Advances in gene therapies for Leber congenital amaurosis

Leber congenital amaurosis (LCA) is an early-onset inherited eye disease characterized by profound visual impairment. It represents the most common genetic cause of blindness in children, affecting 1 in 80,000 newborns. Vision loss in children with LCA occurs when the light-sensing photoreceptor cells (rods and cones) in the retina stop working properly. LCA is a monogenic disease (caused by a mutation in one gene) that is usually inherited as an autosomal recessive condition. At least 25 genes have been associated with LCA, which account for 80% of the disease cases, among them, 22 genes cause only recessive forms, two (IMPDH1 and OTX2) are responsible for autosomal dominant subtypes, and one (CRX) causes either recessive or dominant LCA, depending on the particular mutation. The most common forms of LCA are caused by mutations in the CEP290, GUCY2D, CRB1, RDH12 and RPE65 genes. Individuals with LCA usually present only ocular manifestations, while in some subtypes (those associated with mutations in IQCB1, IFT140 and CEP290) children may later develop problems in other organs, in particular the kidneys. Therefore, genetic diagnosis is important, among other things, to identify patients that may require other medical examinations in addition to ophthalmological tests.

Research conducted during the last two decades led last December to the approval by the U.S. Food and Drug Administration of Luxturna™ (voretigene neparvovec; Spark Therapeutics), the first gene therapy for patients with LCA caused by mutations in the RPE65 gene. The RPE65 protein is produced by the retinal pigment epithelium (RPE) cells at the back of the eye and is essential for normal vision because it participates in the visual cycle. Luxturna™ is a gene replacement therapy, which works by administering normal copies of the RPE65 gene to the cells of the RPE via subretinal injection. Participants in a Phase III clinical trial that enrolled people with LCA between 4 to 44 years-old reported functional vision improvements that have persisted for at least three years.

A different gene therapy (QR-110, developed by the Dutch biotech company ProQR) is being evaluated for the treatment of people with another form of LCA caused by a specific mutation in the CEP290 gene: p.Cys998X. This mutation, also known as c.2991+1655A>G, leads to aberrant splicing of the CEP290 messenger RNA (mRNA) and a non-functional CEP290 protein and is the most prevalent mutation responsible for LCA. QR-110 is an antisense oligonucleotide (AON) specifically designed to repair the effect of the c.2991+1655A>G mutation in the mRNA of CEP290 in order to obtain a correct mRNA and thus, a CEP290 protein with normal function. The ultimate goal is to repair the defect to halt the disease progression or reverse some of the more severe alterations. An international Phase I/II trial is being conducted to examine safety and efficacy of different doses of QR-110 administered by intravitreal injections in 10 participants. ProQR recently announced positive results from an interim analysis conducted at 3 months. Sixty percent of the participants showed improvements in vision, as measured by visual acuity and their ability to navigate a mobility course. Moreover, treatment with QR-110 was well tolerated with no serious adverse effects. ProQR is planning to start a Phase II/III clinical trial next year to gather more data on efficacy of this promising QR-110 treatment.

Currently there are clinical trials ongoing to evaluate safety and efficacy of gene therapies for other inherited ocular diseases, including choroideremia and Leber hereditary optic neuropathy.