CLRN1 robustly durably rescues hearing. Overall, our data indicate is promising candidate therapeutic delivery the human

Language: Английский

---

Choice of vector and surgical approach enables efficient cochlear gene transfer in nonhuman primate

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: March 15, 2022

Abstract Inner ear gene therapy using adeno-associated viral vectors (AAV) promises to alleviate hearing and balance disorders. We previously established the benefits of Anc80L65 in targeting inner outer hair cells newborn mice. To accelerate translation humans, we now report feasibility efficiency surgical approach vector delivery a nonhuman primate model. Five rhesus macaques were injected with AAV1 or expressing eGFP transmastoid posterior tympanotomy access round window membrane after making small fenestra oval window. The procedure was well tolerated. All but one animal showed cochlear expression 7–14 days following injection. 2 animals transduced up 90% apical cells; markedly less efficient at equal dose. Transduction for both declined from apex base. These data motivate future translational studies evaluate human

Language: Английский

---

Toward Optogenetic Hearing Restoration

Annual Review of Neuroscience, Journal Year: 2024, Volume and Issue: 47(1), P. 103 - 121

Published: April 10, 2024

The cochlear implant (CI) is considered the most successful neuroprosthesis as it enables speech comprehension in majority of million otherwise deaf patients. In hearing by electrical stimulation auditory nerve, broad spread current from each electrode acts a bottleneck that limits transfer sound frequency information. Hence, there remains major unmet medical need for improving quality with CIs. Recently, optogenetic cochlea has been suggested an alternative approach restoration. Cochlear optogenetics promises to more information, hence hearing, light can conveniently be confined space activate nerve within smaller tonotopic ranges. this review, we discuss latest experimental and technological developments restoration outline remaining challenges en route clinical translation.

Language: Английский

---

μLED‐based optical cochlear implants for spectrally selective activation of the auditory nerve

EMBO Molecular Medicine, Journal Year: 2020, Volume and Issue: 12(8)

Published: June 29, 2020

Article29 June 2020Open Access Transparent process μLED-based optical cochlear implants for spectrally selective activation of the auditory nerve Alexander Dieter orcid.org/0000-0002-9154-4833 Institute Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Germany Göttingen Graduate School Neurosciences Molecular Biosciences, Search more papers by this author Eric Klein orcid.org/0000-0003-2593-059X Department Microsystems Engineering (IMTEK), Freiburg, Daniel Keppeler orcid.org/0000-0002-2638-8731 Lukasz Jablonski orcid.org/0000-0002-4288-6917 Optogenetics Laboratory, German Primate Center, Tamas Harczos orcid.org/0000-0003-3888-5636 Gerhard Hoch Vladan Rankovic orcid.org/0000-0003-0285-5232 Restorative Cochlear Genomics Group, Oliver Paul orcid.org/0000-0002-2371-7448 BrainLinks-BrainTools, Cluster Excellence, Marcus Jeschke orcid.org/0000-0002-9109-8765 Cognitive Hearing in Primates Patrick Ruther Corresponding Author [email protected] orcid.org/0000-0002-7358-003X Tobias Moser orcid.org/0000-0001-7145-0533 Max Planck Experimental Medicine, Excellence "Multiscale Bioimaging: from Machines to Networks Excitable Cells" (MBExC), Goettingen, Information Dieter1,2,†,‡, Klein3,‡, Keppeler1, Jablonski1,4, Harczos1,4, Hoch1,4, Rankovic1,4,5, Paul3,6, Jeschke1,4,7, *,3,6 *,1,2,4,8,9 1Institute 2Göttingen 3Department 4Auditory 5Restorative 6BrainLinks-BrainTools, 7Cognitive 8Auditory 9Cluster †Present address: Synaptic Wiring Lab, Neurobiology Hamburg, Hamburg-Eppendorf, ‡These authors contributed equally work *Corresponding author. Tel: +49 7612 037197; E-mail: 5513 963070; EMBO Mol Med (2020)12:e12387https://doi.org/10.15252/emmm.202012387 See also: SR Kitcher & CJC Weisz (August 2020) PDFDownload PDF article text main figures. Peer ReviewDownload a summary editorial decision including letters, reviewer comments responses feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures Info Abstract Electrical (eCIs) partially restore hearing enable speech comprehension than half million users, thereby re-connecting deaf patients scene surrounding them. Yet, eCIs suffer limited spectral selectivity, resulting current spread around each electrode contact causing poor recognition presence background noise. Optogenetic stimulation might overcome limitation as light can be conveniently confined space. Here, we combined virus-mediated optogenetic manipulation spiral ganglion neurons (SGNs) microsystems engineering establish acute multi-channel implant (oCI) adult Mongolian gerbils. oCIs based on 16 microscale thin-film light-emitting diodes (μLEDs) evoked tonotopic pathway with high selectivity modest power requirements These results prove feasibility nerve. Synopsis effectiveness individuals remains electric cochlea. This study explores potential optogenetics restoration through combining engineering. rodent The strength induced scales number recruited emitters. μLED-evoked neural are selective. combination gene therapy enables higher precision paper explained Problem electrically stimulating As spreads far electrode, electrical is limited, frequency resolution implants. Results optogenetically rendered gerbil sensitive μLED-based, 16-channel We demonstrated that precision. Impact suggest μLEDs improved suffering sensorineural loss. Introduction According World Health Organization (Adrian et al, 2019), 6.1% human population suffers disabling loss, an economic impact 750 billion dollars spent treatment development. Approximately 90% cases loss dysfunction cochlea and/or today, causal therapies do not exist. Hence, methods choice aids (eCI). When profound or complete, used bypass dysfunctional lost sensory hair cells stimulate SGNs. utilize intrinsic place-frequency map (known tonotopy) SGNs provide patient information acoustic stimuli (Zeng 2008). However, while open achieved most approximately 700,000 eCI there substantial unmet clinical need improvement restoration. Current electro-conductive fluids limits spatial—and thus spectral—selectivity SGN consequently sound encoding. ultimately compromises signal perception, especially noisy environments (Kral 1998; Friesen 2001; Middlebrooks 2005). While efforts being undertaken toward activation, e.g. via multipolar (Berenstein 2008) direct electrode-neural interfacing (Middlebrooks Snyder, 2007), it seems excitation bottleneck eCIs. Recently, has been suggested stimulation, which—as opposed current—can space, could activate selectivity. Thus, (oCIs) increase artificial encoding (Richter 2011; Hernandez 2014). Two approaches have proposed SGNs: (i) infrared 2011) (ii) (Hernandez remained controversial (Verma 2014; Thompson 2015; Baumhoff use light-gated ion channels (Channelrhodopsins, ChRs) consistently reported several laboratories Duarte 2018; Hart 2020). Establishing challenging, multidisciplinary task (Kleinlogel 2020; Moser, Weiss 2016; Richardson 2017). major objectives must met: First, render coding at good temporal Second, allow Temporally precise control established fast gating ChR variants (Duarte Mager 2018). Furthermore, spatially individual fibers shown elicit 2019). studies biomedical prerequisites revealed very promising results. Toward development implants, fabricated both commercially available (LEDs) gallium nitride-based, custom-developed LEDs micrometer range (Goßler Schwaerzle Xu LED-based (Schwaerzle 2018) typically carried 10–15 emitters sized 0.22 1 mm, were manufactured up 144 60 × μm (Klein Individual these achieve output mW (corresponding emittance 400 mW/mm² μLED surface), maximum temperature K (driven 10 mA, s water) 2018), efficient enough drive ChRs safe vivo application. Peak intensity extraction further increased (by 95% 83%, respectively) implementation conical concentrators spherical micro-lenses emitter surface 2019b). any yet. In study, viral transfer ChR-variant CatCh into gerbils 16-channel, oCIs. demonstrate μLED-mediated 32-channel recordings multi-neuronal clusters midbrain manner. Modest was even some μLEDs, substantially when recruiting additional Finally, four neighboring compared clinical-style proof raises hope indeed limitations quality future. Multi-channel To sensitive, intramodiolarly injected suspension adeno-associated virus (AAV-PHP.B; Deverman 2016) carrying calcium translocating channelrhodopsin CatCh, fused reporter protein eYFP, under synapsin promoter, (Wrobel Functional expression probed brainstem activity upon illumination laser-coupled fiber round window early 4 weeks after injection (Fig 1A). Opsin function (robust optically responses, oABRs) 15/35 animals (~43%; Fig EV1). SGNs, lack obvious inner cells, post-mortem immunohistochemistry subset oABR-positive 1B–D), only sparse opsin found oABR-negative animal EV2). Animals detectable oABRs subsequent electrophysiological multi-unit central nucleus inferior colliculus (ICC) using linear multi-electrode arrays (IC datasets recorded 12 out 15 animals). For housing individually addressable (peak wavelength: 462 nm; μm, 1E F) pitch either 100, 150, 250 (center-to-center distance) embedded biocompatible epoxy medical-grade silicone 1G; roughening amounted 0.76 (± 0.21 SD) driven mA 1H) 3.15 1.1 all oCI 40 (Appendix S1). Using retroauricular approach, inserted isoflurane-anesthetized cochleostomy, whereby covered maximally third basilar membrane length 1I J). Figure 1. A. Optically response AAV-CatCh-injected ms laser pulse ˜35 (mean 1,000 stimulus presentations Hz repetition rate). B–D. Catch-eYFP-expressing apical turn identified parvalbumin (B) CatCh-eYFP (C). inlay (D′) merged immunostaining (D) indicates CatCh-EYFP (dashed white line). Scale bar: 20 μm. E, F. Scanning electron micrographs (60 footprint) structured sapphire substrate showing non-emitting p-contact side (E) emitting (F), transferred onto substrate. GaN roughened KOH etching characteristic pyramidal structures (F, inset). G. Picture 100 flexible substrate, #5 #13 (from tip) active. H. Radiant flux driving current. thick line mean, error bars SD mean. Non-functional (which did emit light, 158 560 μLEDs) excluded. I. black lines) cochleostomy basal (black, solid niche highlighted dashed line, line. SA: stapedial artery. J. 3D X-ray tomography reconstruction implanted window. Cables marked blue, indicated arrowhead; green. size Download figure PowerPoint Click here expand figure. EV1. responsesFunctional verified CatCh-injected start experiment before recordings. Optical occurred pulses ~35 radiant duration rate delivered 200 Each trace represents average one animal. oABR top right also 1A. Gray animals, which no IC data obtained (due death misplacement array). EV2. (recording parameters EV1) response. Catch-eYFP-staining transduction few 50 Acoustic calibration interpret compare across positioning along axis ICC physiologically confirmed pure tones varying intensity. Frequency tuning recording sites accessed performing cranial surgeries measuring oABRs. Characteristic frequencies derived responsive slopes calculated fit depth EV3A). Median 4.34 octaves/mm 0.42 median absolute deviation, n = 11), consistent previous where between 4.08 4.58 (Harris 1997; Schnupp deafened probe stereotactically slope regular assigned since mapping performed (n 5; EV3B). EV3. Tonotopy (normally distributed jitter 0.05 octaves added unit reduce overlay points better visualization). Tonotopic linearly fitting given depths (N 11). Data different colors. Inset: Distribution 11 contributing study. B. Electrode position 5). silicon placed normal but tonotopy mapped. Inferior first evaluated peri-stimulus time histograms (i.e., active intensity, ~3.15 mW; raw trace, scatter plot, PSTH Appendix S2), occur 3.5–17.5 onset. Since transient artifact observed traces onset, quantify set 3–20 order avoid without discarding responses. During window, increasing sorted two-dimensional matrix according corresponding site From matrix, cumulative discrimination index (d-prime, d′) spike rates intensities, starting zero condition baseline; 2007; Richter d′ quantifies change i.e., equal rise firing SD. estimate patterns spatial curves (STCs) constructed iso-contour lines integer values 2A–D). A bilateral intracochlear application kanamycin, leads cell hence creates model Deafening clicks. Mean thresholds click-evoked 30 ± 0 dB SPL deafening 5), clicks 5–10 days kanamycin 2E). still possible 2F G). Neural vanished sacrificed 2H). 2. evoke A–D. Exemplar STCs single (A), block (B), CatCh-transduced (C) wild-type (WT; D). spaced E. (average Hz) click (left) (right; star: threshold). (right), elicited duration, (1,000 presented Hz), same system deafening. Differences amplitude waveform likely due electrodes fiber. G, CatCh-transduced, kanamycin-deafened (G) (H) sacrifice. Maximum (indiv.; 129/77 N 9/3 hearing/deaf gerbils), (block; 62/27 blocks (all; 24/9 gerbils) (˜35 stimulations (one-way ANOVA (F-value: 73.25, degrees freedom, P 5.19 10−45) post-hoc multiple comparison test; indiv. vs. block: 9.9 10−9; all: 0.0096; fiber: 0.0016; WT: 10−9;**P < 0.01, ***P 0.001, n.s. non-significant). WT 7/7 oCIs, 2/2 (post-mortem; 5/1 gerbils). Brown dots indicate animals. Number (d′ > 1; mean 30.18, 1.42 10−21) 6.8 10−5; 0.006; 0.25; **P Responses hearin

Language: Английский

---

Is there an unmet medical need for improved hearing restoration?

EMBO Molecular Medicine, Journal Year: 2022, Volume and Issue: 14(8)

Published: July 14, 2022

Language: Английский

---

Optical stimulation of neural tissue

Healthcare Technology Letters, Journal Year: 2020, Volume and Issue: 7(3), P. 58 - 65

Published: May 19, 2020

Electrical stimulation has been used for decades in devices such as pacemakers, cochlear implants and more recently deep brain retinal electroceutical treatment of disease. However, current spread from the electrodes limits precision neural activation, leading to a low quality therapeutic outcome or undesired side-effects. Alternative methods optical offer potential deliver higher spatial resolution activation. Direct is possible with infrared light, while visible light can be activate neurons if tissue genetically modified sensitive ion channel. Experimentally, both have resulted highly precise little activation at least cochlea, each advantages disadvantages. Infrared does not require modification tissue, but very high power requirements. Optogenetics achieve lower power, only conjunction targeted insertion channel into nervous system via gene therapy. This review will examine limitations using cochlea an exemplary model recent developments stimulation.

Language: Английский

---

Hybrid optogenetic and electrical stimulation for greater spatial resolution and temporal fidelity of cochlear activation

Journal of Neural Engineering, Journal Year: 2020, Volume and Issue: 17(5), P. 056046 - 056046

Published: Oct. 1, 2020

Abstract Objective. Compared to electrical stimulation, optogenetic stimulation has the potential improve spatial precision of neural activation in neuroprostheses, but it requires intense light and relatively poor temporal kinetics. We tested effect hybrid which is combination subthreshold optical stimuli, on spectral fidelity cochlea by recording multiunit activity inferior colliculus channelrhodopsin (H134R variant) transgenic mice. Approach. Pulsed or biphasic pulses were delivered cochlear spiral ganglion neurons acutely deafened mice, either as individual stimuli for timing pulse had a varied delay relative start pulse. Response thresholds, spread entrainment data obtained from multi-unit recordings auditory midbrain. Main results. Facilitation occurred when applied at end of, up 3.75 ms after pulses. The resulting was significantly narrower than electrical-only optical-only (p < 0.01), measured equivalent suprathreshold levels loudness that are relevant implant users. Furthermore, fidelity, maximum following rates 300 trains bursts 240 Hz, 2.4-fold greater 0.05). Significance. By improving resolution electrical- increase number perceptually independent stimulating channels implant.

Language: Английский

---

Utility of red‐light ultrafast optogenetic stimulation of the auditory pathway

EMBO Molecular Medicine, Journal Year: 2021, Volume and Issue: 13(6)

Published: May 7, 2021

Optogenetic stimulation of spiral ganglion neurons (SGNs) in the ear provides a future alternative to electrical used current cochlear implants. Here, we employed fast and very variants red-light-activated channelrhodopsin (ChR) Chrimson (f-Chrimson vf-Chrimson) study their utility for optogenetic SGNs mice. The light requirements were higher vf-Chrimson than f-Chrimson, even when optimizing membrane expression by adding potassium channel trafficking sequences. time intensity coding single putative compared with acoustic clicks. enabled fire at near-physiological rates good temporal precision up 250 Hz stimulation. dynamic range SGN spike rate upon was narrower clicks but larger reported timing, on other hand, more comparable In conclusion, f-Chrimson are promising candidates auditory research

Language: Английский

---