Clinical research for gene editing technology will be aiming to start a Phase I/II interventional trial to treat Leber congenital amaurosis type 10 (LCA10). LCA10 is the most common form of a retinal degenerative monogenic disorder caused by mutations in a gene of the centrosomal protein (290kD). The clinical study plan aims to enrol between 10 and 20 adult and pediatric patients with LCA10 in an open label, dose-escalation study. The trial will evaluate both efficacy and safety, and will measure vision loss in the LCA10 patients.
LCA10 is the most common form of LCA in Europe and North America, arising from mutations in the CEP290 gene. While most CEP290 patients have profound vision loss, fundus examination and OCT analysis show a relatively well-preserved central macular anatomy well into the third decade of life. Despite such, LCA10 is one of the most severe forms of juvenile retinopathies and the most common mutation found in such LCA patients is the p.Cys998X error in CEP290, a nonsense mutation understood to account for up to 20% of all LCA patients in north western Europe. While there are no approved treatments yet available for the disease, several academic and commercial teams are actively engaged in a number of gene therapy related development programmes.
CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) has been a significant development within biotechnology in recent years. The gene editing technology derives from observations made in the repetitive sequences isolated from a number of prokaryotic and archaebacteria, first identified in 1987 by Yoshizumi Ishino and Atsuo Nakata, then at Japan’s Research Institute for Microbial Diseases, Osaka University. Following on from the original observations, three papers in 2005 reported that spacer sequences separating individual repetitive sequences appeared to have a phage (bacterial virus) associated origin. Coupled to this were separate observations that viruses were unable to infect cells that carried spacer sequences corresponding to their own genomes. In essence, the system as a whole appeared to represent an unexpected and sophisticated immune system for prokaryotes, essentially a new mechanism that provided an immune memory of previous phage infections, thereby facilitating rapid clearing of subsequent phage invasions that had previously infected the cell. By 2012 a paper published in Science by Jinek and colleagues at the University of California, Berkeley, in collaboration with the University of Vienna and Umeå University in Sweden, harnessed the technology into a system that is “efficient, versatile, and programmable”, with “considerable potential for gene-targeting and genome-editing applications.” Further iterations and development showed how relatively easy the CRISPR system could be used as an RNA-guided platform for specific control of gene expression. When compared to other editing tools, such as zinc finger proteins or TALENs, CRISPR has proved to be remarkably cheaper and less time consuming to work with.