Base editing as a treatment for Hutchinson-Gilford progeria syndrome

The Hutchinson-Gilford Progeria Syndrome (progeria) is a very rare genetic disorder, which is almost exclusively (>95% of cases) caused by a specific mutation in the lamin A gene, LMNA c.1824C>T. This mutation leads to the expression of a defective lamin A protein in the cell called progerin. Children with progeria show symptoms of early ageing and die in adolescence due to cardiovascular disease. Progerin is also expressed in the tissues of people who do not have progeria and levels have been shown to increase with age. The underlying mechanisms of how progerin leads to the disease symptoms are still unclear. Despite this, more than a dozen different treatment strategies have been developed with several resulting in clinical trials in patients. However, the treatments have been disappointing with limited success in patients. Here we propose so-called adenine base editing as a possible therapeutic strategy for progeria. Base editing has the potential to correct hereditary diseases by eliminating the disease-causing mutation and the possibility of a permanent cure. The technology is based on a modification of the CRISPR/Cas9 system and enables direct transformation of a DNA base without the introduction of double-stranded DNA breaks with low non-specific editing. Our preliminary studies from treatment of cells from progeria patients and a tissue-specific mouse model have shown positive results. In the planned study, we hope to confirm and further substantiate these results.