Guest Column | May 29, 2024

Revolutionizing Modifier Gene Therapy Through A Gene-Agnostic Approach

By Huma Qamar, MD, chief medical officer, Ocugen, Inc.

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The emergence of gene therapy has redefined the treatment landscape for genetic disorders. Traditional methods reliant on individual gene replacement strategies have shown their limitations, targeting only a specific gene for a specific disease. This specialized therapeutic approach can be both slow and costly to develop. Researchers are now hoping to find ways to use a single modifier gene to treat an array of diseases. This gene-agnostic approach utilizing modifier gene therapy could address genetically diverse diseases that are now targeted using conventional gene replacement or editing therapy. Gene-agnostic modifier gene therapy could also expand the spectrum of patients treated in this way.

Decoding The Mechanisms Of Modifier Gene Therapy

Modifier genes play a pivotal role in determining the disease outcomes. They influence the onset, progression, and severity of these conditions, making understanding them and their manipulation crucial for effective disease management. Modifier gene therapy impacts various cellular processes, including the reduction of endoplasmic reticulum stress, improving protein-folding, and promoting the clearance of misfolded proteins. It addresses the underlying genetic dysregulation and restores gene function throughout the body. It does so largely through master gene regulators, which are critical to maintaining homeostasis at the cellular level. Master gene regulators include nuclear hormone receptors (NHRs), which act as modulating switches to adjust the gene activity. A single NHR may regulate gene networks that are involved in a variety of diseases. NHRs can affect disease onset, how the disease manifests, and how fast it progresses. If successfully repaired, NHRs can modify the overall effect of genes involved in the disease regardless of any specific mutation.

A Gene-Agnostic Approach In Modifier Gene Therapy: A Master Gene Regulator

While the promise of gene therapy is significant, complex diseases associated with more than one genetic mutation can present challenges and limit therapeutic benefit when employing traditional techniques that replace or edit a single gene. Given the variations in genetic makeup of individuals – and the mutational burdens that exist in individuals' genomes – the effectiveness of this approach to gene therapy can vary among individuals. Addressing the heterogeneity due to underlying genetic mutations is critical to devising more effective treatment strategies for complex diseases.

The gene-agnostic approach offers a dynamic and adaptable solution to address the genetic complexity and heterogeneity inherent in numerous diseases. By identifying a master gene regulator common to several disorders, therapies can be devised to modulate various disease outcomes. The gene-agnostic approach targets a single master gene regulator that dictates various aspects of gene function and expression without the need to replace or edit each individual gene involved in diseases caused by multiple genetic mutations. This approach holds promise in improving access for patients and for expanding the range of indications for which gene therapy could realistically apply. A gene-agnostic approach may prove more broadly applicable and could transcend the limitations of traditional gene-specific strategies.

The gene-agnostic approach also has the potential to better negotiate the genetic labyrinth involved in many complex diseases and could potentially result in cures for diseases with various genetic mutations at the root. By acknowledging the genetic complexity inherent in various conditions, instead of homing in on a specific mutation, the approach modulates overall genetic interaction networks. Modifying broader genetic landscapes offers a promising avenue to develop more comprehensive and effective therapeutic strategies for a range of diseases.

The Role Of Modifier Genes In Eye Diseases

The eye's unique biological features, such as its accessibility and immune privilege, have rendered it an ideal candidate for modifier gene therapy. Ocugen is developing a gene-agnostic approach using modifier gene therapy in the treatment of several eye diseases. Rather than replacing a diseased gene with a functional copy, this gene-agnostic approach introduces the gene for a particular NHR that is expressed in the tissue and can regulate multiple gene networks.

Researchers at Ocugen have successfully harnessed the nuclear hormone receptor NR2E3 as a modifier gene. This discovery marks a significant breakthrough in the field, illustrating the potential of modifier gene therapy in treating a wide spectrum of retinal diseases with a single therapeutic intervention. Modifier gene therapy that targets NR2E3 resets key retinal transcription factors and gene networks that are integral to maintaining retinal homeostasis. By modulating crucial gene networks, NR2E3 therapy has demonstrated an ability to slow disease progression, restore photoreceptor cell survival, improve retinal function, and restore retinal integrity.

A gene-agnostic approach that addresses the underlying genetic dysregulation holds the potential to restore photoreceptor cell survival, stabilize retinal structure, and normalize retinal function. These auxiliary benefits offer further promise for restoring retinal health and preserving vision in a host of complex retinal conditions.

Modifier Gene Therapies For Inherited Retinal Disorders

The gene-agnostic approach to ocular gene therapy offers a potential avenue for the treatment of patients with inherited retinal disorders (IRDs). IRDs represent a broad spectrum of diseases, each with unique genetic characteristics, caused by a genetic mutation that can result in vision loss. IRDs such as retinitis pigmentosa (RP), a complex ocular disease that exhibits considerable genetic variability, and Leber Congenital Amaurosis (LCA), a form of retinal dystrophy, are complex diseases with no cure. However, recent research into a gene-agnostic approach has yielded promising developments in restoring retinal integrity and function in these IRDs.

The gene-agnostic approach targets a single master gene regulator, NR2E3, to treat a range of IRDs including RP and LCA. Delivering a functional copy of NR2E3 to target cells in the retina helps reset retinal homeostasis, stabilizes cells, and mitigates photoreceptor degeneration. Published results demonstrate the potential for a mutation-agnostic therapy targeting a single modifier gene to elicit a broad-spectrum of therapeutic benefits in early and intermediate stages of RP and LCA.

Another promising development is the exploration of gene-agnostic modifier gene therapy for dry age-related macular degeneration (dry AMD). Dry AMD is common but also multifactorial and complex. Research suggests specific modifier genes impacting and inhibiting the complement system, an immune pathway linked to dry AMD, could be potential therapeutic targets. Targeting a master gene regulator to modulate the complement system could potentially slow or halt disease progression. This gene-agnostic approach offers new hope for those affected by this prevalent cause of vision loss and may also address additional targets and diseases beyond the eye.

Challenges And Future Prospects

Modifier gene therapy, powered by a gene-agnostic approach, is heralding a new era in the treatment of eye diseases. Despite the promise modifier gene therapy holds, several obstacles remain on the path toward widespread clinical application. These include the challenge of refining promoter specificity utilized in the gene-agnostic approach. Long-term safety and efficacy studies are also needed to ensure the successful implementation and accessibility of these groundbreaking therapies. Addressing these challenges will be critical in realizing the full potential of modifier gene therapy in clinical practice. Harnessing the power of modifier genes, this revolutionary approach could redefine the field of ophthalmology and bring hope to those suffering from a diverse array of ocular conditions.

About The Author:

Huma Qamar, MD, serves as the chief medical officer at Ocugen, Inc., where she leads the company's development of gene and cell therapies. She has extensive expertise in a range of therapeutic areas, including gene and cell therapy, vaccines, oncology (Heme-Onc, CAR-T, rare tumors, sarcoma, melanoma, women's health, GU & GI, fetal oncology), rheumatology, dermatology, neurology, cardiology, hepatology, and infectious diseases. Qamar's background in clinical research is distinguished, with contributions to renowned Ivy League institutions such as Yale University, Harvard University, and the University of Pennsylvania.