What Is Inherited Retinal Diseases?
Inherited retinal diseases (IRDs) encompass a group of inherited disorders affecting the retina. They are also called inherited retinal dystrophy or inherited retinal degeneration. The retina functions similarly to film in a conventional camera for normal vision. This is where the images are formed and subsequently transmitted to the brain for processing. The light-sensitive tissue in the back of the eye is called the retina. It has several kinds of retinal cells in it.
The retinal cells in people with IRD do not function normally. IRDs can impact people of various ages and develop at varying speeds. Nevertheless, many are degenerative, meaning that as the condition advances, so will its symptoms. IRDs often exclusively impact the eyes in patients. IRDs, however, can be associated with many health problems. Because of their hereditary nature, treating such diseases has been extremely difficult for many years.
The most common inherited retinal diseases include Leber congenital amaurosis (LCA), cone-rod dystrophy, Stargardt disease, achromatopsia, and choroideremia. Because many disorders are hereditary in nature, treating them has been difficult for many years. However, new developments in gene therapy have given individuals with IRDs new hope.
What Is Gene Therapy?
Gene therapy is a medical approach that uses genes to treat, cure, or prevent a disease or medical condition. The initial objective of gene therapy was to either introduce a new gene into cells to aid in the battle against a disease or introduce a functional copy of a gene to replace the altered copy responsible for the illness. A more recent method corrects genetic differences by taking a different approach by gene editing rather than adding fresh genetic material to cells. Gene therapy has been used to treat acquired problems and inherited genetic diseases.
What Are the Gene Therapy Methods for Retinal Diseases?
Retinal gene therapy methods may vary depending on the nature of the mutation:
1. Gene Replacement Therapy - Gene replacement therapy is a technique that increases the production of functional protein by providing a functioning copy of a damaged or malfunctioning gene. This treatment does not alter the damaged gene but fills up its missing function. Gene replacement therapy is most appropriate for monogenic recessive hereditary disorders (disorders caused by the inheritance of single gene mutations), such as CEP290 gene mutations, which account for 15 to 20 percent of LCA cases. Patients with LCA who have RPE65 mutations of 5 to 10 percent can get a functioning RPE65 gene with gene therapy known as Voretigene neparvovec-rzyl. However, despite Voretigene neparvovec-rzyl seeming successful in the clinic, there have been doubts about its efficacy and durability in patients with various genetic backgrounds.
There are many limitations to implicating gene replacement therapy.
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For instance, retinitis pigmentosa can be caused by over 3000 different gene changes in about 70 genes.
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Sometimes, the gene alterations that cause eye disorders cannot be identified.
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Not all gene alterations may be corrected by adding normal genes in their place.
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Other gene modifications are too effective, while some genes are too large to be replaced.
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Some diseases are caused by many gene changes, making it too expensive and hard for patients to get treatment for each one.
2. Gene Editing - Gene editing modifies an inherited condition by correcting gene mutations or reducing the expression of the mutated protein. Numerous methods for editing genes have been created, such as homing endonucleases or meganucleases, transcription activator-like effector nucleases (TALENs), zinc finger nucleases (ZFNs), and CRISPR/Cas9. Clinical trials are being conducted on gene treatments that utilize CRISPR/Cas9 (Clustered regularly interspaced short palindromic repeats).
In treating retinal disorders, EDIT-101 is a gene editing therapy that attempts to correct a mutation that causes LCA type 10. This mutation causes an error in the assembly of the CEP290 gene, resulting in its dysfunction. CRISPR/Cas9 is the technology used in the therapy to correct this mutation, which restores CEP290's proper function. Prime editing is a different method being researched that can potentially correct tiny modifications and many mutations in the genome. However, it still has difficulties and limitations, much like other conventional gene therapy.
3. Gene Silencing - The control of gene expression in a cell to stop a particular gene from being expressed is known as gene silence. Gene knockdown is similar to gene silencing. Gene expression decreases when it is silenced. Treatments for age-related macular degeneration (AMD), glaucoma, and several other ocular conditions are now being developed that involve gene silencing with small interfering RNA (siRNA) or microRNA (miRNA) that target vascular endothelial growth factor (VEGF). There are now numerous clinical trials using targeted gene silencing methods. However, due to several issues, including RNA (ribonucleic acid) instability, low bioavailability, and nonspecific targeting that might result in off-target effects, clinical trials utilizing this strategy have yet to advance past a certain level in the ocular area.
What Are the Complications and Challenges of Gene Therapy for Inherited Retinal Diseases?
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Gene therapy trials outside the eyes are mostly considered safe, but gene therapy trials to the eyes have reported few serious adverse events. The procedure, combined with retinal gene therapy drugs, can be harmful to the fragile retina. Complications may include inflammation, increased eye pressure, the development of antidrug antibodies, reduced ERG amplitudes, loss of retinal layers, and toxicity in photoreceptors and RPE layers.
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Increased immune responses due to blood-tissue barrier defects can produce neutralizing antibodies, which limit gene therapy effectiveness.
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Inherited retinal diseases consist of a wide range of genetic mutations and variations. So, developing a gene therapy approach to fit all kinds of variations is challenging.
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Choosing the most appropriate delivery system is also essential for gene therapy. It requires careful consideration of safety, efficiency, and scalability factors.
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Another big challenge is getting the product to the right tissue or cells. For example, if given intravenously, the blood-retina barrier can prevent it from reaching the retina.
Conclusion:
Inherited retinal diseases can occur due to variations in the gene, and it can cause progressive vision loss. As it is an inherited condition, normal therapies are not effective. Ocular gene therapy provides a promising therapeutic approach for individuals with genetic defects responsible for inherited retinal diseases. However, this therapy has some challenges and complications. As ongoing research continues to develop, they prioritize minimizing the complications and challenges related to inherited retinal diseases.
