A collaboration between scientists at the Institute of Molecular and Clinical Ophthalmology Basel (IOB) and Beam Therapeutics has resulted in a new base editing therapy for Stargardt disease, the most common form of inherited macular degeneration. Details of their work and the efficacy of the therapy have been published in Nature Medicine in a new paper titled, “High-efficiency base editing in the retina in primates and human tissues.”
The new therapy features a highly optimized adenine base editor that is delivered by adeno-associated viral vectors to correct the most common mutation associated with Stargardt, which affects 1 in 6,500 individuals and is currently untreatable. The IOB research team was led by Bence György, MD, PhD, and Botond Roska, MD, PhD, while work on the Beam side was led by David Bryson, PhD, and Giuseppe Ciaramella, PhD.
According to the paper, the researchers designed a “dual adeno-associated viral vector encoding a split-intein adenine base editor.” The editor is designed to correct the most common loss-of-function mutation in the ABCA4 gene that is associated with Stargardt. This particular G-to-A mutation affects 15% of patients, and results in decreased transporter activity of ABCA4. They then tested the base editor in a series of models with good results in terms of gene correction. György, who heads the ophthalmic translational research group at IOB, said that the team “observed average editing rates of 75% in cone cells and 87% in retinal pigment epithelial cells. These results far exceed what we believe is necessary to provide clinical benefit to patients.”
Importantly, the team demonstrated the effectiveness of their technique in multiple models, including mice, female non-human primates, human retinal organoids, stem cell-derived retinal pigment epithelial cells, human retinas, and human retinal pigment epithelial cells. This comprehensive approach provides very strong evidence for the potential translatability of the treatment to human patients. They also explored the potential for off-target effects and found no evidence of unintended editing in the human models, which bodes well for the potential safety of this type of treatment in humans.
One limitation of the study that the researchers noted in the paper is that the mouse and human models with the mutation did not display the disease phenotype and as such they were “unable to assess whether the observed base-editing efficiency would translate to functional improvements.”
Still, the results are promising. And while this study focused on Stargardt disease, the base editing approach could potentially be adapted to treat other inherited retinal diseases caused by similar types of mutations, according to the team.
