Genes and Gene Therapy in Inherited Retinal Disease

Abstract

LCA LCA describes a genotypically and pathophysiologically diverse group of early-onset IRDs which share common defining phenotypic features of: (1) severe early-onset vision loss, often by age 6 weeks, (2) poorly reactive pupils, (3) sensory nystagmus, and (4) undetectable or minimal ERG response. 51 LCA is widely regarded to be the most visually devastating IRD, as patients develop blindness or near-blindness in early infancy. LCA therefore represents a major cause of visual morbidity, accounting for around 10% to 20% of disabling and irreversible childhood blindness worldwide. [52][53][54] LCA is most commonly inherited in an autosomal recessive manner, though autosomal dominant inheritance has also been reported. 55 At least 20 distinct genes have been implicated in the disorder, 56 most commonly RPE65, CEP290, GUCY2D, and CRB1. Other relatively common genes that have been implicated in LCA include LRAT, MERTK, and TULP1. As these genes affect a variety of biomolecular functions, a number of pathophysiologic pathways can give rise to LCA, including defects in phototransduction (GUCY2D, AIPL1), the visual (retinoid) cycle (RPE65, LRAT, RDH12), photoreceptor development and structure (CRB1, CRX), cell transport in the connecting cilium (CEP290, TULP1, RPGRIP1, LCA5), and RPE phagocytosis (MERTK). 51 As a consequence of this underlying molecular diversity, LCA phenotypes can vary considerably 57 while sharing aspects of the 4 defining features above. At least 16 major genetic subtypes of LCA have been described. 58 Patients with LCA typically present due to wandering nystagmus noted by parents or primary care providers. Best-corrected visual acuity is usually significantly depressed, though certain genotypes (eg, RPE65, CRB1) may be associated with better visual prognosis than others (eg, GUCY2D, AIPL1). 59 As in the case of other blinding disorders of infancy and childhood, obsessive eye rubbing, known as the oculodigital sign, may also be observed and is thought to be caused by the child attempting to provoke entoptic visual sensation by mechanical stimulation of the retina. Enophthalmos and keratoconus may develop as complications of this habit. 51 As with most IRDs, LCA was traditionally considered incurable. In late 2017, the FDA approved voretigene neparvovec (LUXTURNA, Spark Therapeutics) for the treatment of RPE65-associated IRD, rendering it the first gene therapy approved for the treatment of an IRD. Voretigene neparvovec and other gene therapies for LCA are discussed below.Progressive Cone and Cone-Rod Dystrophies (COD/CORD) COD and CORD describe a phenotypic class of degenerative photoreceptor disorders characterized by primary progressive cone degeneration (COD), followed by later rod degeneration in the case of CORD. The Genes and Gene Therapy in IRD ' 7