Periodic Reporting for period 4 - HURET (The human retina at single cell resolution: functional architecture, disease mechanism and therapy development)
Berichtszeitraum: 2025-05-01 bis 2025-10-31
Project Overview
The ERC-funded research project HURET advanced our understanding of human vision and developed innovative therapies to restore sight in patients with blinding diseases. The work spanned three major aims: characterizing the diversity of vision-processing cells in the human retina, uncovering why specific cells die in retinal diseases, and developing therapies to restore vision in blind patients.
A. Main Achievements
1. Understanding the Human Visual System
A fundamental challenge in vision science has been understanding how the human retina processes visual information. Unlike animal models, the human retina has been largely inaccessible for detailed functional study. We overcame this barrier by developing novel methods to record electrical signals from human retinal cells obtained postmortem, keeping them functional for weeks after death.
Using these techniques, we discovered and characterized the diverse types of ganglion cells—the neurons that transmit visual information from the eye to the brain. Our findings revealed fundamental aspects of how human retinal circuits compute visual features relevant to perception. We also developed single-cell gene delivery technology that allows precise manipulation of individual neurons, enabling detailed circuit analysis. This method, which we initially pioneered in mouse brains, has broad applications beyond vision research.
2. Protecting Vulnerable Cells from Degeneration
Retinal degenerative diseases affect millions worldwide, often leading to irreversible blindness. A major barrier to developing treatments has been understanding why certain cell types die while others survive. We tackled this question through multiple complementary approaches.
We created 20,000 human retinal organoids—miniature retinas grown from stem cells—with fluorescently labeled cone photoreceptors, the cells responsible for color vision and high-resolution sight. Using these organoids, we systematically tested 2,707 drugs to identify compounds that either protected cones from death or accelerated their demise. This large-scale screen identified several promising therapeutic candidates, that robustly protected dying cones. We also discovered that certain commonly used drug classes have unexpected toxic effects on cones, providing novel safety information for future therapy development.
We also investigated retinitis pigmentosa, a disease where rod photoreceptors (responsible for night vision) die first, eventually leading to complete blindness. Through systematic screening in mouse models, we identified a previously unknown biological pathway that drives rod cell death, opening new avenues for therapeutic intervention.
3. Restoring Vision Through Advanced Technologies
Perhaps the most ambitious goal was developing methods to restore vision in patients already blind from retinal degeneration. We pursued multiple approaches, achieving several new results.
Near-infrared vision represents a new sensory capability. We engineered heat-sensitive proteins from snakes and mammals to respond to near-infrared light, then combined them with gold nanoparticles that convert light to localized heating. When delivered to surviving retinal cells in blind mice, this system restored light-driven behavior, effectively giving the animals infrared vision. By tuning the nanoparticle size and protein sensitivity, we could adjust the wavelengths and intensities that triggered vision. We successfully adapted this technology to human retinal tissue, demonstrating its translational potential.
We also achieved a milestone in optogenetics—using light-sensitive proteins to control neural activity. Working with Jose Sahel and other clinical partners, we treated blind retinitis pigmentosa patients with a gene therapy vector encoding a light-sensitive protein (ChrimsonR) and provided engineered goggles that detected objects and projected corresponding light patterns onto the retina. Months after treatment, several patients regained the ability to perceive, locate, count, and touch objects using only the treated eye with the goggles. Brain recordings confirmed visual cortex activation during object perception—something absent before treatment. This first demonstration of functional recovery from a neurodegenerative disease using optogenetic therapy opens new possibilities for treating blindness and other neurological conditions.
B. Scientific Impact and Future Directions
This project generated fundamental insights into human retinal function and developed multiple therapeutic strategies now advancing toward clinical application. The human retinal recordings enable detailed functional analysis of human vision in the eye. Our organoid-based drug screening platform provides a scalable approach to identify neuroprotective compounds for various retinal diseases. The optogenetic vision restoration technologies represent a major step in treating inherited and degenerative blindness.
The work resulted in high-impact publications with several additional manuscripts under review. Perhaps most importantly, we have trained the next generation of vision scientists and demonstrated that interdisciplinary approaches can solve long-standing challenges in neuroscience and medicine.
Looking forward, these discoveries lay the foundation for clinical trials testing photoreceptor-protective drugs, precision gene therapies for inherited retinal diseases, and advanced optogenetic vision restoration systems. The fundamental knowledge gained about human retinal circuits will inform the development of more sophisticated gene therapies targeting specific cell types. This project demonstrates how basic research into the mechanisms of human vision can directly translate into treatments for blindness.
The ERC-funded research project HURET advanced our understanding of human vision and developed innovative therapies to restore sight in patients with blinding diseases. The work spanned three major aims: characterizing the diversity of vision-processing cells in the human retina, uncovering why specific cells die in retinal diseases, and developing therapies to restore vision in blind patients.
A. Main Achievements
1. Understanding the Human Visual System
A fundamental challenge in vision science has been understanding how the human retina processes visual information. Unlike animal models, the human retina has been largely inaccessible for detailed functional study. We overcame this barrier by developing novel methods to record electrical signals from human retinal cells obtained postmortem, keeping them functional for weeks after death.
Using these techniques, we discovered and characterized the diverse types of ganglion cells—the neurons that transmit visual information from the eye to the brain. Our findings revealed fundamental aspects of how human retinal circuits compute visual features relevant to perception. We also developed single-cell gene delivery technology that allows precise manipulation of individual neurons, enabling detailed circuit analysis. This method, which we initially pioneered in mouse brains, has broad applications beyond vision research.
2. Protecting Vulnerable Cells from Degeneration
Retinal degenerative diseases affect millions worldwide, often leading to irreversible blindness. A major barrier to developing treatments has been understanding why certain cell types die while others survive. We tackled this question through multiple complementary approaches.
We created 20,000 human retinal organoids—miniature retinas grown from stem cells—with fluorescently labeled cone photoreceptors, the cells responsible for color vision and high-resolution sight. Using these organoids, we systematically tested 2,707 drugs to identify compounds that either protected cones from death or accelerated their demise. This large-scale screen identified several promising therapeutic candidates, that robustly protected dying cones. We also discovered that certain commonly used drug classes have unexpected toxic effects on cones, providing novel safety information for future therapy development.
We also investigated retinitis pigmentosa, a disease where rod photoreceptors (responsible for night vision) die first, eventually leading to complete blindness. Through systematic screening in mouse models, we identified a previously unknown biological pathway that drives rod cell death, opening new avenues for therapeutic intervention.
3. Restoring Vision Through Advanced Technologies
Perhaps the most ambitious goal was developing methods to restore vision in patients already blind from retinal degeneration. We pursued multiple approaches, achieving several new results.
Near-infrared vision represents a new sensory capability. We engineered heat-sensitive proteins from snakes and mammals to respond to near-infrared light, then combined them with gold nanoparticles that convert light to localized heating. When delivered to surviving retinal cells in blind mice, this system restored light-driven behavior, effectively giving the animals infrared vision. By tuning the nanoparticle size and protein sensitivity, we could adjust the wavelengths and intensities that triggered vision. We successfully adapted this technology to human retinal tissue, demonstrating its translational potential.
We also achieved a milestone in optogenetics—using light-sensitive proteins to control neural activity. Working with Jose Sahel and other clinical partners, we treated blind retinitis pigmentosa patients with a gene therapy vector encoding a light-sensitive protein (ChrimsonR) and provided engineered goggles that detected objects and projected corresponding light patterns onto the retina. Months after treatment, several patients regained the ability to perceive, locate, count, and touch objects using only the treated eye with the goggles. Brain recordings confirmed visual cortex activation during object perception—something absent before treatment. This first demonstration of functional recovery from a neurodegenerative disease using optogenetic therapy opens new possibilities for treating blindness and other neurological conditions.
B. Scientific Impact and Future Directions
This project generated fundamental insights into human retinal function and developed multiple therapeutic strategies now advancing toward clinical application. The human retinal recordings enable detailed functional analysis of human vision in the eye. Our organoid-based drug screening platform provides a scalable approach to identify neuroprotective compounds for various retinal diseases. The optogenetic vision restoration technologies represent a major step in treating inherited and degenerative blindness.
The work resulted in high-impact publications with several additional manuscripts under review. Perhaps most importantly, we have trained the next generation of vision scientists and demonstrated that interdisciplinary approaches can solve long-standing challenges in neuroscience and medicine.
Looking forward, these discoveries lay the foundation for clinical trials testing photoreceptor-protective drugs, precision gene therapies for inherited retinal diseases, and advanced optogenetic vision restoration systems. The fundamental knowledge gained about human retinal circuits will inform the development of more sophisticated gene therapies targeting specific cell types. This project demonstrates how basic research into the mechanisms of human vision can directly translate into treatments for blindness.
1. Developed new methods to record electrical signals from human retinal cells postmortem and keep them functional for weeks.
2. Created and screened 20,000 human retinal organoids with 2,707 compounds to identify drugs that protect cone photoreceptors from death.
3. Discovered a previously unknown biological pathway driving rod photoreceptor death in retinitis pigmentosa.
4. Engineered the first near-infrared vision restoration system by combining heat-sensitive proteins with gold nanoparticles.
5. Achieved the first functional recovery in a neurodegenerative disease using optogenetic therapy.
6. We disseminated these results through publications in peer reviewed journals and numerous invited talks at conferences.
7. We formed a spin-off company, RhyGaze (rhygaze.com) to advance our vision restoration discoveries toward clinical trials.
2. Created and screened 20,000 human retinal organoids with 2,707 compounds to identify drugs that protect cone photoreceptors from death.
3. Discovered a previously unknown biological pathway driving rod photoreceptor death in retinitis pigmentosa.
4. Engineered the first near-infrared vision restoration system by combining heat-sensitive proteins with gold nanoparticles.
5. Achieved the first functional recovery in a neurodegenerative disease using optogenetic therapy.
6. We disseminated these results through publications in peer reviewed journals and numerous invited talks at conferences.
7. We formed a spin-off company, RhyGaze (rhygaze.com) to advance our vision restoration discoveries toward clinical trials.
We provided the first recordings of light evoked activity from human retinas.
We performed the first cell type targeted compound screen in human retinal organoids.
We described the first method to restore visual activity using near-infrared light.
Together with Jose Sahel we reported the first blind patient who partially regained vision after optogenetic therapy.
We formed a spin-off company, RhyGaze (rhygaze.com) to advance our vision restoration discoveries toward clinical trials.
We performed the first cell type targeted compound screen in human retinal organoids.
We described the first method to restore visual activity using near-infrared light.
Together with Jose Sahel we reported the first blind patient who partially regained vision after optogenetic therapy.
We formed a spin-off company, RhyGaze (rhygaze.com) to advance our vision restoration discoveries toward clinical trials.