Results from the largest cohort of children who received a gene therapy for a rare immunodeficiency condition have shown the long-term safety and efficacy of the curative treatment.
An international team of researchers led by Great Ormond Street Hospital (GOSH), University College London (UCL), and University of California, Los Angles (UCLA) developed a gene therapy for children with the rare immune condition, known as ADA-SCID. They then followed the children's recovery and progression for an average of 7.5 years. Those treated had a 100% survival rate and over 95% of children were cured of their condition.
Published in the New England Journal of Medicine, this study represents the largest cohort of data of children who have received the most standard type of gene therapy, known as lentiviral gene therapy, to date.
What is ADA-SCID?
Adenosine deaminase deficient severe combined immunodeficiency (ADA-SCID) is a rare, life-threatening disease that prevents children from living a normal life. It is caused by mutations in the gene that creates the enzyme adenosine deaminase, which is essential to a functioning immune system.
Children with ADA-SCID have no immune system and, if left untreated, the condition can be fatal within the first two years of life. Day-to-day activities like going to school or playing with friends can lead to dangerous infections. Newborn screening for SCID has been implemented in some countries to help diagnose conditions like this early in life.
Prior to the gene therapy, the standard treatment would be once or twice weekly enzyme-replacement therapy, monthly infusions of immunoglobulin (antibodies) and preventative antibiotics until a matched bone marrow donor - usually a close family member - can be found.
Results from the study
The study followed 62 patients the international team treated in the UK and USA with the gene therapy between 2012 and 2019. They selected this cohort so the team could follow patients for 5 years or more. On average patients were followed up for 7.5 years, with 5 children followed up for over a decade - making this study the largest cohort of children who have received an ex vivo stem cell gene therapy to date.
Results have found that 100% of the children treated survived the gene therapy, and 59 patients (95%) were cured. All the patients who responded remained off enzyme-replacement therapy after 6 months and have responded to routine childhood vaccinations like such as tetanus or measles, mumps, and rubella (MMR) - something that was previously impossible for these children.
None of the children and young people had serious complications and the few who didn't respond successfully went on to have bone marrow transplants. These results show the progression of lentiviral gene therapy technology.
Lentiviral gene therapy is the standard type of ex vivo gene therapy. This is where a patient's cells are removed and modified in a laboratory, before being returned to the patient, with the aim of them replacing the original damaged cells.
Professor Claire Booth, consultant in paediatric immunology at GOSH and Mahboubian Professor in gene therapy at UCL Great Ormond Street Institute of Child Health and lead for the clinical trial, said:
"We're so pleased to see that almost 100% of the patients we've treated with gene therapy for ADA-SCID have been cured. This is also very reassuring for other conditions treated using the same techniques - showing that it works in the long term and is safe.
"For almost 25 years, GOSH has been at the forefront of developing and delivering gene therapies. This wouldn't have been possible without all the support of patients and families across the years."
Andy's story
One of the patients who took part in the trial was Andy Cash from Portlaoise in Ireland. He was diagnosed with ADA-SCID when he was just 3 weeks old, when mum Mary became concerned he wasn't feeding well and was becoming breathless.
Andy was transferred from his local hospital to Children's Health Ireland in Crumlin, Dublin, where tests done by Dr Leahy showed he had the condition.
Andy's mum Mary said: "We heard of the condition ADA-SCID before but didn't know much about it and because of how serious it was, Andy had to be kept in isolation to keep him safe. He started having enzyme-replacement therapy injections straight away and the clinical team looked for a bone marrow transplant donor but one couldn't be found globally. Family members and his three older siblings were tested but none of them were a match unfortunately, and then Dr Leahy and his team told us about the gene therapy trial at GOSH and explained everything about it because we never heard of it before.
"We isolated in hospital for a few months and then at home, before taking the ferry to England and travelled through the night to GOSH to make it as safely as possible for
Andy, where we met Claire and the team. We stayed at GOSH for two months after the gene therapy treatment when Andy was 5 months before returning to Ireland.
"We were so pleased for Andy to have the gene therapy and were hopeful for the future, as it had been such a difficult time for us a family. His siblings had to move in with extended family as Andy was still so vulnerable to catching infections."
Andy is now 9 years old and is thriving - a keen member of Portlaoise boxing club.
Mum Mary continues: "You wouldn't know Andy was so poorly when he was born and had such a challenging start. He's full of energy and makes friends wherever he goes - he's like a mini celebrity, wherever he goes everybody loves him, he's very charming! We're incredibly grateful he was able to have the gene therapy treatment at GOSH as it's been lifechanging. It's not slowed him down and he's made great progress - he's managed to have all his childhood vaccinations and go to school with his siblings and friends."
Looking to the future
In 2024, GOSH, supported by GOSH Charity and LifeArc, announced plans to explore whether GOSH could become the first hospital in the UK to hold the market authorisation, or licence, for this gene therapy treatment for children and young people with ADA-SCID. Meaning patients with rare diseases can more easily access and benefit from the treatment.
A big challenge with developing treatments for rare diseases is that due to small patient numbers they are often not commercially viable for companies to invest in and keep on the market, even if the treatment has been proven to cure a condition.
This cohort of data will feed into discussions to aid the process of exploring market authorisation. The study was supported by National Institute for Health and Care Research GOSH Biomedical Research Centre (NIHR GOSH BRC) and supported in particular by NIHR GOSH BRC-funded research nurses, Gene and Cell Therapy Facility manufacturing team, project managers, and patient pathway coordinators. The initial part of the study was funded by Orchard Therapeutics.
Professor Claire Booth is part of the NIHR GOSH BRC leadership for the Gene, Stem and Cell Therapy theme.
