Genomics: Insight

What is neurotrophic keratitis?

Neurotrophic keratitis is a rare ocular disease that leads to the damaging of corneal nerves. The cornea is like a regenerative shield for the eye, providing it with protection from foreign particles. Because the cornea focuses light that enters the eye, it lacks blood vessels, which would cloud an individual’s vision, and instead has nerves running through the cornea. These nerves become damaged in an individual with neurotrophic keratitis, which may lead to corneal ulcers and blindness.

Neurotrophic keratitis is a rare ocular disease that leads to the damaging of corneal nerves.

Recombinant Human Nerve Growth Factors to Treat Disease

In the past two years, scientists produced recombinant human nerve growth factors in the lab through the use of the bacteria, E. coli, in order to treat neurotrophic keratitis. Neurotrophic keratitis did not have an FDA-approved drug treatment until the Italian pharmaceutical company, Dompe, patented Oxervate, a drug that makes use of recombinant human nerve growth factors.

What are nerve growth factors?

Nerve growth factors (NGF) are proteins that are part of a family of growth factors called neutrophins. These growth factors are responsible for the growth and development of nerve cells. Nerve growth factors trigger events that promote cell growth when they bind to receptors called tyrosine kinases.

How is neurotrophic keratitis treated?

In the past, neurotrophic keratitis was controlled through the use of preservative-free artificial tears to prevent degradation of the cornea. Tear production, which is reduced by neurotrophic keratitis, is an integral part of maintaining the cornea’s integrity. In addition to artificial tears, physicians have administered antibiotic eye drops to prevent infection of the eye at later stages of the disease. The purpose of these two methods was to minimize the damage of neurotrophic keratitis given that there was no drug treatment available. In 2018, however, Dompe introduced Oxervate, the first drug treatment for neurotrophic keratitis, which takes advantage of gene cloning technology to mass produce human nerve growth factors using bacteria. These human nerve growth factors are present in the Oxervate eye drop solution as the molecule, cenegermin-bkbj. When placed on a damaged cornea, Oxervate eye drops can induce nerve growth and healing, which the previous artificial tears and antibiotic eye drops were unable to accomplish. The artificial tears and antibiotic eye drops were mainly used to prevent further damage to the cornea, but the Oxervate eye drops are used to heal the damage done by neurotrophic keratitis.

When placed on a damaged cornea, Oxervate eye drops can induce nerve growth and healing, which the previous artificial tears and antibiotic eye drops were unable to accomplish.

How is Oxervate made?

The fact that all genetic code is composed of either DNA or RNA allows gene splicing technology between different organisms. Scientists have used the power of recombinant DNA  to replicate the DNA sequence of the human NGF in the bacteria E. coli. Gene splicing can be compared to an elementary school cut and paste project. First, scientists  identify the gene that expresses cenegermin-bkbj and cut around it. When splicing the gene from the human genome, the scientists must leave single-stranded “sticky ends” on either side of the gene to allow for complementary base pairing to occur between the human gene and the bacterial genome. Like an arts and crafts project, these sticky ends allow the gene that has been cut to fit into a new

place. Then, the E. coli genome is cut too, and the sticky ends of both pieces can be pasted, or ligated, together. After cutting and pasting the targeted gene into the E. coli genome, scientists can grow the E. coli to exponentially. As the E. coli replicate, they express genes including the human nerve growth factor gene. Using its own DNA replication system, the bacteria synthesize the cenegermin-bkbj in large amounts, allowing pharmaceutical companies to extract these proteins for clinical use.

What are the implications?

Although recombinant DNA is not brand-new technology, Oxervate is a perfect example of how this technology is still viable today. In the future, cures for more diseases can potentially be manufactured if scientists link specific genes with proteins that participate in pathways relating to that disease.