Cell Therapy

Last updated on: January 1st, 2023

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Gene therapy: Leber Congenital Amaurosis


Inherited retinal diseases

Inherited retinal diseases are a group of genetic conditions that cause degradation of the light-sensitive cells in the retina. Frequently progressive and irreversible, these diseases result in significant vision loss. Degraded retinal cells decrease light detection, color discrimination, and peripheral vision, ultimately leading to total blindness.

Leber congenital amaurosis type 2

Leber congenital amaurosis (LCA) is an inherited retinal disease. Many distinct gene mutations are related to LCA; these are often found in both copies of the gene in each chromosome of the homologous chromosome pair (biallelic mutations). LCA's clinical symptoms are diverse, including low light sensitivity (photophobia), altered shape of the eyes (nyctalopia), outward bulging of the cornea (keratoconus), cataracts, and more. However, four clinical features are described in all forms of LCS: early and pronounced visual loss, lack of pupillary light reflex (amaurotic pupils), nystagmus, and a lack of electrical signs on electroretinogram. Nystagmus is generally the first sign, apparent at the age of 6 weeks. LCA is a form of retinal dystrophy without major systemic implications.

One LCA type, LCA type 2 (LCA2), is caused by the biallelic mutation of the gene coding for the retinal pigment epithelium-specific 65 kDa (RPE65) protein.

RPE65 and the visual cycle

The RPE65 protein is an enzyme that plays an essential role in the visual cycle, a sequence of biochemical reactions in the retina that are required for vision. In response to light, 11-cis-retinal, a small molecule attached to a light-sensitive protein, changes its molecular arrangement into all-trans-retinal. This change triggers biochemical reactions that convert light stimuli into electrical signals. Maintenance of this sequence of reactions requires further regeneration of all-trans-retinal into 11-cis-retinal. RPE65 is one of the proteins required for that regeneration. Gene mutations affecting RPE65 function will block regeneration of 11-cis-retinal. Consequently, the visual cycle, and vision, will be compromised. Ultimately, death of photoreceptor cells and blindness result.

Gene therapy approach for LCA2

In LCA2 patients with viable retinal cells, the lack of functional RPE65 can, in principle, be overcome through the supply of an artificial gene coding for this protein. The gene is packed inside viral particles that are surgically injected into the patient’s retina. Viral particles will deliver the gene into retinal cells, which will produce RPE65, to restore the visual cycle. The preferred viral particles are adeno-associated viruses. These lack pathogenicity and cause only minor immune responses. They can also maintain regular levels of therapeutic gene expression in non-dividing cells. The outcome of gene therapy in LCA2 patients is frequently assessed using a multi-luminance mobility test.

Multi-luminance mobility test

In a multi-luminance mobility test, the patient is placed inside a room containing obstacles and arrows on the floor. The patient is asked to navigate different routes and avoid obstacles. Each route is navigated under a different light intensity. The accuracy (affected by hitting obstacles and deviating from the indicated path) and speed (related to the time needed to complete the test) of the patient are scored using an algorithm. The minimum light intensity correlated to a specific score is informative of the patient’s visual capacity.

Gene therapy potential of the eye

The eye has unique features that make it an ideal site for gene therapy interventions. It is easily accessible via injection or surgery. As retinal cells stop dividing about 12 months after birth, a single gene therapy intervention is, in principle, sufficient after this age. As the eye is a relatively small compartment, small treatment dosages are also, in principle, sufficient. Moreover, one eye can serve as a control of the other. The physical isolation of the eye from the rest of the body decreases the risk of affecting other parts of the body, minimizing side effects. The eye's specific immune status makes it less predisposed to immune reactions than most human organs. Its accessibility also facilitates the assessment of therapeutic outcomes by non-invasive medical procedures.

FDA approval

There is currently one gene therapy modality approved by the Food and Drug Administration (FDA) of the United States for the treatment of LCA2: voretigene neparvovec. It consists of a single subretinal injection of adeno-associated non-replicating viral particles containing a gene coding for RPE65. Gene therapies for other inherited retinal diseases, including retinitis pigmentosa, choroideremia, achromatopsia, and Leber’s hereditary optic neuropathy, are undergoing clinical trials.

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