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  • Writer's pictureEmily Poulin

Eyes on Gene Therapy: How Mutations Cause Disease and How Gene Therapy is Making a Comeback

Updated: Jul 25, 2019

Chances are if you’re reading this you have relatively perfect vision, maybe with the help of glasses or contacts.

But now imagine that this is not the case. That even with the help of glasses or contacts, you are slowly losing the ability to see. Maybe it starts with the loss of peripheral vision, or trouble seeing at night. Then it gets so bad you have to give up driving. This may mean you become dependent on your family and friends to get you to your job. That is if you are able to continue at that job.

About 1 in 4000 people have a condition called retinitis pigmentosa (RP), a hereditary blindness disorder that is caused by inherited genetic mutations. RP is part of a larger family of inherited blindness disorders (also called inherited retinal dystrophies) in which slow degeneration of cells in the eye results in blindness.

Inherited retinal dystrophies are associated with mutations in more than 200 genes. These affected genes are critical for the normal structure and operation of the retina and the cells in the retina that sense light, permitting you to see. Without these cells, light is not processed and the brain does not form an image. Individuals with inherited retinal dystrophies eventually become blind due to the loss of function and degeneration of these light-sensing retinal cells, called photoreceptors.

On December 19, 2017, the FDA approved a gene therapy developed by Spark Therapeutics called Luxturna. Luxturna was approved as a treatment for individuals with retinal dystrophy driven by mutations in the RPE65 gene. This news is a big deal for many reasons.

There are few treatment options for individuals with hereditary blindness who have to cope with the slow loss of vision and the associated complications. Most treatments have focused on damage control: protecting the photoreceptors that are still alive. But since the inherited defect is the cause of photoreceptor sickness and death, a better therapy would be to fix the defect, an option that has been impossible.

Until now.

To understand more about what gene therapy is and how it works, we have to take a couple steps back. Every one of the 37.2 trillion cells in our bodies starts out with the same copy of DNA, or genetic blueprint for building each of us lovely unique individuals.

However, DNA is not one long uninterrupted sentence, but is more like a book. For example, if the genetic book is equal to one cell’s DNA, each chapter would be a chromosome, structures into which DNA is organized. Within each book chapter are sentences, or genes. Finally, each sentence of a chapter is composed of letters, and the case of DNA, these components are also letters, or base pairs, of which there are only four.

That’s right, the entire blueprint to generate a human is made up of combinations of only four letters. Simplicity at its finest.

So how do we get such complexity if every cell has the same code? Why aren’t we just a collection of the same cell types?

To answer this we have to get back to genes. Every gene has the ability to be switched on or off and not every gene is turned on in every cell or organ in our body. While many genes are turned on everywhere, your eye, for example, needs eye-specific genes to be turned on and say, heart-specific genes to be turned off.

At a basic level, each gene is the code for what is known as a protein. Proteins are what physically operate a cell. These molecules each perform a specific duty, and therefore, their ability to function properly is critical for normal cellular operations.

Now picture this: a spelling mistake occurs in the DNA letters that make up a gene sentence. This is called a mutation.

Mutations result in the words of the gene sentence changing so that they no longer make sense. When a nonsensical gene sentence is translated, it codes for a mutated protein. If that mutation affects how that particular protein functions, it can lead to diseases like cancer, or in this case, blindness.

There are different ways in which mutations can occur. For example, UV radiation can cause DNA mutations in skin cells, which can lead to skin cancer. These types of mutations are randomly acquired throughout life, and do not occur in every cell in the body.

Today though, our focus is on inherited mutations, which are passed down from our parents. Our DNA is built from a random combination of our parents’ DNA. If by chance you receive parental DNA that contains a mutation, every cell in your body will contain that mutation.

So how can a single spelling mistake cause disease?

Let’s go back to inherited retinal dystrophy and take one gene as an example.

Multiple inherited retinal dystrophies are caused by mutations in a gene called RPE65, including RP and Leber’s congenital amaurosis. RPE65 is turned on in a group of retinal cells called the retinal pigment epithelium, or RPE. These cells communicate with the light-sensing photoreceptors and the function of both the RPE and photoreceptors is critical for the processing of light into a visual image.

Within the RPE, RPE65 is responsible for performing a chemical reaction that generates a molecule (11-cis-retinol) that is required by photoreceptors to process light into an image. RPE65 mutations are thought to negatively affect the function of the RPE65 protein or its proper production. In the absence of a functional RPE65 protein or in its absence altogether, 11-cis-retinol is not efficiently produced and photoreceptor cells are unable to function normally. This leads to an inability to process light and eventual onset of blindness.

So where does gene therapy come in?

The concept behind gene therapy is actually quite simple. Gene therapy seeks to replace a mutated gene with the normal version. This replacement in theory should result in the production of the non-mutated protein, which should in turn reduce the toxic effects of the mutated version.

Almost like white-out for the DNA spelling mistake.

Although the theory is simple, the application of gene therapy has been difficult to safely implement and is haunted by the death of Jesse Gelsinger in 1999.

Gene therapy faces major challenges, including efficient delivery of the normal gene and the ability of that gene to produce the normal form of the protein.

Gene therapy delivery has largely been achieved using viruses as carriers. Viruses cannot reproduce on their own, but require our cells as hosts to do so. When harmful viruses infect a cell, they transfer their genetic material, which codes for proteins to make more viruses. These harmful viruses take over our cells and turn them into virus factories, perpetuating production of that virus.

Now picture this. The viral DNA that codes for harmful viral parts is deleted and replaced by the normal form of a gene that causes a disease.

For Luxturna, Spark Therapeutics made a non-pathogenic virus carrying the normal non-mutated form of RPE65. This RPE65-carrying virus was injected into the back of the eye, in an area called the subretinal space. This proximity allows the virus to infect the RPE and start using the cellular machinery to make normal RPE65.

The next step is where Luxturna did what has never been done before.

The best we can do is to deliver a gene therapy as close as possible to the cells that need it. Whether the cells accept the virus, make the new protein, and whether the new protein actually heals the damaged cells and improves sight was all unknown before now.

And this is why Luxturna is such a big deal.

This is the first FDA-approved gene therapy that targets a direct disease-causing gene and results in symptom and disease improvement. Not only that, but this advancement also serves as a proof-of-principle and may be a model by which some of the other 200+ genes that cause blindness could be targeted.

In 1999, Jesse Gelsinger died because of an immune reaction to the delivery vehicle carrying his gene therapy, not because of the gene itself. Almost 20 years later, technology and a lot of research have improved the entire procedure and made it safe.

Now, we can look to the future of gene therapy and see its potential with hope.


Do you know anyone affected by an inherited disease? If so, we can cover the research here at Out of the Ivory Tower. Let me know in the comments or by email how I can help demystify the science that affects your life!

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