Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Observational
Official Title: Natural History Study of Patients With Leber Congenital Amaurosis Associated With Mutations in RPE65
Brief Summary:
The inherited retinal dystrophies are a clinically and genetically heterogeneous group of conditions, which often present in childhood. These disorders can be usefully divided according to whether they (i) are stationary or progressive; and (ii) exhibit predominantly rod or cone involvement, or central receptor disease. The underlying molecular genetic basis of the majority of monogenic inherited retinal disease has now been characterised.
Leber Congenital Amaurosis (LCA) is a diagnosis for a group of severe, autosomal recessively inherited rod - cone dystrophies that typically result in complete visual loss in the third or fourth decade of life. One form, LCA2, is caused by a mutation in the gene encoding RPE56, an RPE-specific 65-kDa isomerase. Non-functional RPE65 results in photoreceptor cells that are unable to respond to light resulting in these patients being visually impaired.
Proof of principle studies for RPE65 gene replacement therapy has been demonstrated with the use of recombinant adeno-associated virus serotype 2 (rAAV2/2) vectors in animal models. Furthermore clinical trials of gene replacement therapy in RPE65 associated LCA (RPE65-LCA) have shown significant promise. All three clinical trials showed improvement in visual function over the first year, however longer term follow up demonstrated progressive visual loss and that initial improvements were not maintained.
Greater efficacy was noted in animal models and we feel the relatively lower efficacy of treatment in participants was most likely due to insufficient production of RPE65 protein from AAV2/2 hRPE65 in the human eye. As the maximal tolerated vector dose had been reached for AAV2/2 hRPE65, an optimised therapeutic vector (AAV2/5-OPTIRPE65) has been developed to drive higher transgene expression l