Introduction:
Over the past two decades, various advancements have taken place in genetic characterization, which has led to the identification of over 260 causative inherited mutations with retinal disorder. So, what was thought to be incurable has been made permissible with the supplementation of gene therapy. In this gene replacement therapy, the disease-causing gene gets replaced by a functional copy. Genetic therapies have been inculcated to slow disease progression and restore vision. Gene therapies are delivered to the retinal cells through the subretinal (SR) or intravitreal injections (IVT). As discoveries of novel disease-causing mutations continue to be discovered annually, gene therapy remains under development for many clinical and preclinical models of inherited retinal diseases (IRD).
What Are Inherited Retinal Diseases and Their Types?
These are a group of genetically inherited heterogeneous disorders leading to irreversible visual disorders worldwide. Over 260 disease-causing genes have been identified for IRDs. These disorders tend to alter the function and structure of the retina and impair vision. These are rare and have various types. Most IRDs affect the light-sensitive cells called “photoreceptors,” which reduce and prevent light responses in the retina, leading to vision impairment. There are various disorders are being targeted for gene therapy, namely:
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Retinitis Pigmentosa (RP): This disorder affects the retina. It makes the retinal cells slowly break over time and cause loss of vision.
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Leber Congenital Amaurosis: A family of congenital retinal dystrophies causing vision loss at an early age.
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Choroideremia (CHM): Affects males and is caused by the loss of retinal cells, leading to night blindness in childhood, loss of peripheral vision, and inability to make out details.
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Achromatopsia (ACHM): Limited or no color-vision, extremely sensitive to light.
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Leber’s Hereditary Optic Neuropathy: This condition starts early in infancy, and crossed eyes and farsightedness are noted.
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Usher Syndrome (USH): There is a dual sensory impairment of auditory and visual impairment.
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X-Linked Retinoschisis: It affects the males. There is an early loss of central vision as the splitting of the retinal layers takes place.
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Stargardt Disease: Stargardt disease damages the macula, the retinal part which provides straight-ahead vision.
The IRDs are projected to affect both the eyes typically.
What Are Gene Therapies?
The word gene therapy refers to gene replacement. Gene replacement therapies currently form the most active clinical trials for IRDs. In this, the wild-type gene of the pathogenic gene is introduced into the retinal target cells through the viral and nonviral vectors. These therapies aim to slow the disease's progression and restore visual function. Various approaches are required, such as gene suppression and gene editing for dominant IRDs. The subretinal injections (SR), the main delivery method, allow direct access to photoreceptor and RPE cells. The alternative to SR is intravitreal injections (IVT), which are much simpler and safer and typically used for the inner retinal cells, and in this, widespread retinal areas are targeted. For gene therapy, a vehicle is needed to deliver the genetic material.
Is the Eye an Ideal Target for Gene Therapy?
The human eye has always presented itself as an appealing target for gene therapy for the following reasons:
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Firstly, due to blood-retinal barriers, the retina is considered an immune-privileged site, as introducing foreign material into it leads to an inflammatory reaction.
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The eye is a small and compartmented organ. Thus, a lower therapeutic dose is required, and the risk of systemic dissemination is negligible.
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As eyes are in pairs, using the other eye as the control is always possible to assess the safety and efficacy.
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Eyes are easily accessible from both points of surgery and diagnostic standpoints.
What Are the Different Types of Gene Delivery Systems?
There are two types of gene delivery systems:
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Non-Viral Delivery System: It is advantageous over the viral delivery system; it has a greater and unlimited cargo delivery system. It has an inexpensive manufacturing system. It uses physicochemical agents to compact the DNA and transport it across the membranes.
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Viral-Delivery System: The primary vehicles are the recombinant Adeno-associated viral vectors (AAV), which serve as the primary vehicles for the gene augmentation trials of IRDs. These provide long-term transduction for various types of retinal cells, but they offer a limited carrying capacity. Apart from this, other vectors are also being used, like AAV2, AAV8, and Lentiviruses. The Lentiviruses (LT) have a greater carrying capacity, safely transferring large genes of interest. Currently, many clinical trials are still in progress.
What Are the Routes of Administration?
The success of gene therapy is based on the route of administration. Two injection modalities are being used currently, namely (subretinal and intravitreal).
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Subretinal Injections (SRI): It is a delicate procedure in most clinical trials. It allows vector administration near the common cell target site. It offers zero risk of immune reaction as it places therapeutic material in closed compartments. But despite this, it is associated with complications like retinal tears, progression of cataracts, and retinal/choroidal hemorrhages.
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Intravitreal Injection: This is technically challenging and less invasive. It offers gene-based accessibility to a larger audience. It can be performed in the clinical setting. A much higher dose might be required for the non-immune privileged sites.
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Suprachoroidal Delivery: It is being studied. Therapeutics are conveyed in the space between the sclera and choroid.
How Does Gene Therapy Compare to Traditional Treatments for Inherited Retinal Diseases, Medications, or Surgeries?
In comparison to the traditional treatment gene therapy offers:
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It targets the root cause.
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It aims for long-lasting and permanent effects by altering the patient's genetic makeup.
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Gene therapy can be tailored according to the genetic profile of the patient.
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At times, one-time gene therapy can aim to provide a sustained therapeutic effect.
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It has the potential to treat a larger group of disorders.
Ultimately, the choice between the two varies depending on the specific disease characteristics, the individual patient, and the current state of medical technology. The field of gene therapy is evolving continuously, and more research in this regard can enhance our knowledge.
Conclusion:
Gene therapy has proved promising for quality of life and improved vision. As the progression of research continues synergy of scientific innovation and clinical application brings all close to a future where gene therapy becomes a beacon of light for those affected by such debilitating diseases.
