Orphan odyssey: zebrafish-derived bio-actives in multi-target networks for rare retinal ganglion cell degenerations mimicking glaucomatous optic neuropathy

To the Editor,

The degeneration of retinal ganglion cells (RGCs) leads to vision loss in glaucomatous optic neuropathy, one of the leading causes of irreversible blindness worldwide. Nevertheless, there are rare forms of RGC degeneration mimicking glaucoma that remain orphan diseases with little therapeutic recourse. Zebrafish models open new vistas because of their unique ability for retinal neuroregeneration and resistance against RGC loss, offering translational insights into neuronal preservation and axonal regrowth^[1–3].

The neurotech screening of zebrafish bioactive peptides has identified candidates recently for targeting complex hubs of the network involved in the loss of synaptic and axonal integrity of RGCs. The peptides target multi-target protein networks (ComplexDnet) implicated in glaucomatous pathology, mediating neuroprotection through synaptic preservation and triggering regenerative pathways. In vivo optical coherence tomography (OCT) imaging demonstrates that the application of these bio-actives (+35%; axonal survival) leads to considerable functional recovery that has not been documented with current standard therapies. New markers based on OCT hold promise as early endpoints for detection and therapeutic monitoring^[3–5].

The regulatory regime fails to provide recognition of aquatic bio-actives for orphan visual neuropathies, despite a good amount of preclinical evidence suggesting their potential. Certain provisions in current orphan drug policies do not cover natural products from non-mammalian species, thus delaying their transition to clinical trials. Thus, given the significant need for effective therapy for disabling rare RGC conditions, expedited regulatory pathways should prioritize zebrafish-derived peptides as orphan drugs to catalyze clinical development^[6,7].

The treatment of rare retinal neurodegenerations has undergone a paradigm shift with the emergence of neuroprotection and regeneration, particularly through the integration of network pharmacology with zebrafish-based platforms for the discovery of such pharmacotherapy drugs. OCT, a non-invasive in vivo imaging technique, will be used to allow precise quantification of disease progression and treatment effects. Collaboration between government regulators, industry, and academia is appropriate to accelerate the transition toward the clinic^[3,5].

In summary, zebrafish bio-actives represent a bright future of multi-target neuroprotection and regeneration in rare glaucomatous neuropathies. The regulatory science should be modified to ensure that our promising preclinical results would have a real impact on the patients by accommodating such natural aquatic compounds as orphan drug candidates. Therefore, accelerating their growth will address an acute unmet desire, which will eventually restore vision in debilitating RGC degenerations to which no viable treatments have been developed to date.

This letter to the editor adheres to the Transparency in the Reporting of Artificial Intelligence in Research (TITAN) guideline^[8]. During the preparation of this manuscript, generative AI tools (DeepSeek, DeepSeek Inc., June 2025 version; temperature parameter = 0.7) were used only as auxiliary aids to assist in formatting standardization, organization of background information, and language consistency checks. All AI-assisted text was thoroughly reviewed, edited, and refined by the authors. The conceptualization, literature interpretation, synthesis of ideas, and manuscript writing were performed entirely by the authors, ensuring the academic rigor, accuracy, and originality of the review.

Ethical approval

Not applicable, as the data have not been obtained from a patient.

Consent

Not applicable, as the data have not been obtained from a patient.

Sources of funding

No funding resources are required; primary and corresponding authors mainly support these.

Author contributions

All authors have made significant contributions in accordance with the ICMJE authorship criteria. M.T. contributed to the conception and design of the study, data collection, analysis, and drafting of the initial manuscript. A.I. was involved in data acquisition, statistical validation, literature review, and refinement of the methodology. U.U.R. participated in data interpretation, manuscript editing, preparation of figures and tables, and critical revision of the content. R.K.M. conceptualized the study, supervised the entire research process, performed final data analysis, critically reviewed the manuscript for intellectual content, and approved the final version for submission. He also serves as the corresponding author and guarantor, taking full responsibility for the integrity and accuracy of the work.

Conflicts of interest disclosure

All authors agree on the manuscript data and have no conflicts of interest.

Research registration unique identifying number (UIN)

This is new and not registered anywhere.

Guarantor

Raghabendra kumar Mahato.

Provenance and peer review

Not peer-reviewed or published elsewhere.

Data availability statement

No datasets were produced or examined for this article; therefore, data sharing is not relevant.

Patient consent

Not applicable – no patient identifiable data are included.