Choroideremia (CHM) impairs the vision of about 1 in 50,000 males who begin to experience difficulty seeing at night during their teens. As this is a progressive condition, peripheral vision loss becomes prominent and often leads to legal blindness by the age of 40. At this time, there is no cure for this condition.
Choroideremia is caused by a change in the REP1 gene found on the X chromosome. This change prevents the gene from functioning properly. This gene encodes the Rab escort protein 1. Since men have an X and a Y chromosome whereas women have two X chromosomes, men with a faulty REP1 gene are affected but it is rare for female carriers to be severely affected. This is because the copy of the REP1 gene found on the second X chromosome in women is typically able to compensate for the faulty gene.
X-linked inheritance with a carrier mother.
This genetic eye condition has an X-linked inheritance pattern. Female carriers have a 50/50 chance of having an affected son or a carrier daughter and a 50/50 chance of having an unaffected son or a non-carrier daughter. Affected men will not have affected sons but all of their daughters will be carriers.
X-linked inheritance with an affected father.
Stem cell therapy is the use of stem cells to treat or prevent a disease or condition. This is NOT the approach our team at the University of Alberta is taking to study the potential treatment of choroideremia.
The study of retinal stem cells holds great promise for the treatment of diseases of the eye. The two most prominent areas of this research involve:
1) Understanding how to change retinal stem cells isolated from the eye into the various different cell types it contains. It is thought that one day we may be able to expand retinal stem cells in the lab and produce sufficient quantities of mature retinal cells (e.g. rods and cones) for transplantation after injury.
2) Using retinal stem cells as a model to identify novel pharmaceutical compounds that enhance their ability to divide and differentiate into mature cells. Such compounds could be used to enhance the limited regenerative capacity of the eye, and treat ocular disease without the use of cell transplantation.
For more information about stem cell therapy research, click here.
Gene therapy is an experimental technique that introduces genes into cells in the body to treat or prevent diseases. Many refer to human gene therapy as human gene transfer. Gene therapy is not a drug.
Although gene therapy is promising for a variety of conditions, the technique is experimental and remains risky. Research about gene therapy focuses on inherited disorders, some types of cancer, and certain viral infections. Currently, gene therapy is only being tested for diseases that have no curative treatment options such as choroideremia. Gene therapy still needs to be proven to be safe and then effective in clinical trials before it can become a part of standard clinical care.
In the future, gene therapy may allow doctors to treat a disorder by inserting a working copy of the gene into the cells of a patient instead of using drugs or surgery. Researchers are testing several approaches to gene therapy, including:
- Inserting a healthy copy of a gene into specific cells to replace the function of a mutated gene. The choroideremia gene therapy clinical trial takes this approach.
- Inactivating, or “knocking out,” a mutated gene that causes the disease in the body.
- Inserting a new gene to help fight a disease in the body.
Adapted from Genetics Home Reference, accessed November 12, 2014.
Genes produce proteins that are necessary for cells to grow and function properly. Choroideremia is caused by a mutated gene that makes a faulty protein in specific eye cells in the retina. Gene therapy is designed to introduce a healthy copy of the gene into these cells to test whether the normal function of the protein can be restored. It can only work in living cells. This technique cannot revive dead cells and then improve cellular function.
A carrier called a vector is required to introduce the healthy copy of the gene into the cells. Certain viruses are often used as vectors because they have natural infective properties as well as other beneficial characteristics. The viruses are modified so they can no longer cause disease when used in people. The healthy copy of the gene is then attached to the virus through genetic engineering. Some types of virus, such as retroviruses, integrate their genetic material (including the new gene) into a chromosome in the human cell. Other viruses, such as adenoviruses, introduce their DNA into the nucleus of the cell, but the DNA is not integrated into a chromosome. The choroideremia gene therapy trial will use a version of an adenovirus. There are also other types of vectors that are not viruses, which are being tested for gene therapy.
The vector can be injected or given intravenously (by IV) directly into a specific tissue in the body (in vivo), where it is taken up by individual cells. The gene therapy in the choroideremia gene therapy trial will be given by injection underneath the retina. If the gene therapy is successful, the new gene delivered by the vector will make a functioning protein.
Researchers must overcome many technical challenges before gene therapy will be a practical approach to treating disease. For example, scientists must find better ways to deliver genes and target them to particular cells. They must also ensure that new genes are precisely controlled by the body (adapted from Genetic Home Reference, accessed November 12, 2014).
We do not expect gene therapy to reverse the effects of choroideremia and restore vision. If this type of intervention is successful, we hope that it will stop further progression of vision loss.
A clinical trial is a research study that investigates the use of an experimental health-related intervention in consenting humans. Interventions include but are not restricted to drugs, cells and other biological products, surgical procedures, radiologic procedures, devices, behavioural treatments and preventative care. There are four phases of clinical trials. The choroideremia gene therapy clinical trial is a Phase 1 clinical trial. The main goal of a Phase 1 trial is to determine how safe the intervention is in humans. Phase 1 trials are based on experimental data from cells and animals studied in the laboratory. Safety data from clinical trials for similar, but not identical conditions are also considered by agencies that regulate clinical trials. In Canada, Health Canada regulates clinical trials.
As research passes through the different phases, more and more participants are recruited. The focus of Phase 2 trials is on both safety and effectiveness. This continues for Phase 3 trials, where the number of participants is even larger. All serious reactions to the experimental intervention are documented and reviewed. Phase 4 trials are conducted after the intervention has been marketed. These trials are designed to monitor the effectiveness in the general population and continue to collect data on any adverse effects of the intervention (adapted from the WHO website, accessed November 9, 2012).
For more information about clinical trials, visit www.clinicaltrials.org. This is a National Institutes of Health website that allows you to search for approved trials that are recruiting or will be recruiting.
To begin, researchers must receive approval from Health Canada. Health Canada is the Canadian regulatory body that ensures that clinical trials are conducted according to the high standards of the Good Clinical Practice guidelines. Approval for gene therapy clinical trials is only considered if the following criteria are met:
- The faulty gene must be identified and some information about how it causes the condition or disorder must be known. With this information, the vector can be genetically altered for use, and the appropriate cell or tissue can be targeted.
- Once the gene is transferred into the new cell, its expression (whether and when it is turned on or off) needs to be controlled.
- There must be sufficient value in treating the condition or disorder with gene therapy. That is, no simpler way to treat the condition or disorder exists.
- The balance of the risks and benefits of gene therapy for the condition or disorder must compare favourably to other available therapies.
- Sufficient data from cell and animal experiments are needed to show that the procedure itself works and is safe.
Clinical trials are closely monitored on a continuous basis by ethics boards and government agencies for the safety of the participants (adapted from Health Canada, accessed October 31, 2012).
It is important to note that gene therapies are not considered drugs. The field of gene therapy is new and therefore is less certain and riskier than drug therapy.
- Pre-clinical phase: Cell and animal studies are performed in the lab to prove a concept. This takes between 2 to 10 years.
- Phase 1: Studies in human subjects are performed to demonstrate the safety of the drug. This can take about 2 years.
- Phase 2: Studies in human subjects are performed to demonstrate the effectiveness of the drug. This can take about 3 years.
- Phase 3: Studies in many more human subjects are performed to demonstrate the effectiveness of the drug on a larger scale. This can take about 4 years. After completion of phase 3 trials, a drug can be authorized for regular medical use by Health Canada.
- Phase 4: Additional studies in human subjects are performed during post-marketing testing often to optimize the use of a drug. This can take another 2 years.
Because experimental gene therapy is new, many additional steps are built into the regulation of gene therapy clinical trials. This was done intentionally to monitor and reduce the risks as much as possible.
Therefore, experimental gene therapy will likely take longer than experimental drugs to be widely available to patients.