Girl born 'without an immune system' like a 'normal child' after experimental gene therapy

·6 min read
Sarah (pictured as a toddler) was born with a genetic disorder that left her without a functioning immune system. (Supplied: Great Ormond Street Hospital)
Sarah (pictured as a toddler) was born with a genetic disorder that left her without a functioning immune system. (Supplied: Great Ormond Street Hospital)

A four-year-old girl who was born "without an immune system" is like a "normal child" since having gene therapy.

Known only as Sarah, the youngster's mother knew something was wrong when the then 10-day-old's bleeding nappy rash was not healing.

Sarah, from South Yorkshire, was later diagnosed with a genetic disorder that affects as few as one in 1 million people worldwide, caused by a mutation to a gene that is essential for a functioning immune system.

Untreated patients rarely survive more than two years, with most requiring a bone marrow transplant.

Read more: Second HIV patient 'cured' after stem cell transplant

With a suitable donor not always available, and transplants often causing severe side effects, Sarah was one of 50 patients referred for experimental gene therapy. 

Several years after the one-off treatment, Sarah – along with 47 of the other children – no longer has symptoms of the immune disorder.

As a baby, Sarah endured unexplained weight loss, vomiting and a bleeding nappy rash that would not heal. (Supplied: Great Ormond Street Hospital)
As a baby, Sarah endured unexplained weight loss, vomiting and a bleeding nappy rash that would not heal. (Supplied: Great Ormond Street Hospital)

Speaking of her daughter's symptoms, Sarah's mother Maria said: "Her nappy rash was always bleeding and sore, she was being sick and losing weight."

Tests later revealed Sarah had adenosine deaminase deficiency-severe combined immunodeficiency (ADA-SCID).

The disease, which affects one in every 200,000 to 1 million people worldwide, leaves patients unable to fight off most infections.

This is due to a mutation to the gene that creates the protein adenosine deaminase, which is essential for a healthy immune system.

Read more: Woman's immune system cured her of HIV without stem cell transplant

"I remember the exact time I saw the paper that had the blood test results on and the diagnosis," said Maria. "I was incredibly upset.

"I wasn't allowed to kiss my daughter or sleep next to her. 

"Everything had to be highly sterilised to keep her safe. It was horrible to not be able to do normal things with my own daughter."

ADA-SCID symptoms often emerge when a patient is less than six months old. They tend to endure pneumonia, chronic diarrhoea, rashes, slow growth and developmental delay.

Watch: HIV-based gene therapy offers hope for SCID

Sarah and the other 49 children were referred for an experimental stem cell gene therapy between 2012 and 2017, carried out at Great Ormond Street Hospital (GOSH) and the University of California, Los Angeles (UCLA).

ADA-SCID is typically treated via an adenosine deaminase injection once or twice a week while a patient waits for a suitable bone marrow donor.

If no match is found, the patient requires lifelong ADA injections, along with other drugs to ward off infections and pneumonia. 

A bone marrow transplant from a healthy sibling is effective in around 70% of cases. 

Read more: Lung transplant 'only hope' for some severe COVID patients

To expand a patient's treatment options, the GOSH/UCLA scientists tested the potential of a new form of gene therapy.

Some of the patient's blood-forming stem cells were first removed. Stem cells are basic cells that can change into a more specialised form of cell.

In the laboratory, a virus was used to carry a healthy copy of the ADA gene into the patient's cells' DNA.

The corrected stem cells were then returned to the patient, producing "a seemingly continual supply of healthy immune cells capable of fighting infection" in most of the children.

Results – published in the New England Journal of Medicine – reveal 48 of the children "are no longer showing symptoms of ADA-SCID", but will require lifelong monitoring.

"The overall results were very encouraging," said co-lead author Dr Donald Kohn, from UCLA.

"All the patients are alive and well, and in more than 95% of them, the therapy appears to have corrected their underlying immune system problems."

Sarah's symptoms began to improve six months after receiving the therapy.

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"She's doing so well now and can do everything a normal child her age would do," said Maria.

Sarah's ordeal has even inspired Maria to train to be a nurse.

"I know how it feels to have your child as a patient and to be so sick, and I want to use my experience to help others in a similar position," said Maria.

The two children who did not have successful gene therapy went back on the standard treatment, with one later having a bone marrow transplant.

Since having gene therapy, Sarah (pictured with her mother Maria) 'can do everything a normal child her age would do'. (Supplied: Great Ormond Street Hospital)
Since having gene therapy, Sarah (pictured with her mother Maria) 'can do everything a normal child her age would do'. (Supplied: Great Ormond Street Hospital)

Overall, no serious side effects occurred in the study. Mild or moderate adverse events came about from "the necessary preparation for the gene therapy" or the immune system rebuilding.

Gene therapy for similar diseases has been linked to serious side effects, like leukaemia. Using so-called lentiviruses as the gene carrier is said to have improved patient safety, however, this approach is not approved by any health regulator.

"If approved in the future, this treatment could be standard for ADA-SCID, and potentially many other genetic conditions, removing the need to find a matched-donor for bone marrow transplant and the toxic side effects often associated with that treatment," said co-lead author Dr Claire Booth, from GOSH.

Bone marrow transplants can lead to mouth pain, nausea, vomiting, infections, bleeding, lung tissue inflammation and graft-versus-host disease – when a donor's immune cells attack the recipient's organs.

"We need and want guidelines to change so we can start offering this potential cure to children and provide it as a first-choice treatment," said Dr Booth. 

"This research could set those wheels in motion."

Cora Oakley was diagnosed with the same disease at seven days old. The now four-year-old is a 'rough and tumble, outdoors kind of kid' after receiving gene therapy prepared from frozen stem cells. (Supplied: University of California, Los Angeles)
Cora Oakley was diagnosed with the same disease at seven days old. The now four-year-old is a 'rough and tumble, outdoors kind of kid' after receiving gene therapy prepared from frozen stem cells. (Supplied: University of California, Los Angeles)

Ten of the 50 children were treated by UCLA medics via a frozen preparation of stem cells, with these youngsters having similar outcomes to the other patients.

ADA-SCID patients may therefore be able to have their stem cells collected locally, before being processed elsewhere and shipped back to a local hospital, removing the need for an individual to travel.

Cora Oakley, from Morristown in New Jersey, was one of the patients who received frozen stem cells.

The now four-year-old was diagnosed with ADA-SCID via genetic screening at just seven days old. 

"I remember asking the doctor if my daughter was going to die," said Cora's mother Chelsea. 

"His response was, 'I hope not'. It was the darkest day of my life."

Cora had gene therapy in September 2017. Nearly four years later, she is a "rough and tumble, outdoors kind of kid".

A trial into the potential of frozen stem cells is underway at the UK's Zayed Centre for Research into Rare Diseases in Children, in partnership with GOSH.

"We started gene therapy at GOSH around 20 years ago and now have refined the process to offer a potential cure for children born with this debilitating condition," said co-author Professor Adrian Thrasher. 

"Over 200 patients with various genetic conditions across the world have now been treated with this type of gene therapy. This is another very significant breakthrough."

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