Visual Neurophysiology OptoG 1675 Lecture 15 PDF

Visual Neurophysiology OPTOG 1675 Prosthetics, Stem Cells, New Technology Lecture 15  Learning Objectives Gain a basic familiarity with some of the ocular prosthetics that are available or in development – Ocular devices – Retinal implants – Other t...

Visual Neurophysiology OPTOG 1675 Prosthetics, Stem Cells, New Technology Lecture 15  Learning Objectives Gain a basic familiarity with some of the ocular prosthetics that are available or in development – Ocular devices – Retinal implants – Other types Understand how stem cell and gene therapy are being used to restore vision – RPE cells – Photoreceptors – RPE-65 – Optogenetics Be acquainted with new technologies being developed to restore or improve visual functioning in visually impaired patients  Topics Ocular prosthetics – Optical devices – Retinal implants – Optogenetic approaches Stem cells and gene therapy – RPE cells – Photoreceptors – RPE-65 New technology Ocular Prosthetics Optical Devices  Artificial Iris Custom Flex Artificial Iris approved by FDA in 2018 Can be implanted in the bag or behind residual iris material Used for aniridia, albinism, iris removal due to melanoma Used to decrease photosensitivity and for cosmesis https://www.humanoptics.com/en/physicians/artificialiris/ , 2021 Treatment of aniridia  Artificial Cornea FDA approved For use in end stage corneal disease Used after multiple corneal transplant failures or when patient is not a good candidate Nonpassopon et al. 2020 for a corneal transplant Boston Type I Keratoprosthesis – Advanced ocular surface disease, corneal burn or irradiation, etc. Type I Type II 12 to 20% failure rate at 3y (Boston Type I) – Retroprosthesis membrane formation (Cassard et al. 2015) (https://crstoday.com/articles/mast – Extrusion ering-the-complexities-of-cornea- care/type-2-boston- keratoprosthesis-for-end-stage- ocular-cicatricial-pemphigoid)  3D Printed Cornea “Ink” – Decellularized corneal stroma - e.g., collagen polymers – Stem cells in periphery - autologous or heterologous corneal stem cells 3D Printing – Printing protocol is key to get clear stroma with cells in correct location – Can be printed in lab or on patient’s eye New cornea needs to be biocompatible and resistant to rejection Technology being investigated by several groups - mainly in academia https://www.sculpteo.com/blog/2018/08/31/3d-printed-eyes-how-far-the-research-has-moved-on/  Implantable Miniature Telescope Approved by FDA for use in advanced AMD A central or paracental scotoma can dramatically reduce useful vision, even if small The telescope does not eliminate the scotoma, but increases size of image Scotoma becomes a smaller (Cornea Consultants of Texas website, 2014) part of central visual field Effect of Scotoma on Vision Acuity Using Telescope Visual acuity declines with eccentricity from the center of the macula (~ 5 minutes of arc) – Highest cone density is 0.3mm area comprising the fovea Larger visual areas are seen clearly by moving the eye so that all regions are brought to the fovea The best acuity will be that of the area immediately surrounding the scotoma – If scotoma wipes out central 5 degrees, best acuity will be ~20/60 View Without IMT Same View with IMT Device Ocular Prosthetics Retinal Implants  Argus II Retinal Prosthesis Approved by FDA for advanced RP Approximate cost = $115,000 Image is by acquired by “glasses” and processed Processed information is transmitted to receiver attached around eye Receiver is connected to array of 60 electrodes placed over macula on outer retina Electrodes directly stimulate retinal ganglion cells Argus II Components Arevalo et al., 2021  Argus II Limitations 60 electrodes (200 in next generation device) compared to millions of cones Physical size of electrodes and leads may limit maximum size of array Ignores circuitry of retina and directly stimulates ganglion cells – Retina is not just light detector, but has processing functions Surgery is done in adults – less plasticity  Argus II – Functional Restoration 23% can resolve 13° grating (~20/1200) Locate lights and windows Follow lines in a crosswalk Avoid running into large objects Determine where other people are located in a room Read very large letters (9”) Sort laundry Pixium Vision - IRIS II Epiretinal Implant Epi-retinal implant – Attached on the surface of the retina – Can be ex-planted for upgrade 150 IR powered electrodes on surface of retina Glasses – “Bioinspired” camera – Sends IR signal to electrodes In clinical trials, restores vision to 20/250  The Prima System Subretinal wireless photovoltaic implant – 378 electrodes – Each with its own local return circuit Glasses – Camera and digital projector – Power source for electrodes Pocket computer – Processes camera input with “breakthrough algorithms” – Sends information to projector Muquit etal. 2024 In clinical trials  PRIMA 4 Year F/U Subretinal implantation of PRIMA in subjects with GA was well tolerated No reduction was seen in natural peripheral vision up to 48 months With prosthetic vision (with zoom – up to 8X magnification) – Reliably recognize letters and sequences of letters – Product names on food packages – Signs outdoors and indoors – Train timetable – Improved VA by up to 8 ETDRS lines (best improvement at 24 months) PRIMA 4 year F/U 20/600 20/250 20/400 20/200 20/125 Muquit etal. 2024 Nano Retina NR600 Chip placed in inner retinal surface – Responsive to light – Electrodes (n~600) stimulate OPL – Rechargeable by IR light 3DNi neural interface – Processes light signal and stimulates retina through electrodes Wireless, rechargeable glasses – IR recharging of chip – Fine-tuning of implant In clinical trials  Optogenetics Definition: The integration of optics and genetics to control precisely defined events within specific cells in living tissue – Cells are made responsive to light so that their activity levels can be controlled – The effects of very localized changes in cell activity on function can then be studied Has both research and clinical applications  Optogenetics Protocol The gene for a protein that is responsive to light is transfected into cells – Channelrhodopsin-2 (ChR2) is often used – Neurons are often targeted Cells are illuminated, activating the protein and altering their state – Illumination of ChR2 expressed in neurons causes depolarization (Lumercor website 2014) Functional Results Rd 10 mice (no photoreceptors) ChR2 transfected into “ON” bipolar cells Able to run a water maze with a lighted escape arm faster than sham transfected mice Doroudchi et al., 2011 The effect persisted for at least 10 months  Optogenetics in RP Adenoassociated viral vector encoding a light-sensing channelrhodopsin protein – Peak sensitivity of protein (ChrimsonR-tdTomato) is around 590nm (amber color) – Amber light is safer and causes less pupil constriction Administered by a single IVT injection into the worse-seeing eye Light-stimulating goggles capture images using a “neuromorphic” camera that detects changes in intensity, pixel by pixel, as distinct events – Looking for local changes in light intensity – Must be above a threshold to be detected The goggles then transform the events into monochromatic images and project them in real time as local 595-nm light pulses onto the retina – More like normal pattern of ganglion cell stimulation than constant light is  Optogenetics in RP RP patient whose vision was LP in both eyes (single patient study) Task: Identify whether one or more tumblers are present in field (forced choice) – Perceive – Count – Locate EEG also recorded Larger study (Starlight) now Sahel et al., 2021 underway Optogenetics in RP Optogenetics plus Software ChR-2 is expressed in retinal ganglion cells of rd1 mice (lack photoreceptors) Responses of the retinal ganglion cells in a sighted mouse to an image are recorded in the encoder – Each cell recorded while viewing a different part of the movie The transducer presents the required light pattern to produce the same response to the ChR-2 expressing retina The encoded stimulus (bottom middle) produces a response in the retinal ganglion cells that mimics the normal response (top) The response from the un-encoded stimulus (standard, bottom) has much lower fidelity  Ocular Optogenetics Characteristics Advantages – Light stimulation is on a cellular scale – better acuity – Stimulation of bipolar cells preserves part of retinal function – Addition of signal processing may produce more normal ganglion cell responses Disadvantages – Gene therapy is required – Data collection to program system would be required (for system with signal processing) Stem Cells and Gene Therapy  Ocular Stem Cell Research Types of cells employed: – hESC – iPSC Types of ocular cells produced: – Rod photoreceptors – Retinal pigment epithelium (RPE) cells  Rod Photoreceptors Differentiated from iPSC cells (swine) Implanted into subretinal space of swine eyes after elimination of rods (treated with iodoacetic acid) Cells migrated to ONL and produced rod-like segments (arrow) No significant change in ERG (Zhou 2011)  RPE Cells (Schwartz 2015) Differentiated from hESC and injected subretinally Expanded and persisted for up to 37m, no serious adverse effects Currently in clinical trials for Stargardt Macular Dystrophy and AMD (above)  Effects of RPE Visual improvement in 17 AMD of 18 patients with AMD or Stargardt MD (n=9, each) Gained ~15 letters on ETDRS chart (~ three lines) Stargardt’s – Change in AMD was statistically significant Gains persisted for over 10 months  RPE Transplantation Progress Many cells and preparations tried – hESC, iPSC – Autologous vs. donor cells – Cell suspensions – Cell layers Reasonable safety Marginal / mixed results – Damage to RPE cells → damage to photoreceptors – Replacing lost RPE cells = Locking the barn door after the horse is stolen? Gene Therapy – Luxturna Voretigene neparvovec-RZYL intraocular suspension, Spark Therapeutics Adeno-associated virus vector-based RPE65 gene therapy Suspension delivered by subretinal injection (single treatment in each eye, 6 days apart) Indicated for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy, e.g.: Leber congenital amaurosis Autosomal recessive retinitis pigmentosa “Patients must have viable retinal cells” (i.e., RPE cells) Luxturna Clinical Data Pediatric and adult patients Results measured after 1 year Multi-luminance mobility testing showed significant improvement Rated while navigating a course with obstacles of varying height under different levels of illumination Full-field light sensitivity threshold testing also significantly improved VA was unchanged Cost of drug = $850,000 (both eyes) New Technology  Oral Electronic Vision BrainPort Vision Pro Translates digital information from a wearable video camera into electrical stimulation patterns on the surface of the tongue Users feel moving bubble-like patterns on their tongue which they learn to interpret as the shape, size, location and motion of objects in their environment  BrainPort Vision Pro Seventeen adults with profound blindness d/t traumatic injury (Grant et al., 2018) None of the participants could successfully perform any of the functional tasks (below) at baseline After 1 year of independent device use, – 100% could identify objects – 41% identified words beyond chance level – 41% percent of participants could locate a sign – 94% followed a line without veering off – 71% avoided obstacles – 71% walked through a doorway without collision – 100% recognized a door – 71% identified a window. BrainPort Vision Pro  Cortical Implant Orion® - Second Sight Medical Products Cortical implant with sixty electrodes Delivers stimulation directly to V1, based on processed output from camera Patient perceives phosphenes that appear as a spot of light, a circle, an oval, or a line (i.e., the basic visual fields of V1) Patient must learn to “interpret” what they are seeing  Neurable Brain-computer interface Uses advanced machine learning techniques to classify electrical signals produced by brain The signals are converted into actionable “insights” for measuring emotion (keeping people alert) and providing control of connected devices Usable for vision enhancement? Working on earbud version of device neurable.com 2023 Quiz 1. Which of the following devices would have been LEAST useful to Michael May after his corneal burns? A. 3D printed cornea B. Artificial corneal implant C. Artificial iris D. Prima retinal prosthesis 1. Which of the following devices would have been LEAST useful to Michael May after his corneal burns? A. 3D printed cornea B. Artificial corneal implant C. Artificial iris D. Prima retinal prosthesis 2. Which of the following would be the best most helpful for a patient with a central scotoma? A. 3D printed cornea B. Artificial corneal implant C. Implantable miniature telescope D. Luxturna 2. Which of the following would be the best most helpful for a patient with a central scotoma? A. 3D printed cornea B. Artificial corneal implant C. Implantable miniature telescope D. Luxturna 3. Which of the following activities would a patient be LEAST likely to be able to perform after an ARGUS II retinal implant? A. Locate lights and windows B. Follow lines in a crosswalk C. Read street signs while driving D. Sort laundry 3. Which of the following activities would a patient be LEAST likely to be able to perform after an ARGUS II retinal implant? A. Locate lights and windows B. Follow lines in a crosswalk C. Read street signs while driving D. Sort laundry 4. Which of the following types of retinal treatments has the potential to restore the best vision? A. Implantation of Argus II type device, but with many more electrodes B. Implantation of photovoltaic chip with printed pillars C. Subretinal transplantation of RPE stem cells D. Transfection of ganglion cells with photoreceptive proteins 4. Which of the following types of retinal treatments has the potential to restore the best vision? A. Implantation of Argus II type device, but with many more electrodes B. Implantation of photovoltaic chip with printed pillars C. Subretinal transplantation of RPE stem cells D. Transfection of ganglion cells with photoreceptive proteins 5. Which of the following activities were subjects using a BrainPort Vision Pro device LEAST successful at doing? A. Avoiding obstacles while walking B. Identifying simple objects C. Identified words beyond chance level D. Walking through a doorway without collision 5. Which of the following activities were subjects using a BrainPort Vision Pro device LEAST successful at doing? A. Avoiding obstacles while walking B. Identifying simple objects C. Identified words beyond chance level D. Walking through a doorway without collision