Gene therapy in utero could cure rare brain disease Angelman syndrome

A new gene therapy is being developed to treat the rare genetic condition Angelman syndrome, while the fetus is still in the womb. 

The treatment would deliver the gene therapy via a harmless virus injected directly into the fetal brain. 

It would be a 'one-time treatment for a lifetime effect', Professor Mark Zylka from the University of North Carolina, the neurobiologist who led the work, told the annual conference of the American Association for the Advancement of Science in Washington, DC. So far, tests in mice and in human cells in a dish have been promising, the team reports, leading to hopes of carrying out trials in humans. 

As yet, there is no cure for Angelman syndrome, a severe neurodevelopmental condition affecting one in 15,000 people. Children born with the condition have severe intellectual and physical disabilities, causing problems walking, sleeping and talking.

The syndrome is caused by a loss of function in the UBE3A gene. Ordinarily, the paternal copy of this gene is silenced – in a process known as imprinting – in neurons during embryonic development. If the maternal copy of the gene is absent or has a loss-of-function mutation, it prevents any expression of the UBE3A enzyme which plays a crucial role degrading proteins in the cellular waste-disposal system.

This unusual genetic scenario, however, offers novel therapeutic strategies. Professor Zylka's therapy uses CRISPR genome editing to switch the father's dormant copy of the gene back on. 

Using genome editing, UBE3A was reactivated in key parts of the brain in mice, including the cortex, hippocampus, and the cerebellum. It was switched on to levels thought to be sufficient to ameliorate symptoms of Angelman syndrome. Experiments also established the therapy worked on cultured human brain cells. 'It really does raise the possibility that this gene therapy might be usable in humans,' Professor Zylka said.

Angelman syndrome can be detected as early as ten weeks after conception – but with no treatment available, 'people are getting this diagnosis, and there's nothing to be done,' said Professor Zylka. 'They have to make pretty difficult decisions at that point. This [new therapy] may give them another option.'

The researchers suggest that gene therapy could be administered around the second trimester to have the best chances of treating the condition. 

It is an approach that may pave the way for treating other neurodevelopmental disorders, the researchers say. 'For many of these neurodevelopmental disorders, where the brain has been developing inappropriately because of a gene mutation, the best time to intervene is probably going to be early, very early,' Professor Zykla concluded.