Introduction: What is choroideremia?

Overview

Choroideremia (CHM) is a rare, hereditary disease that causes progressive and permanent loss of sight. The disease affects multiple layers of tissue at the very back of the eye, known as the retina. It causes slow disintegration of the light-sensitive cells,  known as photoreceptors; the structural layer beneath them,  known as the retinal pigment epithelium (RPE); and the vascular layer that provides nourishment to those layers, known as the choroid.¹ The disease manifests initially as a problem perceiving objects at night (nyctalopia) in childhood and subsequently causes loss of peripheral (sideways) vision, culminating in "tunnel vision" and, in a vast majority of cases, total blindness by middle age.²

Who is affected?

Choroideremia is an X-linked disease, meaning the faulty gene is found on the X chromosome, one of the two chromosomes that determine a person’s gender. In people assigned male at birth (people AMAB), due to there being an XY combination of chromosomes, a solo defective copy of the gene found in the individual's X chromosome is enough for people AMAB to be affected by the disease.  People assigned female at birth (people AFAB), who have two X chromosomes (XX), are typically carriers. They have a second, healthy copy of the gene on their other X chromosome, which can usually compensate for the faulty one.² For this reason, people with AFAB  carriers are often asymptomatic or experience only mild symptoms, such as some difficulty with night vision. However, they can sometimes show characteristic patchy changes in the back of their eye, which a doctor can see during an examination.

A flaw in the CHM gene's blueprint

The CHM gene: An instruction manual for a critical protein

In order to understand why choroideremia occurs, it is informative to visualise that our genes are a detailed guidebook for building and running our bodies. The guidebook for this disease lies in a gene known as the CHM gene, which lies on the X chromosome and contains the precise blueprint for building a critical protein that cells require for healthy functioning. ^1,3 The CHM gene's guidebook bears the title Rab Escort Protein 1, or REP1 for short. While problems in choroideremia occur in the eye, the REP1 protein is actually built in cells all over the body.

 The job of REP1: the cell’s essential "escort service‘’

The REP1 protein has a straightforward mission at hand: it acts like a much-needed "escort service" for the inner transport system of the cell. In every cell, there is a complex system that moves material from one place to another, a process given the technical name intracellular vesicular trafficking.^1,3,4 The system is controlled by a massive family of proteins that are called Rab proteins.

For a Rab protein to perform its task, it must be "activated" by a process, known as prenylation, through which a very small lipid (fatty) tail is attached to it. The tail acts like a key and helps the Rab protein adhere to the correct membrane and direct cellular traffic. This is where the escort service of REP1 is very important. REP1 recognises newly made Rab proteins, binds to them, and ushers them toward the enzyme that adds the lipid tail. Once the Rab gets "turned on", REP1 guides it to its correct destination inside the cell. Without a functional REP1 protein, this essential task doesn’t progress, leaving Rab proteins stranded and unable to carry out their duties.

How a faulty gene leads to vision loss: the pathogenesis

What is a gene mutation?

A gene mutation is like a permanent "typo" in the instruction manual that is the CHM gene. ^1,5 This error means the cell receives a faulty blueprint for building the REP1 protein. As a result, the cell either produces no protein at all or creates a shortened, misshapen version that is non-functional and quickly broken down. ³ In either case, the essential "escort service" that REP1 provides is lost, triggering a cascade of problems within the highly active cells of the retina.

How a lack of functional REP1 disrupts the retina

Without the REP1 protein, a chain reaction begins. Those Rab proteins tasked with managing the internal delivery system of cells cannot be initiated because there is no REP1 there to lead them through the prenylation process.^2,3 These inactive Rab proteins build up inside the cells and can no longer attach to the cell membrane to guide the movement of essential materials. As a result, this delivery system breaks down, preventing retinal cells from receiving the oxygen and nutrients they need to stay healthy and function properly.

You might wonder why a protein made throughout the body only causes problems in the eye. The reason is a backup protein called REP2. In most tissues, REP2 can compensate for the loss of REP1. However, this compensation is incomplete in the retina. Certain Rab proteins that are highly active in the photoreceptors and RPE, such as Rab27a, have a strong preference for REP1. Without REP1, these specific pathways fail, leading to the slow, progressive degeneration of the photoreceptors, RPE, and choroid that defines choroideremia.

Common types of CHM mutations

While the ultimate result is the same—a loss of function for REP1—the genetic "typos" that lead to choroideremia may be different. Over 500 distinct mutations of the CHM gene have been found. They come into one of the following categories in general:²

• Frameshift and Nonsense Mutations: They are the most common and account for approximately 51% and 34%, respectively. A frameshift mutation scrambles up the genetic code from that of the error onward, while a nonsense mutation creates a premature "STOP" signal. Both result in a shorter, non-functional protein
• Deletions: They are mutations that involve absent genetic information, from a few genetic "letters" through the entire CHM gene. In some cases, other neighbouring genes are also deleted, and this can lead to other medical issues 
• Splice-Site Mutations: These errors affect the way that the genetic instructions from the gene are spliced together, and they skip or misassemble pieces, providing a garbled message
• Missense Mutations: These are very rare in choroideremia and account for approximately 8%. They are like a single incorrect "word" in the instructions. The fact that they are so uncommon suggests that only a change in a highly critical part of the REP1 protein will cause the disease

Current and future therapeutic strategies

Gene replacement therapy

Gene replacement therapy is the current pre-eminent method of treatment for choroideremia, and it seeks to deliver a correct copy of the CHM gene into malfunctioning retinal cells.^1,2,4 This is done by way of a harmless, modified adeno-associated virus (AAV) delivery vehicle. Phase-one trials demonstrated that this approach was safe and held out much promise, and some patients enjoyed stable or even improved vision.

A subsequent large Phase III trial, unfortunately, did not meet its primary goal of delivering a significant improvement in visual acuity at one year.⁶ This was a lesson learned in hindsight: for a slow disease like this one, treatment should not attempt recovery of lost vision, but should rather focus on prevention of further loss. Later trials are accordingly aiming at more sensitive endpoints that may reflect a slowing of the disease.

Exploring other therapeutic avenues

Other approaches are also under active investigation. In cases of ~34% of patients carrying "nonsense" mutations that impose a premature "STOP" signal, nonsense suppressor therapy makes use of small-molecule drugs that coax cells' machinery into reading through the error. In cases of certain errors in splicing, AONs can correct the way that the genetic "instructions" are "written". Finally, the discovery that the disease has a system-wide effect has led the way for a variety of metabolic therapies that may control the disease's more general effect upon the body, such as oral antioxidants or some lipid-lowering medications, known as fibrates.

Summary

CHM is a rare hereditary disease caused by a mutation in the photoreceptors, RPE, and choroid of the eye, which develops into progressive blindness among male patients. The disease arises due to the occurrence of point or frameshift mutations in the CHM gene, which gives the template for an extremely important protein, REP1. REP1 plays a role of modulating the internal delivery system of a cell through promoting a process, which is referred to as prenylation of other crucial proteins. In case a mutation results in a non-functional REP1, the crucial transport system weakens and causes the slow death of cells in the retina. Gene replacement therapy is the prime treatment method that focuses on transplanting a correct copy of the CHM gene into the eye. Grasping all these mechanisms is necessary, and more research into some other methods of therapy offers hope for developing effective therapies for this disease.

FAQs

How is choroideremia different from retinitis pigmentosa (RP)? 

While both result in progressive loss of vision, doctors can normally distinguish between the two. In CHM, retinal capillaries are spared until late stages, and "bone spicule" pigment aggregations typical of RP are not observed. Diagnosis is definitive when genetic testing confirms a mutation in the CHM gene.

Are there any treatments to help with symptoms now? 

Symptoms can be managed, although no cure yet exists. Low-vision aids, for instance, magnifying glasses, can be employed for optimising preserved sight. Eye examination is also advocated at regular intervals for monitoring curable complications, such as cataracts or macular oedema (edema), at sometimes observed in cases of CHM. 

Can diet or lifestyle changes slow down vision loss?

There is no special diet demonstrated thus far that slows choroideremia. Investigations have noted increased systemic oxidative pressure in patients that would implicate antioxidants as useful adjuvants, yet this remains theoretical at this stage. Patients should always consult new supplements starting with their doctor and lead a healthy diet for general well-being.