ARVO 2024   7

Spotlight on State of the Art in Neurodegenerative Blindness Therapies @ARVO 2024

From stem cells to gene editors, the future of stopping and even reversing neurodegenerative blindness is bright. Key players in the field presented the latest therapeutic strategies in cracking these diseases during a Day One morning session at ARVO 2024.

Few avenues of research possess the headline-grabbing pizzazz of therapeutics that reverse or halt the progress of neurodegenerative retinal diseases. 

Triumphs in the form of patients—often children—whose sight has been restored are among the most powerful stories in eye care. Countless practicing ophthalmologists and starry-eyed prospective researchers have been inspired by the prospect of bringing light to the darkness. 

Little wonder, then, at the standing room-only crowd at a Day One 8:00 am symposium, entitled, Advancing Therapeutic Strategies for Neurodegenerative Blindness, at the 2024 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO 2024) in Seattle. 

From breathtaking innovations in Leber congenital amaurosis (LCA) to novel approaches to retinal pigment epithelium (RPE) regenerative therapies in age-related macular degeneration (AMD) and beyond, attendees in Seattle were treated early and often to just what they came to ARVO 2024 to see: life-changing therapies at the cutting edge of ophthalmic medicine. 

Gene editing’s latest flourish

The symposium kicked off with one of the space’s most promising subtopics: gene editing. In his talk, Eye on Genome Editing, Dr. Krzysztof Palczewski of the University of California at Irvine briefly surveyed the current landscape in gene editors in ophthalmology before sharing his own work on the promise of prime editing. 

“In the last five years, there has been a quiet revolution in medicine with the invention of genome editing,” said Dr. Palczewski. This revolution, according to Dr. Palczewski, includes the evolution of gene therapies from CRISPR, Cas9, and base editing to prime editing. 

Prime editing’s promise is wrapped up in its ability to be a more versatile and specific form of genome editing. With this technology, therapies can make all 12 types of DNA substitutions, support both deletions and insertions, and solve challenges facing base editors like bystander editing, where unwanted bases near the target sequence are changed. 

At the moment, Dr. Palczewski identified the greatest issue with prime editing as optimization. “The process is still under intense scrutiny,” he explained. “How we improve efficiency, how we design the peg (prime editing guide) RNA—it’s not as trivial as it is with a base editor, but progress is truly weekly. It’s immense,” he said. 

By the end of his talk, Dr. Palczewski described his current, groundbreaking work with virus-like particles (VLPs) as a means of delivering prime editing components. This midway point between viral delivery like adeno-associated virus (AAV) and non-viral delivery mechanisms might hold the key to solving ongoing efficiency and optimization issues with prime editing, according to Dr. Pelczewski. 

Dr. Pelczewski’s presentation, which leaned on elements from papers from his group, is just the beginning for his group’s VLP-based prime editing technology.1,2

Much more of a flood of this promising work will be released throughout ARVO 2024. “It’s a very powerful technique,” he concluded. “We can measure outcomes very well, and we can do it for any disease, and we have already studied several of these genetic modifications.”

New ophthalmic horizons in stem cell treatments

Gene editing, however, is far from the only research avenue with massive promise in neurodegenerative retinal disease. Dr. Ruchi Sharma of the United States’ National Institutes of Health (NHI) was next with an update on her lab’s use of induced pluripotent stem cells (iPSC) patches in treating age-related macular degeneration (AMD).

The group’s hypothesis is that autologous iPSC-derived RPE replacement therapy for patients with AMD can stop photoreceptor degeneration and potentially regenerate the choriocapillaris.  

Much of Dr. Sharma’s work is in the proof-of-concept phase and is being done on pig eyes. One critical advancement has come using an AI algorithm called REShAPE for morphometric-based analysis to reduce iPSC-derived RPE batch-to-batch variability.3

“REShAPE analyzes every aspect of REP you can think of,” she said. “It can tell you how many neighbors each REP has, it can tell you how big or small the cell is, it can tell you how high signal the cell is.

Advances in optical coherence tomography-angiography (OCT-A) and adaptive optics have also given her team new tools to advance the technology by giving precision views of the iPSC-derived REP patch and how the host eye is responding. 

These were just a few of the developments she shared. Other techniques to be presented at ARVO 2024 include her lab’s technique of a dual patching technique and the partnerships springing up around her lab with industry to streamline tissue creation and transplantation. 

Dr. Rachael Pearson of King’s College London picked up the cell-based therapy mantle with her lab’s stem-cell suspension-based solutions in photoreceptor replacement therapy. 

She demonstrated that human pluripotent stem cells (hPSC) hCones—generated via her team’s established Good Manufacturing Process-(GMP) compatible method—can restore retinal function in certain models. 

Critically, these results could also be seen in aged mice or in other models via rescue in the case of complete photoreceptor loss. One other key feature in Dr. Pearson’s Work also stood out. 

“I think, really excitingly, the transplanted retinas do seem to be able to process spatially defined stimuli,” she added. “I think the work going on from here is to unpick the restored connectome in terms of how normal of a circuitry can really be there.” 

Intriguing industry updates

Two clinician-scientists with companies translating some seriously next-gen tech into commercially available therapeutics rounded out the slate. 

Dr. José-Alain Sahel of GenSight Biologics (Paris, France) gave updates from the company’s long-time candidate for Leber hereditary optic neuropathy, Lumevoq (lenadogene nolparvovec). 

GenSight’s REFLECT Phase III trial has shown sustained efficacy four years after a one-time bilateral injection of the drug in terms of best corrected visual acuity, with a favorable safety profile. One triumphant result Dr. Sahel announced was that these clinical trial successes also carried over to compassionate-use cases—showing great potential for meaningful results in the real world.4

Dr. Shannon Boye of Atsena Therapeutics (North Carolina, USA) also gave an update on her company’s drug candidate ATSN-101 for patients with Leber congenital amaurosis subtype 1 (LCA1).5

The data showed that both ATSN-101 is meeting the trial’s primary endpoint (safety) and secondary endpoint (efficacy). As of month 12, no serious adverse events were reported, and ocular inflammation observed has been minimal, reversible with steroids and infrequent. 

Efficacy-wise, the good news continues. Full-field stimulus testing (FST) showed improvement across all three colors tested with a dark-adapted FST. Multi-luminance mobility test (MLMT) results have been similarly encouraging. Three of the high-dose subjects improved by ≥ 2 levels. 

Dr. Boye also gave the presentation a personal touch by showing a video of a patient treated with ATSN-101. LCA1 is a leading cause of inherited pediatric blindness, and in the video, a young girl looked around in wonder as she was able to see snowflakes fall for the first time. A reminder, of sorts, of what is at stake with some of these diseases, and the difference that the clinicians gathered at ARVO 2024 can make in the lives of their patients. 

Editor’s Note: The Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO 2024) is being held from 5-9 May in Seattle, Washington, USA. Reporting for this story took place during the event. 


  1. An M, Raguram A, Du SW, et al. Engineered virus-like particles for transient delivery of prime editor ribonucleoprotein complexes in vivo. Nat Biotechnol. 2024. [Epub ahead of print.]
  2. Banskota S, Raguram A, Suh S, et al. Engineered virus-like particles for efficient in vivo delivery of therapeutic proteins. Cell. 2022;185(2):250-265.e16. [Epub 2022 Jan 11.]
  3. Ortolan D, Sharma R, Volkov A, et al. Single-cell-resolution map of human retinal pigment epithelium helps discover subpopulations with differential disease sensitivity. Proc Natl Acad Sci U S A. 2022;119(19):e2117553119. [Epub 2022 May 6.]
  4. Newman NJ, Yu-Wai-Man P, Subramanian PS, et al; LHON REFLECT Study Group. Randomized trial of bilateral gene therapy injection for m.11778G>A MT-ND4 Leber optic neuropathy. Brain. 2023;146(4):1328-1341. 
  5. Jacobson SG, Cideciyan AV, Ho AC, et al. Night vision restored in days after decades of congenital blindness. iScience. 2022;25(10):105274.
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