Inherited retinal diseases meet their therapeutic match

(Image Credit: AdobeStock/Anastasiia)

Our understanding of genetics and hereditary disease dates to Hippocrates and Aristotle, whose ideas mirrored those of Darwin on pangenesis. A more modern view was proposed by the Augustinian friar Gregor Mendel in 1865, and less than 2 decades later, Walther Flemming, using dyes, discovered a thread-like structure in cells that he called chromatin (colorable material). We now know them as chromosomes.

In 1910, Thomas Hunt Morgan showed that our 2 sets of 20,000 genes reside on specific locations on those 2 sets of 23 (46 total) human chromosomes. Alfred Sturtevant constructed the first chromosomal map of a biological organism in 1911, and Frederick Griffith first demonstrated that bacteria are capable of transferring genetic information in 1928.

DNA sequencing came about in the 1960s; early attempts at DNA modification took place in 1980, by Martin Cline. Stem cell therapy using an adeno-associated virus (AAV)–enabled genetic modification was first established^1,2 by David Williams, MD, and David Nathan, MD, at Boston Children’s Hospital in the early 1980s. Altogether, this reflects a lasting human curiosity about the genome, the hereditary information that makes up the codes of our human cells. Though interest in genetics dates back centuries, our understanding of genetic editing spans only a few decades. In ophthalmology, inherited retinal disease (IRD) is the primary proving ground for genetic therapies.

IRDs: Fertile research territory

IRDs are present in 1 in 1400 individuals. Each IRD is caused by at least 1 gene that is not working as it should. More than 350 eye diseases are attributed to hereditary factors, including albinism, aniridia, color blindness, keratoconus, Leber congenital amaurosis (LCA), retinoblastoma, congenital stationary night blindness, and retinitis pigmentosa.

Today, patients with IRDs are fortunate because the eye is a particularly attractive target for gene therapy. Accessibility to gene therapies is of particular importance now, especially as the eye has an immune-privileged status.^3-5

There are limitations: Most vectors are based on modified viruses with a limited carrying capacity (5 kilobases). The cost of developing therapies may amount to hundreds of millions of dollars, and the cost of a single dose can be prohibitive for patients. In December 2017, the biotech company Spark Therapeutics obtained FDA approval for voretigene neparvovec-rzyl (Luxturna), the first ocular gene therapy that has improved vision in children and young adults with an IRD due to biallelic RPE65 mutations. A dose of voretigene neparvovec-rzyl can cost $425,000.

Leber congenital amaurosis: A focal point

LCA affects 1 in 50,000 infants and is responsible for 20% of legal blindness in children. It can be caused by mutations in one of more than 24 different genes.6RPE65, one of these genes, is involved in recycling vitamin A in the retinal pigment epithelial cells. The conversion of light into electrical signals that are transmitted to the brain in our retinal photoreceptor cells uses vitamin A, which subsequently needs recycling. When light hits photosensitive pigments in these cells of the retina, it changes a molecule called 11-cis retinal (an active form of vitamin A) into all-trans retinal (inactive).

LCA symptoms include nystagmus and heightened light sensitivity; babies’ eyes may also return an abnormal result in electroretinogram testing. Parents can watch for behaviors that seem aimed at stimulating the eye (some children will poke their eyes with their fingers); other, less-common symptoms include cataracts, keratoconus, photophobia, and nonocular symptoms including motor skill impairment, hearing impairment, and epilepsy.

LCA is progressive, resulting in severe vision loss and often causing blindness by 1 year of age, making it a focal point for pediatric gene therapies. Over time, the retina deteriorates, and pigmentary changes appear.

A new generation of gene therapies is poised to reshape the treatment of age-related macular degeneration (AMD). Currently, AMD can be treated with repetitive intravitreal injections, which may present a significant burden of care.^7-10 A gene therapy approach raises the potential that a single injection will protect patients with neovascular AMD for a lifetime.

More than 2 million people worldwide have genetically determined retinal diseases, and over 325 genes have been found to be responsible for these conditions. Gene therapy has tremendous potential for retinal conditions due to its ease of accessibility and immune-privileged status limiting systemic adverse effects of the drugs.¹¹ Advances in gene therapy in retinal conditions have increased significantly.

Gene therapies can be delivered to the retina by ocular or systemic routes, preferentially, via subretinal injections for outer retina cells and intravitreal injections for inner retina targets.

There is also potential for future applications of gene therapy in cancer treatment: These therapies could alter characteristics of cancer cells so that they become sensitive to radiotherapy or chemotherapy. Since the approval of voretigene neparvovec-rzyl in 2017, the FDA has approved 24 additional cell and gene therapies for other nonretinal diseases.

Presently, there are more than 40 active clinical trials or follow-ups for ocular diseases using AAV vectors alone.¹² In the United States, more than 1000 gene therapy studies are active for a wide range of diseases and conditions. This indicates there is hope for hundreds of millions of patients.

Frank Joseph Goes, MD

E: frank@goes.be

Goes is the founder of the Goes Eye Center in Antwerp, Belgium, and serves as a consultant to the center. He extends his thanks to Bart Leroy, MD, PhD, for reviewing this article. Relevant financial disclosures: none.

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