Challenges of Gene Therapies for RP

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Gene therapy, in which we have very high expectations to cure genetic disorders, is currently being translated from preclinical assays to the clinical practice for retinal degeneration diseases, with successful achievement up till now for the LCA, due to mutations in the RPE65 gene. This gave hope to cure RP of different genetic origins.

Currently, our gene therapy research team is focusing on gene replacement therapy, gene editing therapy and optogenetic gene therapy. With these promising therapies, though, comes relevant challenges.

Over 300 genes are associated with inherited retinal degenerations and only a small proportion of these will be suitable for gene replacement therapy. Gene replacement therapy can only be applied to genetic diseases with missing functional genes. And it also involves importing foreign genes, which is difficult to completely match the expression in the body, this will affect the treatment efficacy.

Gene-editing therapy only modifies the mutated gene, it does not affect the regulatory sequence. It has a more permanent effect. Like CRISP editing tools is used to amend genetic missenses, however, it needs to fix secondary effects, which related to the immune response. And if it is regarding a large fragment deletion that exceeds the scope of gene editing, gene replacement therapy is required.

The two strategies: gene replacement and gene editing therapies have their own advantages and disadvantages, they are complementary to each other.

Optogenetic gene therapy may regain sight in advanced RP, regardless of the gene mutation type. The phase 2b trial by Nanoscope Therapeutics starts in June 2021. It’ll involve a single intravitreal injection of MCO genes into the retina, where they express opsins enabling vision in the different color environments. However, it had a limited scope of clinical benefit because the opsins had a narrow band of activation, unlike the natural light environment. MCO is sensitive to broadband light and activatable by ambient light, thus eliminating the risk of photo-toxicity from long-term use of external intense light stimulation devices. Furthermore, like many other cell -, gene-, and protein-based therapies, it might be complicated by the possibility of immune responses. The introduction and expression of foreign molecules, such as a light-activated opsin, comes with the risk of eliciting a response from our immune cells.

How to optimize the gene therapies and offer the best results is crucial for scientists.

Although gene therapies promise to drastically improve RP patients’ vision, they are expensive and complex to develop. Therefore, another big challenge is the price, these therapies might be expensive for patients, as we know, the first gene therapy, which is called Luxturna, costs nearly one million US dollars for both eyes.

Gene therapy offers so much potential and the field is moving forward quickly. Improving manufacturing efficiency and sharing learnings across the industry will help to make these treatments more accessible to the patients who need them. As regulatory bodies continue to become more familiar with gene therapy, the road to commercialization will become more efficient as well. Let’s hope for the best.