Researchers design genetic therapy to prevent brain deterioration

Doctor points at child's brain scan

A research team at the Francis Crick Institute and Great Ormond Street Hospital (GOSH)/UCL Great Ormond Street Institute of Child Health have identified potential treatments for children with rare genetic conditions.

The researchers have shown that problems with calcium underlie these progressive diseases. Stabilising calcium levels in the brain could therefore be a target for new treatments, to protect the brain from damage over time.

‘Mosaic mutations’ – genetic changes which appear in some cells in the body but not all – in two genes, GNAQ or GNA11, cause a spectrum of conditions including Sturge-Weber syndrome and Phakomatosis Pigmentovascularis with Dermal Melanocytosis (PPV-DM).

These mutations affect the skin, brain and eyes, leading to seizures, impaired development, severe headaches, blindness, and birthmarks on the face.

Calcium build-up in the brain

Calcium deposits were known to build up in the brain in these conditions. They form parallel lines in the blood vessels, called ‘tramlining’, which can be seen on X-rays. Doctors believed the calcium deposits were non-specific signs of brain damage, but this research challenges this view.

The researchers examined 42 children with either Sturge-Weber syndrome or PPV-DM at GOSH. They found that 74% of the children had at least one abnormal measurement of calcium in the blood, and their calcium brain deposits were getting worse over time.

Analysis of patient samples revealed that too much calcium was being released inside cells all the time. This led to the cells pulling in even more calcium from outside to keep up with the demand, through transporters on the cell called CRAC channels.

Success with genetic therapy

To try and treat the cells in the lab, the team tested a new genetic therapy to silence the overactive gene and a drug to block the CRAC channels. Both treatments were able to improve the calcium problems, but the genetic therapy was the most effective.

The researchers hope early intervention with the genetic therapy or with a drug that targets the calcium pathway will prevent the calcium deposits building up in the brain cells and contributing to seizures.

Veronica Kinsler, Principal Group Leader of the Mosaicism and Precision Medicine Laboratory at the Crick, Professor of Paediatric Dermatology and Dermatogenetics at GOSH/UCL, and NIHR Research Professor, said: “We have finally been able to understand the calcium deposits in the brain that doctors have seen in the clinic for years. We think there’s a window of opportunity where we can now try to make a difference for children diagnosed with these severe diseases.”

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