• Age-Related Macular Degeneration (AMD)
• Cataract
• Glaucoma
• Diabetic Retinopathy
• Strabismus
• Amblyopia
• Refractive Errors

In the United States, more than 4.2 million individuals are considered by the Social Security Administration (SSA) to be legally blind or have a low vision [1].

1. How Is the Structure of the Eye Related to Its Function?

The eye is made of structures that allow light to enter the eye, refract it, and transform it into two-dimensional images by the retina [2]. The eye contains the following structures:

The eye (eyeball) occupies a space or cavity in the skull known as the orbit where it is connected to the optic nerve, muscles, and blood vessels.

The optic nerve is a sensory nerve located at the back of the eye and responsible for the transmission of visual information from the eye to the brain.

The eye muscles are responsible for eye movements.

The blood vessels provide oxygen and nutrients for the tissues of the eye.

Around the eye, there are structures involved in the production of tear (lacrimal gland), and its draining, including the tear sac (lacrimal sac), the tear ducts (canaliculi), and the lacrimal duct (nasolacrimal duct).

The eyeball is made of the following structures and tissues:

1.1. The Episclera

The episclera is a loose conjunctive tissue that covers the back of the eye (the part inside the socket) and connects with the conjunctiva.

1.2. The Sclera

The sclera or tunica albuginea oculi is the white part of the eye made of collagen and elastic fibers and which role is to protect the eye.

1.3. The Choroid

The choroid is the middle part tissue layer of the eye found between the sclera and the retina. It mostly contains blood vessels that supply oxygen and nutrients to the outer part of the retina.

1.3. The Retina

The retina is the innermost layer of the eye responsible for creating two-dimensional images of the visual world.

The retina is made of blood capillaries and photoreceptors, including cones and rods.

Cones are photoreceptors that detect color and are also responsible for the production of sharp and detailed central vision.

Cones are mostly concentrated in a region of the retina known as the macula

Rods are photoreceptors responsible for night vision and side vision. They are not capable of detecting color but are more sensitive to light.

Rods are mostly found at the periphery (side) of the retina.

The visual information from the cones or rods is then transferred through synapses to neurons known as retinal ganglion cells that are just below their ends.

1.4. The Optic Disc

The optic disc is the beginning of the optic nerve and contains the axons of retinal ganglion cells.

1.5. The Conjunctiva

The conjunctiva is an epithelial membrane that covers the front of the eye.

1.6 The Cornea

The cornea is the transparent part in front of the iris and the pupil and which role is to refract light entering the eye.

1.7. The Pupil

The pupil is the black hole in the middle of the iris which lets the light through the light coming from the cornea and towards the retina.

1.8. The Iris

The iris is a structure made of pigmented epithelial cells that control the diameter and size of the pupil.

1.9. The Lens

The lens is the structure found behind the iris and is involved in refracting light coming to the cornea and pupil.

It is suspended in place by the suspensory ligament of the lens.

1.10. The Vitreous Body

The vitreous body or vitreous humor is a clear gel that fills the inside of the eye between the retina and the lens.

It is made of a fibrillous mesh of extracellular matrix and which role is to keep the eye clear to let the light coming through the lens toward the retina.

2. Age-Related Macular Degeneration (AMD)

Age-related macular degeneration is a chronic degenerative disease mostly affecting individuals over the age of 60 years.

It is characterized by atrophy of the epithelium of the macula and the degeneration of the photoreceptors.

AMD manifests with the following symptoms:

• Difficulties seeing faces, reading smaller prints, and driving.
• Blind spot in the center of the vision.
• Blurred or distorted vision
• Seeing straight lines as wavy
• Objects looking smaller than normal
• Hallucinations

There are several factors that increase the risk of AMD such as being over 50 of age, smoker, being hypertensive (hypertension), and having a high-fat saturated diet.

Unfortunately, there is no available treatment for AMD.

3. Cataract

A cataract is characterized by the clouding of the eye lens that can affect one or both eyes. There are several causes of cataracts:

• Age
• Genetics (a family history of cataract)
• Trauma (eye injury)
• Medications (long-term treatment with steroids)
• Alcohol
• Smoking

A cataract is characterized by a clouded or blurred vision that can lead to blindness.

Treatment of cataracts involves surgical removal of the cataract.

4. Glaucoma

A glaucoma is a group of diseases that are mainly characterized by an increased pressure in the eye which damages the optic nerve; however, other types of glaucoma do not involve high intraocular pressure.

They are divided into open-angle and close-angle glaucoma based on the timing of appearance. Open-angle glaucoma develops slowly and without evident signs until the glaucoma is at an advanced stage, while a close angle appears suddenly.

Glaucoma is caused an increased pressure in the eye associated with the build-up of fluid (aqueous humor). Another cause is genetics which involves a family history of glaucoma.

Open-angle glaucoma manifests with symptoms such as Blindspot in the center of the vision, and tunnel vision.

Closed-angle glaucoma presents symptoms including blurred vision, ocular pain, severe headaches, nausea, and vomiting, and decreased vision.

The treatment of glaucoma is preventive and involves early detection to prevent or slow down the progression of glaucoma.

5. Diabetic Retinopathy

Diabetic retinopathy is associated with Diabetes Miletus that causes the blockage of blood vessels that supply oxygen and nutrients to the retina causing its damage.

However, diabetic retinopathy develops through stages including:

• Stage 1: Microaneurysms
• Stage 2: Blockage of some blood vessels of the retina
• Stage 3: Blockage of more blood vessels leading to ischemia
• Stage 4: Retinal damage

Diabetic neuropathy manifests with the following symptoms:

• Blurred vision
• Gradual worsening of vision and its sudden loss
• Redness of the eye with pain
• Floating shapes in the field of vision

The diagnosis of diabetic retinopathy is performed using diabetic eye screening to see if there are anomalies in the eye.

The treatment involves laser treatment, injection of steroids (Triamcinolone) in the eye, and surgery.

6. Strabismus

Strabismus is a lack of alignment between the two eyes when looking at an object. It is caused by anomalies with the extraocular muscles or nerves that control them.

The extraocular muscles are responsible for controlling the eyes’ movements.

Strabismus manifests with symptoms such as double vision, eye strain, fatigue when reading, and headaches.

Treatment of strabismus involves the use of eyeglasses or surgery to align the extraocular muscles.

7. Amblyopia

Amblyopia or lazy eye is a visual impairment due to the brain failure in processing visual stimulation in the early first few years of life [3].

It can be caused by strabismus or a difference in refractive errors (anisometropia) between the two eyes.

Amblyopia manifests with symptoms that affect one eye such as poor visual acuity, low sensitivity to contrast and motion, and poor pattern recognition.

The treatment involves correcting the refractive errors between the two eyes by putting a patch on the normal eye.

8. Refractive Errors

Refractive errors are anomalies that affect the capacity of the eyes to focus light on the retina.

Refractive errors include myopia (near-sightedness), farsightedness (hyperopia), astigmatism, and presbyopia [4].

• Myopia (Near-Sightedness)

Myopia is a disorder of the eye where distant objects appear blurry. Other symptoms of myopia may involve headache and eye strain.

Although the causes are unknown, genetic, and environmental factors may be involved.

• Farsightedness (hyperopia)

Farsightedness is a disorder of the eye where close objects appear blurry. Other symptoms of farsightedness may involve headache and eye strain.

It is caused by variations during the development of the eye.

• Astigmatism

Astigmatism is due to an anomaly of the shape of the eye which affects its refraction of light causing objects that are close and far away to look blurry.

Other symptoms of astigmatism may involve headache, migraine, eye strain, and double vision.

Although the causes of astigmatism are unclear, genetics appears to play a role.

• Presbyopia

Presbyopia is a progressive decrease in the capacity to clearly focus on objects that are close and that affects individuals over the age of 40.

Other symptoms of presbyopia may involve headache and eye strain.

It is caused by the hardening of the lens due to age.

Refractive errors are treated using eyeglasses or corrective lenses and surgery.

Conclusion

The eye is a very sensitive organ and any anomalies, even smaller, that affect the eye tissues results in changes in the vision.

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To introduce or replace defective genes, this approach involves using viral or non-viral vectors to insert healthy copies of genes into the cells of affected people to re-establish their normal function within the targeted cells, tissues, and organs [1].

I. What is CRISPR Gene Editing?

Inserting healthy copies or correcting mutations genes rely on the use of genetic engineering techniques, such as the CRISPR gene editing method that can be specifically designed to recognize the defective gene, cut it at the desired location or replace it with a healthy and functional gene [2].

1- What Is Crispr?

Clustered regularly interspaced short palindromic repeats (CRISPR) are DNA sequences that are originally found in the genomes of microorganisms such as bacteria or archaea.

Because bacteria and archaea can be infected by a virus known as bacteriophage (phage), CRISPR sequences are used by bacteria and archaea to flank or tag the bacteriophage DNA that has been integrated into their genome by the bacteriophage.

CRISPR is used to quickly recognize and destroy the bacteriophage DNA that was inserted into their genome. Therefore, CRISPR is used as a form of acquired immunity for bacteria and archaea [3].

2- How Does Crispr Gene Editing Work?

When an infection by a bacteriophage happens, which involves the insertion of the bacteriophage DNA into the bacteria or archaea genome, bacteria or archaea produce an enzyme known as CAS9 (CRISPR-Associated protein 9) that recognize, cleave, and remove the CRISPR sequences that flank the bacteriophage DNA [3].

Therefore, the CRISPR/Cas9 technology can be used to specifically target defective or mutated genes within the cells of the human body by directing Cas9 directly to these genes are then recognized and cleaved by Cas9.

However, in the human body, Cas9 requires guidance towards the gene of interest to be cleaved.

In this case, the CRISPR/Cas9 technology uses specific RNA molecules known as RNA guides (gRNA) that contain the specific information about the gene of interest within the cells of the body and that will help Cas9 to recognize that specific gene and cleave it.

II. How Is Crispr Delivered in the Body?

Viruses or non-viral vectors are considered for the delivery of Cas9 and the gRNA in the cells of the body.

1- What Are Viral Vectors?

Viruses have the capacity to bind and introduce their genetic material to the host cells. Once the genetic material is introduced, new viruses are made using the infected cells by hijacking their ability to produce proteins.

Therefore, after making these viruses incapable of causing disease by removing some parts of their genetic material, these can be used to introduce Cas9 and gRNA to cleave and remove the gene of interest.

• Retroviruses

Retroviruses are RNA viruses which means that their genome is not made of DNA but of RNA.

When these viruses enter the host cells and with the help of a viral enzyme known as transcriptase, they start making DNA copy from the RNA.

The newly generated viral DNA is then integrated into the host genome by another enzyme known as integrase.

Once integrated into the genome of the host cells, the viral DNA is transcribed in a similar way as the host DNA leading to the production of proteins and enzymes that help the multiplication of the virus.

Therefore, retroviruses can be used to introduce Cas9 and gRNA within the host cell which then go and recognize and cleave the gene of interest.

The advantage of using retroviruses for the delivery of Cas9 and gRNA is in their capacity to infect both dividing and non-dividing cells within the body as they can replicate their genes when the infected host cell is dividing.

• Adenoviruses

Unlike retroviruses, adenoviruses are DNA viruses which means that their genome is made of DNA. Adenoviruses do not integrate their DNA in the host genome as they do not have an integrase.

This inability of integrating the DNA of the host, makes their replication limited as their genes are not replicated when the infected host cell is dividing.

Therefore, adenoviruses are best used for introducing Cas9 and gRNA in cells that do not divide, and therefore, are fully differentiated.

2- What Are Non-Viral Vectors?

Although the use of viruses for the delivery of Cas9 and gRNA into the host cells is an efficient method, they also have limitations such as immunogenicity of the host (immune response) and their production at large scales.

These limitations can be overcome through the use of non-viral vectors.

• Injection of Naked DNA

Although the efficiency is limited, this method involves the injection of DNA into the muscles, which is then integrated by the cells.

• Lipoplexes

Lipoplexes are liposomes that form complexes with nucleic acids, such as DNA and RNA, for delivery into the cells of the host. Because of their lipid nature, lipoplexes fuse with the cell membranes of the host cells and deliver their nucleic acids.

• Polymersomes

Polymersomes are synthetic liposomes that also form complexes with nucleic acids for delivery to the host cells.

• Nanoparticles

Nanoparticles are chemically synthesized or assembled products that have sizes that are within the nanometer ranges, and which include dendrimers, liposomes, metal nanoparticles, nanocrystals, nanosuspensions, polymer nanoparticles, block copolymer micelles, and polymer therapeutics.

Due to their small size, nanoparticles are used to form complexes with nucleic acids to ease their delivery to host cells.

• Virosomes

Virosomes are made of liposomes that have nucleic acids (DNA, RNA) and viral proteins to facilitate their recognition and intake by the host cells.

III. Medical Applications of CRISPR Gene Editing

Gene therapy has been proposed for the treatment of several genetically related diseases, including cancer, hemophilia, cystic fibrosis, amyotrophic lateral sclerosis, age-related macular degeneration, sickle cell anemia, progeria, beta-thalassemia, Huntington disease, and Duchenne’s muscular dystrophy [1] [5].

However, so far, clinical trials to cure beta-thalassemia and sickle cell disease in human patients have shown promising results [4].

Conclusion

Although gene therapy is a promising medical approach, challenges regarding its efficacy, safety, and specificity must be further investigated before its use in clinics. Nonetheless, this therapy is highly fascinating and could provide significant hope in developing medical cures against deadly genetic diseases.

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