Retina Today - First Gene Therapy FDA-Approved for an Inherited Retinal Disease (April 2018)

摘要

The idea of gene therapy has been discussed in the medical literature since as early as the 1970s. In 1972, Friedman and Roblin proposed that it was theoretically possible to introduce “good” DNA to replace defective DNA.1 Over the years, a number of gene therapy clinical trials emerged in efforts to treat genetic diseases of inborn errors of metabolism, all with varying degrees of success. AT A GLANCE • The most common type of gene therapy is replacement gene therapy, in which a mutated gene that causes disease is replaced with a healthy copy of that gene. • RPE65 gene mutations account for up to 10% of autosomal recessive Leber congenital amaurosis and early-onset retinal dystrophy cases • The positive results of gene therapy clinical trials for RPE65-mediated retinal dystrophy led to the first US regulatory approval of a gene therapy in January 2018. The basic principle of gene therapy is to put corrective genetic material into cells to treat genetic disease. Several gene therapy approaches, including replacement gene therapy, optogenetics, addition of a growth factor, suppression gene therapy, and gene editing, have been proposed in attempts to treat various ophthalmologic conditions. Optogenetics focuses on creating artificial photoreceptors to restore photosensitivity. This is accomplished by gene delivery of light-activated optogenetic tools (channels or pumps) to surviving cells, such as ganglion cells, that remain intact in the retinal circuit in various diseases.2 It has been posited that genetically added growth factor proteins, such as adenovirus-expressed endostatin and angiostatin gene products, could have anti-VEGF properties.3 Short-interfering RNAs could be used for down-regulation of gene expression, resulting in functional inactivation of the targeted genes.4 Finally, technologies such as CRISPR (standing for clustered regularly interspaced short palindromic repeats) could allow editing of one or several sites within the mammalian genome.5 The most common type of gene therapy is replacement gene therapy, which involves replacing a mutated gene that causes disease with a healthy copy of that gene. It is first necessary to identify the causative mutated gene. This technology works best in autosomal recessive biallelic disease with loss-of-function mutations. A vector is then created to carry a wild-type copy of the gene into the cell of interest. The transfected gene is not incorporated into the host DNA but is expressed, resulting in production of a protein with normal function. Scientists and companies have spent decades perfecting the use of vectors for genetic material and identifying ways to deliver them to increase therapeutic efficacy and treatment duration. Early investigations used viruses that delivered genes to every cell in the body, which triggered a massive immune response that could lead to organ failure. More recently designed vectors deliver specific genes to specific cells. TARGET: IRDs With the eye’s unique immunologic privilege, inherited retinal diseases (IRDs) have become one of the leading targets in gene therapy research over the past 15 years. Successful treatment and restoration of vision in vivo was first achieved in canine models with RPE65-related retinal degeneration.6 The successful delivery of a wild-type RPE65 gene using a recombinant adeno-associated virus (AAV), with positive results, paved the way for human clinical trials. In healthy eyes, RPE65 is expressed in the retinal pigment epithelium (RPE) and encodes an RPE-specific 65 kD protein, all-trans retinyl ester isomerase, an enzyme crucial to the retinoid cycle. The enzyme plays an essential role in the visual cycle. RPE65 is responsible for the conversion of all-trans retinyl esters to 11-cis retinol during phototransduction. The 11-cis retinol is converted to 11-cis retinal and is used in visual pigment regeneration in photoreceptor cells.7 However, de