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Inherited Retinal Disease and RNA Therapeutics
Context:
The landscape of treating Inherited Retinal Diseases (IRDs), which are a significant cause of vision impairment and blindness, is rapidly changing with advancements in RNA-based therapies.
Understanding Inherited Retinal Diseases (IRDs)
- IRDs are genetic conditions that progressively lead to vision loss and blindness.
- Causes: They result from mutations in over 300 genes that impact the retina, the light-sensitive tissue at the back of the eye.
- The severity of IRDs varies—some individuals experience blindness at birth, while others suffer from gradual deterioration over time.
- Types of IRDs: There are many types of IRDs, including Retinitis Pigmentosa (RP), Stargardt Disease, Choroideremia, Cone-Rod Dystrophy, and Leber Congenital Amaurosis (LCA), among others.
- Symptoms: Symptoms vary depending on the specific type of IRD but often include difficulty seeing in low light, loss of peripheral vision, and eventual loss of central vision.
- Early intervention can slow or prevent vision loss in many cases.
The Global Burden of Vision Impairment
- According to the World Health Organisation (WHO), over 2.2 billion people worldwide suffer from some form of vision impairment. The leading causes include cataracts, diabetic retinopathy, glaucoma, age-related macular degeneration, and inherited retinal diseases (IRDs).
- An estimated 5.5 million people worldwide are affected by IRDs, with a prevalence of 1 in 3,450 people. However, the situation in India is more severe, with significantly higher prevalence rates:
- 1 in 372 individuals in rural South India
- 1 in 930 in urban South India
- 1 in 750 in rural Central India
Gene Therapy for Blindness
- In 2017, the FDA approved the first-ever gene therapy for blindness caused by mutations in the RPE65 gene. This marked a historic step, opening the door to treatments for other genetic causes of blindness.
- Gene therapy, although groundbreaking, is not a universal solution, and its availability in India remains limited. This is where RNA-based therapies have the potential to make a larger impact.
The Promise of RNA-Based Therapies
- Unlike DNA-editing therapies, which make permanent changes, RNA-based treatments offer a safer, temporary approach to treating genetic diseases. These therapies modify RNA to correct mutations without altering the underlying DNA, reducing the risk of unintended genetic consequences.
- One of the key RNA-based therapies currently being explored is antisense oligonucleotides (ASOs), which have shown success in treating conditions like spinal muscular atrophy and Duchenne muscular dystrophy.
- Now, these therapies are being explored for retinal conditions, including Stargardt disease, Leber congenital amaurosis, and retinitis pigmentosa.
- Another cutting-edge approach involves using ADAR enzymes for RNA editing to correct specific mutations, potentially restoring the production of essential proteins in retinal cells without altering DNA.
- Suppressor tRNAs, which bypass stop-codon mutations to enable the production of full-length proteins, represent another innovative strategy that could restore retinal function in patients with IRDs.
- Additionally, PTC124 (ataluren) has shown promise in treating cystic fibrosis and Duchenne muscular dystrophy, and clinical trials are now underway to test its efficacy in treating aniridia, a rare developmental eye disease.
India’s Role in Precision Therapeutics
- Precision medicine tailors treatments based on an individual’s genetic makeup, environment, and lifestyle, providing a more targeted alternative to conventional therapies.
- For IRDs, identifying prevalent genetic mutations in different populations is essential for developing effective RNA-based therapies. However, India lacks large-scale genetic studies for IRDs.
- For instance, while the ABCA4 gene is a common IRD mutation globally, its prevalence in Indian patients remains unclear.
Challenges in India
- The mutation spectrum of IRDs in the Indian population remains under-researched, limiting the development of targeted treatments.
- There is no large cohort study (with 500+ patients) to map out the most common mutations in India.
- Genetic mutations can vary significantly across India’s diverse population, making it difficult to identify consistent genetic targets for treatment.
- Lack of awareness and infrastructure, particularly in rural areas, hinders early diagnosis and access to therapies.
India’s Path Forward
- Mapping Mutations: Research into the genetic mutation profiles of IRD patients in India is essential. By collaborating with global research institutions and local healthcare providers, India can accelerate the development of RNA-based therapies tailored to the Indian context.
- Example of Collaboration: A 2024 study by the CSIR-Institute of Genomics and Integrative Biology and L.V. Prasad Eye Institute led to a precision therapy for a specific form of IRD, showcasing the importance of local research partnerships.
The Need for Collaborative Research:
- Prioritise genetic research to understand mutation profiles in different ethnic groups
- Expand partnerships between global and local pharmaceutical companies
- Improve clinician awareness of emerging RNA-based treatments
- Establish national-level genetic screening programmes
