A groundbreaking study from South Korea has spotlighted a promising method to coax the mammalian eye into repairing itself, potentially reversing vision loss caused by retinal diseases. This innovative approach hinges on disabling a specific protein that acts as a molecular “stop sign” for the eye’s natural regenerative processes. The treatment, tested successfully in mice, could pave the way for human therapies that restore sight once considered permanently lost.
The Roadblock to Retinal Repair: Prox1 Protein
The retina’s ability to regenerate damaged nerve cells is severely limited in mammals, unlike in certain cold – blooded animals such as zebrafish, which can naturally restore retinal neurons after injury. The culprit behind this difference is a protein called prospero homeobox protein 1 (Prox1). While Prox1 plays essential roles in cell regulation and neural differentiation, it also suppresses the regenerative potential of Müller glia (MG) cells-the retina’s support cells responsible for maintenance and repair.
In healthy mammalian retinas, Prox1 is present in retinal neurons but not produced by MG cells themselves. After retinal injury, Prox1 protein accumulates inside MG cells, not because these cells make it, but because it is transferred from neighboring retinal neurons through intercellular protein transfer. This transfer is mediated by Prox1’s homeodomain, a structural feature that allows it to move between cells. Once inside MG cells, Prox1 inhibits their ability to dedifferentiate into retinal progenitor cells (RPCs), a crucial first step in regeneration.
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How Blocking Prox1 Sparks Regeneration
The South Korean research team developed an antibody – based therapy designed to intercept Prox1 before it reaches MG cells. By neutralizing extracellular Prox1, the treatment lifts the molecular blockade, enabling MG cells to revert to a progenitor-like state. These reprogrammed MG cells can then proliferate and differentiate into various retinal neurons, including photoreceptors, which are vital for capturing light and enabling vision.
This approach was delivered using an adeno-associated virus (AAV) vector carrying the gene encoding the Prox1-neutralizing antibody (referred to as AAV2-Anti-Prox1). In mouse models of retinal degeneration, including retinitis pigmentosa, the therapy restored the photoreceptor layer and improved visual function. Remarkably, these effects persisted for over six months, demonstrating sustained retinal regeneration-a milestone never before achieved in mammals.
Molecular Insights and Limitations
Gene expression analyses revealed that blocking Prox1 triggers upregulation of neurogenic factors and cell cycle genes within MG cells, promoting their reprogramming. Interestingly, this reprogramming appears to occur independently of Ascl1, a known proneural transcription factor, suggesting alternative molecular pathways are at play.
However, the researchers caution that inhibiting Prox1 alone may not fully replicate the robust regenerative capacity observed in zebrafish. Additional molecular events – such as inhibiting Notch signaling after MG reprogramming and maintaining activation of Yap/Taz pathways-might be necessary to enhance proliferation of MG – derived progenitor cells and achieve complete retinal restoration.
Testing Across Disease Models
The therapy was evaluated in two distinct mouse models of retinitis pigmentosa: an early-onset model characterized by rapid vision loss, and a late – onset model with slower degeneration. In the early – onset mice, the treatment delayed vision loss temporarily, while in the late-onset mice, it substantially preserved and even restored vision after degeneration had begun. These findings underscore the therapy’s potential to benefit patients at various stages of retinal disease.
Broader Implications for Eye Health
Retinal degenerative diseases affect hundreds of millions globally, often leading to irreversible blindness. Current treatments mainly aim to slow disease progression, lacking options to restore lost vision. As the global population ages, the incidence of such conditions is expected to rise, amplifying the need for regenerative therapies.
This discovery, published in Nature Communications in March 2025, represents a paradigm shift by demonstrating that mammalian retinas harbor latent regenerative abilities that can be unlocked by targeting key molecular inhibitors. It complements other emerging strategies, such as stem cell transplantation and laser-induced retinal activation, broadening the horizon for vision restoration.
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The Path Forward: Toward Clinical Application
The research team, led by Professor Jin Woo Kim at the Korea Advanced Institute of Science and Technology (KAIST), has partnered with Celliaz Inc., a biotech startup founded on this research, to advance the therapy toward clinical trials. The Prox1 – neutralizing antibody, named CLZ001, is currently being optimized for safety and efficacy in preclinical studies, with human trials anticipated to begin around 2028.
Dr. Eun Jung Lee, a key contributor, emphasized the goal of providing new treatment options for patients facing blindness due to retinal diseases. If successful, this therapy could transform the outlook for millions by restoring sight through the eye’s own regenerative machinery.
This breakthrough marks a significant leap toward reversing vision loss by harnessing the eye’s own repair capabilities, signaling a promising future for regenerative ophthalmology.
Unlocking Retinal Regeneration by Targeting Prox1 Protein
A detailed study published in Nature Communications on March 25, 2025, further elucidates the role of Prox1 as a critical barrier to retinal regeneration in mammals. The research confirms that Prox1 transfers from damaged retinal neurons to Müller glia cells, where it suppresses their ability to revert to progenitor cells essential for regeneration. By neutralizing Prox1 with a specific antibody, the regenerative potential of Müller glia is restored, enabling long – term recovery of retinal neurons and vision in mouse models. This work highlights anti – Prox1 therapy as a promising strategy to overcome the intrinsic limitations of mammalian retinal repair.
Gene Therapy Breakthrough Restores Vision in Retinal Degeneration Models
Scientists at KAIST have developed a revolutionary gene therapy that blocks the transfer of the Prox1 protein, allowing Müller glia to reprogram and regenerate damaged retinal neurons. Delivered via an adeno – associated virus vector, this therapy has demonstrated sustained restoration of the photoreceptor layer and visual function in mice with retinitis pigmentosa. The treatment’s effects persisted for over six months, marking a significant advancement in regenerative ophthalmology. The research team is currently optimizing the Prox1-neutralizing antibody, CLZ001, with plans to initiate clinical trials by 2028.
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The Molecular Mechanism Behind Retinal Regeneration
Further investigation into the molecular pathways involved revealed that Prox1’s inhibition of Müller glia dedifferentiation is a key factor preventing retinal regeneration in mammals. Neutralizing Prox1 triggers upregulation of neurogenic and cell cycle genes, enabling Müller glia to become retinal progenitor cells. Interestingly, this process appears to bypass the classical Ascl1 pathway, suggesting alternative transcription factors may be involved. The researchers note that combining Prox1 inhibition with modulation of other signaling pathways, such as Notch and Yap/Taz, could enhance regenerative outcomes.
Broader Impact and Future Prospects
With over 300 million people worldwide affected by retinal degenerative diseases, this breakthrough offers hope for therapies that do more than slow disease progression they could restore lost vision. The aging global population underscores the urgency of developing such treatments. KAIST’s pioneering work, supported by Celliaz Inc., represents a critical step toward clinical solutions that harness the eye’s own regenerative capabilities. The anticipated clinical trials could transform the treatment landscape for retinal diseases, providing new options for patients currently facing irreversible vision loss.
These related studies collectively underscore the transformative potential of targeting Prox1 protein to unlock retinal regeneration, offering a beacon of hope for millions affected by vision loss worldwide.
