Not all gene therapies are alike.  Two treatments for retinal diseases, invented by Neena Haider, PhD, that currently are in clinical trials run by Ocugen, represent a conceptually broad, new approach that could herald a sea change in preserving sight for millions of people, and could lay the groundwork for gene therapies for other diseases as well. 

Rather than replacing or repairing a defective gene (as other gene therapies in development seek to do), modifier gene therapy restores the proper functioning of multiple genes and thereby entire biological pathways that are responsible for maintaining healthy tissue and protect the retina from further damage. This is especially relevant when it comes to addressing diseases such as age-related macular degeneration (AMD) that are  associated with multiple genes.

“Using gene replacement or gene editing therapies, you’d have to develop a unique therapy for each of the defective genes identified in each AMD patient — it simply cannot be done. Currently, while we know genes associated with AMD, we have yet to identify specific causative gene defects for AMD,” explains Dr. Haider. “By restoring proper function in many of the dysfunctional genes in dying photoreceptor cells, vision can be rescued from further loss and preserved.” While it is not possible to revive dead cells, it is possible to restore function in photoreceptors that are still alive to help patients regain some sight, she adds.

Ocugen’s OCU400, for the treatment of retinitis pigmentosa (RP), was recently given FDA approval to enter Phase 3 clinical trials after demonstrating safety and efficacy in Phase 1/2 human trials. While RP is due to a single genetic defect, there are many types of RP caused by genetic defects in any one of over 100 genes, OCU400 is designed to treat the disease irrespective of the specific gene defect.

Months into Ocugen’s OCU400 Phase 1/2 trials, most patients reported stabilized or improved vision.

For Geographic Atrophy and Stargardt’s (a form of earlier onset macular degeneration), initial patient dosing with OCU410 is underway for Phase 1/2 trials. No adverse events have been reported from patients already dosed in the study.

“This work began decades ago, with careful thought as to what the underlying causes of AMD may be (genetic and environmental), says Dr. Haider. “My lab discovered the role of nuclear receptors as master regulators of the many mechanisms that are perturbed in AMD patients such as metabolism, inflammation, oxidative stress, cell survival, cell death, and neuroprotection. This one category of genes could, in effect, reset many of the gene networks perturbed in AMD disease and thereby provide a more robust therapy than any other currently available.

“I’ve had tremendous support from Ocugen, plus Roche, the Thome Foundation and others, as we’ve sought to revolutionize the AMD therapy space.  I am especially grateful to the American Macular Degeneration Foundation, who funded high risk, out-of-the-box projects that I thought of, which have now led to these revolutionary clinical trials.”

Both OCU400 and OCU410 are designed to require only a single treatment, currently delivered by subretinal injection, which requires a hospital setting.  

According to Dr. Shankar Musunuri, Chairman, CEO and Co-founder at Ocugen: “Until now, there has been only one marketed product to treat one of the 100 gene mutations associated with RP. Now, with OCU400, there is real hope for all RP patients. And for patients with GA, there are currently two recently approved products.  Both require around six to twelve intravitreal injections annually and only target the complement system.” OCU410, he notes, addresses additional mechanisms associated with dry AMD.

OCU400 and OCU410 will be extensively discussed at the upcoming international  annual meeting of the Association of Researchers in Vision and Ophthalmology (ARVO).

“There is so much good news coming out of these advances,” says  Matthew Levine, Director of Grants, Advocacy and Partnerships at the American Macular Degeneration Foundation (AMDF). “OCU410 offers the hope to those whose vision is already deteriorating that their remaining vision could be preserved. It also seems possible that, after further study, modifier gene therapy could prevent others with an early dry AMD diagnosis from developing any significant vision loss.”