Newly designed genetic therapy could alleviate debilitating giant moles in rare skin condition

The Francis Crick InstituteJun 17 2024

Researchers at the Francis Crick Institute, UCL Great Ormond Street Institute for Child Health and Great Ormond Street Hospital for Children (GOSH) have designed a new genetic therapy that could alleviate debilitating giant moles in a rare skin condition.

In the future, the treatment could potentially be used to reverse the giant moles, and therefore reduce the risk of affected children and adults from developing cancer. It could also potentially reverse other more common types of at-risk moles as an alternative to surgery.

Small skin moles are common in the population, but in congenital melanocytic naevus syndrome (CMN), children are born with up to 80% of their body covered in big, painful or itchy moles, caused by mutations acquired in the womb. These moles can sometimes develop into a severe type of cancer called melanoma.

Published today in the Journal of Investigate Dermatology, the researchers silenced a gene called NRAS, which is mutated in the cells in these moles, in cells in a dish and in mice. NRAS belongs to a group of genes (RAS genes) that, when mutated, can cause moles, and can predispose to cancer.

The team used a genetic therapy called silencing RNA, which silences the mutated NRAS in mole skin cells. The therapy was delivered in special particles directly to mole cells.

They gave injections containing the therapy to mice with CMN, which reduced the silenced the NRAS gene after just 48 hours. They also tested it in cells and whole skin sections from children with CMN. Silencing the gene triggered the mole cells to self-destruct.

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: "CMN is physically and mentally challenging for children and adults living with this condition and for their families. These results are very exciting, as not only does the genetic therapy trigger self-destruction of the mole cells in the lab, but we have managed to deliver it into the skin in mice. This results suggest that the treatment in future could potentially reverse moles in people, however more testing will be needed before we can give it to patients.

"We are very grateful to our patients at Great Ormond Street Hospital, who have been actively participating over many years to help us produce this new potential therapy. After more studies, we hope the therapy can soon enter clinical trials in people."

This research was funded by the National Institute for Health and Care Research (NIHR), Caring Matters Now Charity and Patient Support Group, LifeArc and the NIHR Great Ormond Street Hospital Biomedical Research Centre.

Jodi Whitehouse, CEO of Caring Matters Now, who helped to fund the research, said: "This breakthrough in finding a treatment for CMN could transform the lives of the families we support living with CMN. As someone who was born with CMN covering 70% of my body and having undergone 30+ operations in my childhood to try and remove the CMN because of the fear of melanoma, with no success, this news is awe-inspiring and exciting. It brings real hope to the lives of those living with CMN."

This work is part of our commitment to improving the lives of people living with rare diseases, by investing in promising research and helping scientists to overcome translational research barriers. If successful, we hope to see human clinical trials for this therapy within the next few years."

Catriona Crombie, Head of Rare Disease at LifeArc

The researchers have been working closely with the Crick's Translation team to develop the technology towards patient benefit. This has included securing translational funds from LifeArc, to carry out more research in mice to understand how the treatment works over a longer period.

Family stories

Hanna's story 

Hanna, 7, was born with a large dark lesion covering her back, stomach and thighs. Her skin is very itchy and dry with large lumpy modules making everyday life debilitating, and she can find it difficult to sleep at night. Her skin samples have been used in research like this to understand treatment options with her Mum hoping one day it will transform her quality of life.

Elijah's story  

Elijah, aged 10, was born with CMN on his scalp, which is very dry, fragile and cuts easily. He has to be monitored constantly and be very careful in the sun. In 2023 Elijah had a melanoma scare which was luckily a false alarm. His family don't want to remove the CMN by surgery, but hope for a way to remove the risk of melanoma. They fundraise for CMN research into finding a cure. 

Ada's story 

3-year-old Ada has 70% of her body covered in CMN mostly on her neck and back. Ada loves swimming and the sea, but needs to take extra precautions for her CMN which includes extra sun protection and wearing good clothing. Her CMN can also be very itchy and painful. When she was just 4 months old, she had surgery to remove some of the nodules from her back that were painful and debilitating. At that time, Ada's parents decided to donate some of her skin cells, which have now been used in Dr Kinsler's research.