The isolation of genes involved in inherited eye diseases, the elucidation of their function and the development of retinal gene transfer technologies have been successful areas of TIGEM research since its foundation in 1994. In addition several research tools, including animal models, systematic analysis of gene expression in the eye, technologies for visual function analysis as well as a large collection of patients, have been developed over the years and are available for the scientists working in this field.

The main focus of the IED programme is to evaluate the efficacy of gene transfer in animal models of inherited retinal diseases. Gene transfer represents a promising therapeutic strategy for these diseases, otherwise blinding or severely impairing visual function.
The eye is an ideal target for gene therapies since it is small and enclosed, thus requiring low doses of the therapeutic agent that can be precisely delivered through direct intraocular injections thus minimizing the risks of widespread diffusion. In addition the eye is immune-privileged and therefore relatively protected from immune responses towards the viral-derived therapeutic agents. Furthermore, well-characterized animal models of severe retinal dystrophies are available to test therapeutic strategies.

The vector system used by TIGEM researchers to transfer genes to the retina of animal models derives from the Adeno-Associated Virus (AAV). This system is ideal for retinal gene transfer as AAV-mediated expression in the retina of animal models, from mice to non-human primates, is robust and stable over time following a single intraocular administration.
TIGEM researchers have a long-standing experience in the design, production and delivery of AAV vectors to the adult and fetal retina of animal models. A set of tests including fundus photography, electroretinography, visual evoked potentials, behavioural assessment of visual acuity and state-of-the art histology have been set up over the last years at TIGEM for assessment of efficacy of gene transfer to the retina in small animals. Investigators at TIGEM have successfully exploited the ability of AAV vectors with heterologous surface proteins (capsids) to target different cell types in the adult and fetal retina of animal models, demonstrating the versatility of AAV as a tool to transfer genes to photoreceptors and retinal progenitors.

Small and large animal models of retinal diseases have been successfully treated with AAV and its use has been recently tested in humans. An Eye Working Group (EWG), composed of expert eye clinicians, has been established in collaboration with the Department of Ophthalmology of the Seconda Università degli studi di Napoli in order to aid TIGEM scientists in moving the therapeutic strategies from bench to bedside. The activity of the EWG will allow the identification of young patients with severe inherited retinal diseases who could profit from the potential treatment tested in animal models at TIGEM.

In collaboration with the University of Pennsylvania, the Children’s Hospital of Philadelphia and the Department of Ophthalmology of the Seconda Università degli studi di Napoli, TIGEM participated, with success, in its first gene therapy trial for Leber Congenital Amaurosis (LCA), a severe retinal degeneration. These results set the ground knowledge for the treatment of other retinal diseases and pave the way for TIGEM to participate in further gene therapy studies.