Resetting retinal networks with a gene-agnostic approach

Inherited and age-related retinal diseases remain among the most challenging areas in medicine. Traditional gene therapy approaches have brought progress, but their reach has often been limited to single-gene conditions, leaving large patient populations without options. At Ocugen, a new platform is taking shape - modifier gene therapy - that aims to address the complexity of retinal disease by targeting broader biological networks rather than isolated mutations.

At the centre of this work is Dr Arun Upadhyay, Chief Scientific Officer and Head of Research & Development at Ocugen, who has been leading efforts to develop this platform from discovery through to late-stage clinical trials.

"I lead our R&D efforts focused primarily on our novel modifier gene therapy platform. What drives me is guiding teams through the full journey - from sparking ideas in discovery and innovation and early research to advancing programmes into late-stage global development."

Beyond single-gene therapy

Most conventional gene therapies fall into one of two categories: gene augmentation, where a functional copy of a defective gene is supplied, or gene editing, where the defective gene itself is corrected. While powerful, these strategies have certain drawbacks.

One of the limitations of traditional gene therapy is that it targets only a narrow patient population and cannot address the imbalances that develop in the retina at the molecular and cellular level during the course of disease.

"One of the limitations of traditional gene therapy is that it targets only a narrow patient population and cannot address the imbalances that develop in the retina at the molecular and cellular level during the course of disease."

Diseases such as retinitis pigmentosa (RP) can involve mutations in hundreds of different genes or Stargardt disease where thousands of mutations in a single gene can lead to the disease - adding to genetic and clinical heterogeneity. In practice, a therapy designed to replace a single gene or edit single mutation cannot hope to serve the breadth of patients affected. More importantly, the progression of disease involves multiple pathways, with secondary disruptions that go far beyond the initiating gene mutation.

Ocugen's modifier gene therapy aims to overcome these barriers by delivering regulatory factors that can restore homeostasis in the retina, promoting the survival and function of existing photoreceptors rather than attempting to repair one gene at a time.

Modifier gene therapy aims to restore balance within retinal networks, protecting photoreceptors and preserving vision across diverse genetic conditions. Image credit: MicroScience / Shutterstock

Nuclear hormone receptors as master regulators

The scientific foundation of the platform lies in nuclear hormone receptors (NHRs).

These genes are master gene regulators in the retina. What they do is regulate various cellular and molecular pathways, which are critical for photoreceptor survival and function.

"These genes are master gene regulators in the retina. What they do is regulate various cellular and molecular pathways, which are critical for photoreceptor survival and function."

When retinal diseases develop, these networks become imbalanced. Ocugen's strategy uses NHR-based modifier genes to reset those networks, restoring structure and function in the retina.

The company's lead programme, OCU400, is based on the NHR gene NR2E3. Now in phase III clinical trials for RP, it targets multiple pathways relevant to retinal health: phototransduction, photoreceptor differentiation and maintenance, mitochondrial metabolism and more.

A gene-agnostic approach

One of the most significant advantages of modifier gene therapy is its gene-agnostic potential.

"Irrespective of what the genetic cause is leading to RP, this product is intended to provide benefit to all those patients."

Any therapeutic approach that is trying to protect the photoreceptor from degeneration can have broader and gene-agnostic potential, and that is exactly what our modifier gene therapy does.

Rather than designing a therapy for each mutation - a near impossibility given the thousands of variants across conditions such as RP - the platform seeks to preserve and enhance the function of photoreceptors regardless of the underlying defect.

"Any therapeutic approach that is trying to protect the photoreceptor from degeneration can have broader and gene-agnostic potential, and that is exactly what our modifier gene therapy does."

This offers a way to serve patient populations that conventional gene therapies cannot easily reach.

Meeting scientific and technical challenges

Developing such a platform has not been straightforward. Traditional models for gene therapy - targeting one defective gene in a specific animal model - do not apply.

"Because we are developing gene therapy based on NHR genes, which are not supposed to correct any genetic defect, the challenge has been to demonstrate that this molecule can work in such a vast, heterogeneous disease."

Ocugen's preclinical work involved testing modifier genes across multiple animal models carrying different mutations. By doing so, they demonstrated that NR2E3 could restore molecular homeostasis across mouse models' harbouring diverse genetic mutations linked with inherited retinal diseases, not only preserving photoreceptors but also resetting the expression of other critical retinal genes.

Another challenge lay in delivery. After exploring intravitreal, suprachoroidal and subretinal routes, the team identified subretinal injection as the optimal method - providing efficient local delivery to target cells while minimising off-target effects and systemic exposure.

From preclinical to clinical development

Arun describes the transition from laboratory to clinic as a carefully staged process, beginning with demonstrating pharmacology in diverse models, followed by IND-enabling studies to establish biodistribution, toxicity and safety.

The good news is that when we were just six to nine months into the phase I/II study - and enrolment was completed - we got very good positive data.

From there, Ocugen initiated a phase I/II trial, designed to reflect the heterogeneity of the patient population. Multiple mutations were represented and dose escalation was built in to identify optimal ranges.

"The good news is that when we were just six to nine months into the phase I/II study - and enrolment was completed - we got very good positive data, including an excellent safety profile as well as efficacy data demonstrating the gene-agnostic mechanism of action of this molecule."

These results enabled engagement with the U.S. Food and Drug Administration (FDA) and informed the design of a phase III trial, now under way, using a luminance-dependent navigation assessment (LDNA) as the primary endpoint - a test capable of capturing clinical benefit across patients with varied disease stages - early to advanced.

Regulatory designations

Alongside clinical development, the programme has achieved multiple regulatory milestones.

"This product received orphan designation from both the FDA and EMA, Advance Therapy Medicinal Product (ATMP) classification from EMA and Expanded Access program (EAP) from FDA. It has also received RMAT designation from FDA, which covers breakthrough, fast track and other benefits, as well as expanded access programme designation."

These designations reflect regulatory confidence in the approach and enable patients outside the trial to receive access through expanded programmes. Importantly, Ocugen has also secured alignment with European regulators, meaning the current U.S. and Canadian trial will support submissions to both the FDA and European Medicines Agency (EMA).

Broader impact and future directions

The potential of modifier gene therapy extends beyond inherited retinal disease.

"If we are able to demonstrate the success of this technology in our ongoing phase III study, then I am quite confident that the way we look at ophthalmic disease, especially those which are linked to age or are genetic in nature, is going to change completely."

Arun sees the field shifting towards therapies that offer holistic benefit rather than narrowly correcting individual mutations. This shift could influence not only retinal disorders but also other complex conditions.

"Most importantly, what I see is that this technology has huge potential in other disease areas as well - and one important area is neurological conditions. These include Alzheimer's, Parkinson's and autism spectrum disorders, which are multifactorial in nature."

Conclusion: towards holistic therapies

Modifier gene therapy moves beyond traditional single-gene approaches. Using master regulators of retinal networks, it provides a gene-agnostic strategy that could benefit wider patient groups.

For Dr Arun Upadhyay and his team, the focus is on demonstrating this potential through rigorous science, careful clinical design and transparent regulatory engagement. If successful, the platform may not only advance treatment for inherited retinal diseases but also influence how we approach complex, multifactorial conditions across medicine.

Meet the expert

Arun Upadhyay, PhD, Chief Scientific Officer and Head of Research, Development and Medical at Ocugen, oversees the company's innovation and product development. Leading strategy and operations across various platforms, he manages programmes from discovery and preclinical research through to clinical development, safety, medical support and global regulatory submissions.

With more than 20 years' experience in biotechnology, academia and government, Upadhyay has directed multidisciplinary teams advancing monoclonal antibodies, bi-specifics, vaccines and cell and gene therapies. Before joining Ocugen, he led ophthalmic drug development and delivery research at the University of Colorado Denver, where he designed therapeutics for retinal diseases and pioneered targeted drug delivery systems.

He holds a PhD in biotechnology from the National Institute of Immunology and an MSc in biotechnology from Jawaharlal Nehru University, New Delhi. He has authored more than 40 publications, holds over 15 patents, have legacy of mentorship and public advocacy for vision science, drug delivery and vaccine development. He exemplifies what it means to lead with purpose, excellence and vision. His work not only promises to preserve and restore sight for millions worldwide but also paves the way for future generations of gene-based medicines for age related and genetic conditions impacting mental health (neurodegenerative diseases). He has received the American Association of Pharmaceutical Scientists' Innovation in Nanotechnology Award for novel ocular drug delivery systems and "2024 Trailblazer in Healthcare Award" by City & State Pennsylvania.

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