Base editing in Hutchinson-Gilford progeria syndrome
Hutchinson-Gilford Progeria Syndrome (HGPS, progeria) is a rare genetic disorder, and almost exclusively (>95% of the cases) caused by a de novo point mutation in the lamin A gene, LMNA c.1824C>T, leading to mis-splicing and production of a truncated lamin A protein, named progerin. Children show several symptoms of accelerated aging and die in their teens due to accelerated atherosclerosis and cardiovascular disease. The underlying patho-mechanisms remain unclear and clinical trials have shown only limited success. Here we propose adenine base editing as a possible therapeutic strategy for HGPS. Base editing has the potential to correct inherited diseases by eliminating the disease-causing mutations, offering the possibility of a permanent cure. This novel genome editing technology is based on a modification of the CRISPR/Cas9 system and enables direct conversion of one DNA base without the introduction of double-stranded break formation and low unspecific gene editing. Here we together with our collaborators are developing and testing, both in vitro and in vivo, in HGPS models the potential for base editing in HGPS. Our preliminary results are promising with only low unspecific editing, and no detectable side-effects from the virus. With this very novel approach we can target the disease on a genetic level before complex downstream mechanisms are taking place and aim for a highly precise and efficient gene editing approach with clinical applications. |