A team led by Dr Kiran Musunuru from the University of Pennsylvania and Dr William Peranteau of the Children's Hospital of Philadelphia, successfully employed base editing to change specific sections of DNA according to a paper published last week in Nature Medicine.
'We are excited about the potential of this approach to treat genetic diseases of the liver and other organs for which few therapeutic options exist.' Said Dr Peranteau.
The team cured several mice of hereditary tyrosinemia type one (HT1), a serious disease caused by a mutation in the Fah gene, where a build-up of metabolic products causes severe damage to the liver.
Rather than target the Fah gene directly, the approach disabled an enzyme-coding gene called Hpd, thereby preventing toxic metabolite accumulation. However, Dr Musunuru commented that the same approach used in this study to 'disrupt a mutation's effects' could in the future be used to 'directly correct the mutation'.
To ensure the changes were made in the right tissues, the base editing reagents were delivered into a fetal vein which connects to the liver. 'We wanted to make sure we got the genome editor into the liver rather than everywhere else' said Dr Musunuru.
The treated mice were born healthy and maintained their health until the end of the study, outliving the mice in the group treated with the nitisinone, the current standard of care for HT1.
Base editing uses a modified form of CRISPR Cas to alter single DNA base pairs. enabling exceedingly precise targeting of specific sections of mutated DNA whilst minimising off-target effects. 'We think this represents a safer and more precise way to make changes in the genome,' said Dr Musunuru. 'It's is the better way forward if you want to take CRISPR into the clinic.
While HT1 is quite rare, and most sufferers are treated successfully with nitisinone, the study acts as a proof-of-concept for the use of CRISPR to treat many congenital diseases before birth. However, using this approach in humans is still a way off. 'A significant amount of work needs to be done before prenatal gene editing can be translated to the clinic' Dr Peranteau cautions.