A type of genome editing had been used in mice to treat the symptoms of progeria, a fatal premature ageing disease in children.
Progeria is caused by a single 'letter' change in the LMNA gene, from a C to a T. This causes the production of a toxic protein, progerin, which damages cells. There is currently no cure and patients usually die from cardiovascular failure around age 14-15. A new study offers the first potential disease-altering treatment to extend the lifespan of progeria patients.
'To our knowledge, this work resulted in the strongest rescue of the symptoms of progeria by multiple measures,' said co-corresponding author Professor David Liu from the Broad Institute and Harvard University, Massachusetts.
Professor Lui and his colleagues previously developed a genome-editing approach called 'base editing' which specialises in making single base-pair changes to DNA (see BioNews 848). They partnered with the US National Institutes of Health and Vanderbilt University Medical Centre, Tennessee, on a new approach to treat progeria.
The team used adenine base editors which can convert AT base pairs to GC base pairs at a precise location in the genome. These were packaged inside a viral vector to deliver them into cells.
In lab tests using cultured skin cells from children with progeria, the treatment resulted in correction of the mutation in 87-91 percent of cells.
The researchers then injected the viral-packaged base editors into mice with the progeria mutation. This resulted in sustained reduction of progerin levels, and improvement of cardiovascular tissue. Importantly, the lifespans of the mice dramatically increased, from 215 days to 510 days.
Whilst no off-target effects of the base editing were observed, a number of mice developed liver tumours. This is a known risk of adeno-associated viruses, which were used as the delivery system. Additional safety studies are underway to mitigate these risks.
Following these safety improvements, base editing could offer a possible treatment for progeria.
'This work also provides a blueprint for the potential treatment of other genetic diseases that can be addressed with base editing,' said Professor Liu.
The study was published in Nature.