Seeing is Believing: The Promise of Retinal Gene Therapy

Aakanksha Pathania, B.Optom

The eye is a complex sensory organ that evolved to promote our survival and appreciation of beauty. ⁽¹⁾ Retinal genetic defects cause sight-impairing and blinding disorders that lead to degeneration and death of visual cells. ⁽²⁾  

It is imperative to understand that genetic diseases were once considered untreatable. However, with recent advancements in medical technology, we must acknowledge that there is now a ray of hope for those affected. ⁽³⁾ Ocular gene therapies can greatly enhance the lives of those with inherited retinal disease. ⁽¹⁾

The term gene therapy typically involves replacing a mutated gene in a targeted population of cells with a normal, functional copy delivered by a vector. ^(4,5)

Gene therapy can treat and cure inherited disorders and disease-causing mutations, offering hope to millions. ^(3,6) Gene therapy has come a long way. Before 1990, there were few treatments for retinal genetic diseases. Today, with over 1000 clinical trials (>30 for ocular disease), gene therapy is a beacon of hope for millions. The history of gene therapy is complex, but its advances are impressive. ⁽³⁾

The retina is an ideal target for gene therapy due to its enclosed, immune-privileged site protected by the blood-retina barrier. Additionally, only small amounts of the vector are needed to treat retinal diseases because of the retina’s small size and lack of cellular proliferation in adulthood. ^(1,3)     

There are 4 major approaches to gene therapy, mentioned below:

1. Gene replacement/augmentation:  Gene replacement therapy entails providing a functional copy of a defective gene to boost the production of a functional protein, primarily for monogenic recessive inherited diseases. ⁽³⁾ 

   However, it may not be suitable for all gene mutations. Moreover, its widespread implementation can be costly and limit patient access.

2. Gene Silencing:  With small interfering RNA or microRNA that targets vascular endothelial growth factor, is currently in development for the treatment of age-related macular degeneration, glaucoma, and several other ocular diseases. ⁽³⁾
3. Gene Editing: Gene editing corrects mutations in genes or reduces mutated protein expression to modify disease, but faces challenges like traditional gene therapy, especially the complexity of diseases involving multiple genes. ⁽³⁾
4. Modifier Gene Therapy: Modifier gene therapies are increasingly used for systemic diseases, targeting pathways adjacent to multiple faulty genes without a genetic diagnosis. Nonetheless, pinpointing modifier genes for a particular disease phenotype can be costly and challenging. ⁽³⁾

Challenges of Gene Therapy:

While the retina’s immune privilege makes it an excellent candidate for gene therapies, it also presents challenges like identifying the disease-causing gene or mutation, ensuring targeted delivery, determining the appropriate administration route, assessing feasibility in the clinic, and managing potential immune responses that could harm the delicate tissue. ^(4,5)

Summary:

Gene therapy is advancing as a treatment for previously untreatable forms of retinal blindness. Although the field is young, the enthusiasm from both the scientific community and patient advocacy groups is invigorating. ⁽²⁾

A crucial aspect of future gene therapy development is devising ways to treat genetic diseases without a specific genetic diagnosis or to target multiple mutations with a single product. This approach would tackle two ongoing challenges in gene therapy: the high production costs and the necessity of identifying the genetic cause of a disease on an individual basis. ⁽³⁾

References:

1. Boye, S. E., Boye, S. L., Lewin, A. S., & Hauswirth, W. W. (2013). A comprehensive review of retinal gene therapy. Molecular therapy, 21(3), 509-519.
2. Concepts and Strategies in Retinal Gene Therapy, cited from [Internet][April 14] Available from: https://iovs.arvojournals.org/article.aspx?articleid=2659572#173899463
3. Gene Therapy for Retinal Degenerative Diseases: Progress, Challenges, and Future Directions, cited from [Internet][April,14] Available from: https://iovs.arvojournals.org/article.aspx?articleid=2791262
4. Gene Therapy for Inherited Retinal Disease, cited from[Internet][April,14] Available from: https://www.reviewofophthalmology.com/article/gene-therapy-for-inherited-retinal-disease
5. Samiy, N. (2014). Gene therapy for retinal diseases. Journal of ophthalmic & vision research, 9(4), 506.
6. Lipinski, D. M., Thake, M., & MacLaren, R. E. (2013). Clinical applications of retinal gene therapy. Progress in retinal and eye research, 32, 22-47.