The evolution of gene therapy has transformed treatment possibilities for genetic disorders. Traditional strategies primarily target specific gene mutations by augmenting a defective gene with a functional copy. While groundbreaking, this approach is limited by its narrow focus, which requires tailoring treatments to individual mutations. In contrast, a gene-agnostic approach utilizing modifier gene therapy offers the potential to address the genetic complexity of many retinal diseases, including those caused by multiple genetic mutations. This innovative approach targets nuclear hormone receptors (NHRs), master gene regulators that modulate entire genetic networks, opening the door to broader and more equitable access to gene therapy.
Expanding the Reach of Gene Therapy
Modifier gene therapy takes advantage of the body’s natural genetic regulation mechanisms. NHRs, acting as master switches, influence numerous downstream genes that maintain cellular homeostasis. By targeting these regulators, modifier gene therapy has shown potential to repair or normalize genetic function across diverse mutations, expanding the potential patient population eligible for treatment.
For inherited retinal disorders (IRDs) associated with mutations in many genes, such as retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA), traditional gene replacement approaches are often constrained by the diversity of mutations that drive these diseases. By delivering a single, one-time injection targeting an NHR, therapy can reset genetic networks critical to retinal health, restoring photoreceptor cell survival and stabilizing retinal structure. This approach could revolutionize treatment, offering hope to patients whose conditions were previously untreatable due to their genetic heterogeneity.
Restoring Cellular Balance
Beyond addressing specific mutations, gene-agnostic therapy aims to restore the overall health of the cellular environment, because there may be more gene mutations that a patient doesn’t even know about. Many genetic disorders are not driven by a single malfunctioning gene but by disruptions in complex genetic networks. By targeting NHRs, modifier gene therapy can upregulate these networks, reducing cellular stress to restore homeostasis. Recent advances illustrate the promise of this technology.
Ocugen’s ongoing clinical trials exemplify the transformative potential of gene-agnostic modifier therapy. OCU400, targeting RP, yielded strong results in the Phase 1/2 study. Patients treated with OCU400 demonstrated significant improvements in both retinal structure and visual function, across multiple genetic mutations underlying their conditions. These findings highlight the therapy’s ability to stabilize photoreceptor cells, enhance functional vision, and address the root genetic dysregulation. By focusing on resetting the retinal gene network and restoring cellular homeostasis, OCU400 offers new hope for approximately 98% of RP patients who currently have no treatment options available.
For RP patients, the prospect of retaining their remaining vision is something they didn’t think possible. We are working hard to give them more by potentially restoring vision. The Phase 3 OCU400 liMeliGhT clinical trial is currently underway and on track to meet Biologics License Application (BLA) and Marketing Authorization Application (MAA) filing targets in the first half of 2026.
Building on the success of OCU400, Ocugen’s OCU410 for geographic atrophy (GA), an advanced form of dry age-related macular degeneration, and OCU410ST for Stargardt disease leverage the master gene regulator RORA. Currently available therapies for GA only address one factor of this multifactorial disease, complement system, and require frequent intravitreal injections (~6-12 doses per year). There remain no approved treatments available for Stargardt disease. Early findings suggest very good safety and promising efficacy for both OCU410 and OCU410ST.
The ability to modulate master gene regulators to address complex genetic networks positions this approach as a versatile solution for tackling both IRDs and diseases affecting millions. These advancements demonstrate how targeting NHRs can provide a single therapeutic solution for blindness diseases previously considered too complex for traditional approaches. Modifier gene therapy has the potential to shift the treatment paradigm for nearly all diseases that eventually lead to blindness.
Addressing Challenges and Expanding Access
While the potential is immense, the journey to widespread clinical adoption is not without hurdles. Increasing awareness of this novel modifier gene therapy platform among retinal surgeons, conducting long-term safety studies, and navigating regulatory pathways remain critical challenges. However, these obstacles are surmountable with continued research and collaboration.
The gene-agnostic approach’s ability to simplify and broaden gene therapy applications has profound implications for accessibility. By moving beyond single-mutation treatments, this technology offers the possibility of a “one-size-fits-many” solution, reducing development costs and making therapies more widely available. This is particularly important for diseases like RP, which would require at least 100 separate products to effectively treat all associated gene mutations.
Transforming the Future of Gene Therapy
The promise of gene-agnostic modifier gene therapy extends beyond retinal diseases. Its capacity to modulate complex genetic networks makes it a versatile tool for tackling a wide range of conditions. By addressing genetic heterogeneity and restoring cellular homeostasis, this approach could lead to breakthroughs across various therapeutic areas.
Shankar Musunuri, PhD, MBA
Chairman, CEO, and Co-founder of Ocugen
Dr. Musunuri is a seasoned biotech veteran with 30+ years of results-driven experience advancing and commercializing a diverse portfolio of products. Prior to co-founding Ocugen in 2013, Dr. Musunuri held leadership roles at numerous companies ranging from “Big Pharma” to novel start-up biotechs. After a long tenure at Pfizer, he founded Nuron Biotech, Inc., which he grew to a commercial company in less than three years, serving as President and CEO. Dr. Musunuri spent nearly 15 years at Pfizer, where he gained extensive product launch and life-cycle management experience, playing a key role as Global Operations Team Leader for the most successful launch in vaccine history, Prevnar 13®.
Dr. Musunuri obtained his PhD in Pharmaceutical Sciences from the University of Connecticut and an MBA from Duke University’s Fuqua School of Business. He is a recipient of the Distinguished Alumnus Award from the University of Connecticut’s School of Pharmacy and serves on Board of Advisors at Duke University’s Duke Innovation and Entrepreneurship.
