GENE THEAPY FOR ETINAL DISEASES

Retinal diseases are a major cause of irreversible blindness. These conditions can be caused genetically or acquired later in life. Complex diseases have both genetic and acquired counterparts. Most common forms of multifactorial retinal diseases include macular degeneration, glaucoma, diabetic retinopathy, and retinoblastoma. Inherited retinal degenerations, on the other hand, are entirely linked to mutations in retinal neurons and their underlying epithelium. Retinal cell death is the main cause of vision loss in many blinding conditions, for which gene and cell therapy approaches offer intervention at various stages.

Gene therapy is an emerging therapeutic approach to treat, cure, or prevent a disease by providing a gene with therapeutic action. Diseases associated with loss-of-function mutations can be treated by gene replacement therapy (also referred to as gene supplementation), whereas those associated with gain-of-function mutations require eradication of mutant alleles in addition to supplementing the gene. In all instances, the genetically modifying factors (DNA or RNA and/or their interacting proteins) need to be delivered into the relevant target cells. Most gene therapy studies use viral vectors, such as adenovirus (Ad), adeno-associated virus (AAV), or lentivirus (LV), to enable gene delivery to the retina. Two local administration routes allow viral vectors to access retinal cells. Viral vectors can either be injected into the vitreous cavity via an intravitreal injection, or they can be injected into the subretinal space, created through a transient retinal detachment. Intravitreal injections deliver the vector in proximity to the retinal ganglion cells and are the preferred delivery route for targeting the inner retina. Subretinal injections deliver vectors between the photoreceptors and their underlying retinal pigment epithelium (RPE). As most inherited retinal degenerations are caused by mutations found in the photoreceptor and RPE cells, subretinal injections have been used in most gene therapy studies.

Depending on the cell target, Ad, LV, and AAV have been studied. After subretinal delivery both Ad and LV transduce the RPE efficiently. Ad, however, has been associated with cytotoxic T lymphocyte-mediated removal of the transduced cells that express the encoded Ad proteins,⁴ leading to transient gene expression. More recently, helper-dependent Ad vectors devoid of sequences encoding viral proteins have been developed and shown to target the RPE stably.^5,6 Thus far, photoreceptor transduction remains elusive with Ad and LV vectors despite the great diversity of new serotypes and pseudotype.

. Approved therapies like Luxturna target the RPE65 gene mutation for conditions like Leber Congenital Amaurosis, while other gene therapies are in trials for retinitis pigmentosa by replacing genes like RPGR. Delivery methods include subretinal injection to target photoreceptors and RPE cells or intravitreal injection for inner retinal cells.  

How it Works

1. 1. Gene Replacement:

The primary approach is to introduce a correct, healthy copy of a gene that is mutated in the patient's retinal cells. 

2. 2. Delivery Vector:

Harmless viral vectors, most commonly adeno-associated viruses (AAV), are used to carry the genetic material into the target cells. 

3. 3. Cellular Repair:

The new genetic material enables the cells to produce the necessary proteins to function correctly and survive longer, slowing or halting vision loss. 

Approved and Investigational Therapies

• Luxturna (Voretigene neparvovec-rzyl):

The first FDA-approved gene therapy for inherited blindness, treating conditions caused by mutations in the RPE65 gene, such as Leber congenital amaurosis. 

• Retinitis Pigmentosa (RP) Therapies:

Several therapies are in development for different forms of RP, like the one targeting the RPGR gene. 

Delivery Methods

• Subretinal Injection:

Involves detaching the retina temporarily to inject the viral vector directly into the space between the photoreceptors and the retinal pigment epithelium (RPE), the main target for many inherited retinal diseases. 

• Intravitreal Injection:

A safer and simpler method where the vector is injected into the vitreous humor (the gel-like substance filling the eye), allowing access to a wider area of the retina, particularly for targeting inner retinal cells. 

Challenges and the Future

• Specific Targets:

Gene therapy is most effective for recessive genetic disorders but requires different approaches, such as gene editing or suppression, for other types of mutations.