Gene therapy for glaucoma: Great potential but a long way to fruition

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Terri Pickering, MD, Clinical Instructor, California Pacific Medical Center, and Board of Directors member, Glaucoma Research Foundation, San Francisco, reported that there is increasing evidence for the efficacy of various experimental glaucoma gene therapies. However, the research is still in the early stages and must go through human clinical trials. She discussed this potential therapeutic approach at the Glaucoma 360 annual meeting in San Francisco.

The use of gene therapy to treat ocular disease is not new, ie, 34 gene therapies have received FDA approval to treat ocular diseases.¹ Luxturna (voretygene neparvovec, Spark Therapeutics), which was approved in 2017, is the first viral ocular gene therapy. This technology is a one-time treatment to improve vision in Leber’s congenital amaurosis type 2.²

In the eye, intravitreal or subretinal injections of adeno-associated viruses (AAVs), the most common gene therapy approach, are the vectors of choice for delivering gene therapy to the retinal ganglion cells (RCGs).² “Transfection of RGCs by intravitreal injection has an efficiency of approximately 85%. One intravitreal injection lasts over 7 months, and AAV-delivered genes begin to be expressed 2 to 3 weeks after injection,” Pickering reported.

Another strategy is delivery of non-viral gene therapy³ using a non-viral vector, eg, a lipid nanoparticle or synthetic polymer. This is less efficient than using AAVs, but is less likely to trigger an immune response, according to Dr. Pickering.

Gene therapy in glaucoma

A large number of genes are involved in glaucoma. Genome-wide association studies have identified 170 genetic loci associated with an increased risk of developing primary open-angle glaucoma; however, most people in those studies were of European or Asian descent. A recent study reported that unique gene variants are involved in glaucoma in Black patients,⁴ the largest population affected by glaucoma.

In gene therapy to treat glaucoma, because of the numerous genes involved, the goal is to target the final common endpoint, specifically, the RCGs for direct neuroprotection and the trabecular meshwork and ciliary body cells to lower the intraocular pressure (IOP).² 

Glaucoma studies are being conducted in animal models of optic neuropathy in a DBA/2J mice model of high-tension glaucoma and an optic nerve crush model.

Various studies of neuroprotection also are underway targeting specific RCG genes for growth factors, immunomodulation, neuroinflammation, excitotoxicity, and transcription.²

Neuroprotective targets include axonal transport failure; neurotrophic factor deprivation, activation of intrinsic and extrinsic apoptosis; signaling, mitochondrial dysfunction, excitotoxic insult, oxidative stress; and reactive gliosis and synaptic connectivity breakdown.²

The goal is to lower the IOP by targeting genes involved in decreased aqueous humor production and increased outflow facility.²

Gene therapy advantages/disadvantages

The hope is that gene therapy for glaucoma provides a new treatment option for a disease that is incurable; in other disease treated with gene therapies, disease have slowed or stopped progressing.

Earlier treatment may prevent damage, but it remains unknown if gene therapy can reverse damage.

Because gene therapy targets the underlying disease cause, in theory, treatments can be created to specifically target any gene.

However, gene therapy provides no guarantee of cure or beneficial results, in that research is only just begun and treatment may be ineffective. Gene therapy is complicated and may produce an immune response. In addition, the long-term effects are unknown.

Other limitations are the short-lived nature of some gene therapies and viral vector issues such as toxicity, immune and inflammatory responses, gene control and targeting issues, limited quantities of the engineered genes, high cost, ethical restrictions, and complexity.

However, Pickering is convinced of their future potential. “Giving their promising potential, gene therapies are poised to become an important addition or even alternative to current treatments in glaucoma,” she said.

References:

1. my.clevelandclinic.org

2. Sulak R, Liu X, Smedowski A. The concept of gene therapy for glaucoma: the dream that has not come true yet. Neural Regen Res. 2024;19:92–99; published online 2023 May 31. doi: 10.4103/1673-5374.375319

3. Hakim A, Guido B, Narsineni L, et al. Gene therapy strategies for glaucoma from IOP reduction to retinal neuroprotection: Progress towards non-viral systems. Advanced Drug Delivery Rev. 2023;196:11478.

4. Lanese N. Unique gene variants tied to glaucoma found in Black patients. Live Science. Published Jan 18, 2024.