AAVEYE

GENE THERAPY FOR INHERITED SEVERE PHOTORECEPTOR DISEASES

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 Obiettivo del progetto (Objective)

'The retina represents the visual sensory receptor of the nervous system (CNS). Inherited diseases like Retintitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA), for which no therapies are available, are due to mutations in genes preferentially expressed in the photoreceptor cells of the retina. Vectors derived from the adeno-associated virus (AAV) efficiently transduce the retina of animal models. AAV-mediated gene transfer reverts retinal pigment epithelium (RPE) defects and the safety of this strategy is being tested for the first time in humans by an AAVEYE partner. However, approaches to correct photoreceptor-specific diseases are inefficient. The objective of the AAVEYE consortium is to develop state-of-the art gene transfer to photoreceptors in the retina, and to provide pre-clinical proof-of-concept of gene therapy for severe blinding retinal photoreceptor diseases to be transferred from bench to bedside. AAVEYE, which uniquely combines leading European scientists in the fields of: AAV-mediated gene transfer to the retina, elucidation of the pathogenesis of photoreceptor degeneration and design of molecular diagnostics for inherited retinal diseases, will accomplish this through: 1) development of AAV-based long-term and safe gene transfer to photoreceptors through combinations of endogenous promoters and AAV serotypes. 2) assessment of the impact of AAV-mediated photoreceptor transduction on rescue of visual function in animal models of severe RP and LCA. 3) evaluation of the efficacy of combination of gene replacement with adjuvant molecules on photoreceptor survival. 4) characterization of patients with severe inherited photoreceptor diseases to move from bench to bedside the gene therapies strategies tested. The results of this proposal will provide the knowledge and validation to further develop novel AAV-mediated therapeutic approaches with a broad potential application in the retina and central nervous system.'

Introduzione (Teaser)

The retina represents the visual sensory receptor of the central nervous system. Novel treatment approaches for retinal degeneration disorders based on the transfer of the functional gene could benefit millions of sufferers worldwide.

Descrizione progetto (Article)

Inherited diseases of the retina, like retinitis pigmentosa (RP) and Leber Congenital Amaurosis (LCA), are due to mutations in genes preferentially expressed in the photoreceptor cells. Currently, there are no available therapies for these disorders. Gene therapy constitutes a promising alternative for therapy in the eye mainly because it is an immune-privileged site.

The EU-funded 'Gene therapy for inherited severe photoreceptor diseases' (Aaveye) project proposed a gene therapy approach as an alternative treatment for these disorders. By using vectors derived from the adeno-associated virus (AAV) that are known to efficiently transfer genes into the retina of animal models, researchers aimed to try this approach in the photoreceptor neurons of the retina.

Vector development consisted of the construction of safe AAV vectors that demonstrated efficient gene transfer and regulated gene expression in photoreceptor cells through the use of microRNAs. Experiments in large animals safeguarded against the spread of these vectors to the brain.

Introduction of the normal gene in the photoreceptors of animals carrying the mutations associated with RP and LCA resulted in significant inhibition of retinal degeneration. These results prompted Aaveye partners to plan a clinical trial to test the efficacy and safety of AAV-mediated gene therapy for LCA.

The experimental work also led to the identification of mechanisms leading to photoreceptor death and to the discovery that inhibition of certain cell cycle proteins could rescue cell death.

A cohort of RP and LCA patients were also genetically analysed for mutations in the respective PDE6B and AIPL1 genes, and clinically characterised with respect to disease phenotype. This information will form the basis for future clinical trials of photoreceptor gene transfer in humans.

Implementation of the scientific discoveries from this work in the clinic could have an immediate impact on patients' health. Most importantly, the Aaveye study set the ground for gene therapy as a potent alternative treatment for retinal degenerative disorders.