Gene therapy for eye disease

1. UCL Institute of Ophthalmology Department of Genetics Gene therapy for eye disease • An experimental technique that uses the delivery of genetic material to treat or prevent disease by: • Delivering a working copy of a damaged gene that causes disease – gene supplementation therapy • Inactivating, or “knocking out,” a mutated gene that is functioning improperly – gene silencing • Introducing a new gene into the body to help fight a disease – neuroprotection or angiostatic therapy

2. What is gene therapy? • A carrier called a vector delivers the therapeutic gene to the patient's target cells – the most common vector is a virus that has been genetically altered to carry the therapeutic gene. • Which vector we choose to use depends on the cells we want to target and the size of the gene we wish to deliver to these cells. • The three types of virus usually used to study gene therapy in the eye are lentivirus (such as HIV), adenovirus and adeno-associated virus (AAV).

3. Adeno-associated virus (AAV) • AAV is the most commonly-used vector, as it is not harmful even in its "wild" form. • AAV efficiently delivers genes to light-sensitive photoreceptor cells and the underlying retinal pigment epithelium (RPE), making it an ideal gene therapy vector for inherited retinal disorders When injected under the retina, AAV efficiently delivers a reporter gene, encoding Green Fluorescent Protein, to photoreceptor and RPE cells

4. Direct injection of viral vectors into the eye. • For our gene therapy clinical trials, the surgical procedure involves injecting the virus under the retina, producing a temporary retinal detachment • Recovery time is usually rapid and it is often possible to go home the same day • Quality of sight is reduced temporarily until recovery is complete, which is usually expected to take a few weeks.

5. Targeting different cells in the eye • Ideally, the therapeutic gene should only be delivered to the cells that would naturally produce this protein • The vector may infect many cell types when it is injected, so by using a cell-specific promoter, we can restrict gene expression to certain cell types within a tissue: (a) photoreceptor cells and RPE; (b) RPE only, (c) cone photoreceptor cells only; (d), (e) corneal cells and (f) Muller cells in the inner retina