Gene Therapy
Gene therapy has been investigated as a potential treatment for inherited diseases, including those affecting vision
What is a gene?
A gene is a region of DNA that contains all the instructions needed to make a particular protein. Proteins are complex molecules that do the work in cells, playing a role in almost every biological process. Proteins are required for cell structure and function, and help regulate processes in our tissues and organs. Mutations in genes can change the instructions for making a protein, causing it not to work properly or be completely absent.
What does gene therapy do?
Gene therapy supplies healthy (non-mutated) copies of the gene into a cell. The cell can then use these new genetic instructions to make healthy copies of the protein affected in patients.
How do we get new copies of the gene into cells?
New healthy copies of affected genes can be delivered to cells using viruses. Naturally occurring viruses, like the common cold virus, can infect cells and deliver copies of their own genes. Scientists have modified viruses so that we can deliver copies of human genes into cells. To do this, the disease-causing viral genes have been removed from the virus and replaced with the instructions to make human proteins. Viruses can be modified to produce healthy copies of genes affected by disease, including those affected by genetic mutations.
Small harmless viruses, known as adeno-associated viruses (AAV) are commonly used to deliver genes for gene therapy. Most people carry AAVs, they can naturally infect cells, but don’t cause disease and require the help of other viruses to replicate. AAVs are ideal for delivering healthy copies of genes to the eye because they can infect cells that don’t normally divide, like the retinal pigment epithelium and retinal cells. AAVs have been engineered to cross the cell membrane and transport their gene cargo to the nucleus of the cell, where the genetic material can be used to make new human proteins.
How are AAVs delivered to the eye?
The eye is an ideal organ for gene therapy as it is easily accessible. The eye is a small isolated organ with immune privilege, so only small amounts of drugs are required, and these treatments will not spread to the rest of the body. The effects of gene therapy can be easily assessed by ophthalmologists, using non-invasive tests that can assess vision function and perception, or by recording the electrical signal produced by the RPE or retina.
AAVs can be delivered to the eye by injection. For diseases that affect the RPE or retina, the AAV can be injected in the space between these two tissues. This ensures that the virus is delivered as close to the target cells as possible.
What eye diseases have been treated using AAV gene therapy?
Gene therapy for eye diseases is now available in the clinic. Luxturna, an AAV gene therapy product, has now been approved to treat patients with Leber’s Congenital Amaurosis (LCA). LCA is a rare disease caused by mutations in several genes. Mutations in the RPE65 gene trigger an early onset disease, resulting in severe visual impairment that can ultimately lead to complete vision loss. The Luxturna product delivers healthy copies of RPE65 into RPE cells. The new copies of RPE65 do not replace the mutated gene, instead they provide a new functional copy that can increase the RPE65 protein product in the cell, helping to maintain vision.
Is gene therapy available for patients with Bestrophinopathies?
Currently gene therapy is not available for Bestrophinopathies however, several research groups have been working to develop AAV-based therapies for these diseases.
These studies provide proof of principle for a gene therapy approach to treat Bestrophinopathies, but further work to optimise treatment in patients is required.
1) Gustavo D. Aguirre, from the University of Pennsylvania
https://www.pnas.org/content/115/12/E2839.long
Testing AAV gene therapy in dogs with recessive bestrophinopathy. This approach has shown that delivery of AAV-BEST1 can reverse some of the features of disease, including small detachments between the RPE and retina and subretinal lesions.
2) Tininting Yang and Stephen Tsang, from Columbia University, New York
https://www.nature.com/articles/s41598-019-54892-7
Using patient derived induced pluripotent stem cells to understand the role of Bestrophin1 and develop AAV- based therapies for treatment of Best disease. Delivery of AAV-BEST1 into iPSC-RPE created from patients with recessive and dominant bestrophinopathies restored chloride channel activity in cells.