Children with some rare genetic conditions who would have once died at just a few years old could now have typical life expectancies due to gene-replacement therapy.
“We’re curing kids of fatal diseases. It’s wonderful,” says at the University of California, Los Angeles.
Kohn and his colleagues are trialling a gene therapy – in which disease-causing versions of genes are replaced with normally functioning versions – for leukocyte adhesion deficiency type-1 (LAD-1).
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This rare condition occurs when immune cells called leukocytes can’t travel to the site of a wound or injury, causing otherwise benign skin infections to become chronic. LAD-1 usually results in death before the age of 2, unless the child has a stem cell transplant.
The gene therapy works by replacing a mutated version of the ITGB2 gene, which is responsible for LAD-1. Kohn and his colleagues take a child’s stem cells from bone marrow and insert regular copies of the ITGB2 gene using a virus that has been modified not to cause harm. They then use a low dose of chemotherapy to destroy the remaining bone marrow, and return the edited cells back into the child.
Since 2019, nine children have received ITGB2-replacement therapy, with their age at the initiation of treatment ranging from 5 months to 9 years. Now, none of those children experience chronic skin or lung infections and “they’re leading normal lives, they’re in school, they’re off all their antibiotics”, says Kohn.
This is just one promising clinical trial result for several gene-replacement therapies presented at the , held in Washington DC from 16 to 19 May.
from St. Jude Children’s Research Hospital in Memphis presented positive results for a gene therapy for X-linked severe combined immunodeficiency (X-SCID), another rare immune condition that is usually fatal before the age of 2 without a stem cell transplant.
X-SCID is sometimes known as “bubble boy disease”, because it only affects males, with these children previously having to isolate in plastic chambers to avoid infections.
This therapy replaces the abnormal version of the IL2RG gene that causes the condition, similarly using a virus to deliver normal copies of the gene into stem cells.
Since 2016, 23 infants with X-SCID have received the therapy when aged between 2 months and 14 months. All have now developed fully functional immune systems or are expected to as their treatment progresses, says Mamcarz. “They’re all home with their families and they’re no different to other kids,” she says.
A gene therapy for another rare condition, infantile GM1 gangliosidosis – which progressively destroys nerve cells and is usually fatal before the age of 10 – was presented by from the US company Passage Bio in Philadelphia.
Two children, aged 15 months and 31 months at treatment, received the therapy in March 2021. To replace the abnormal version of the GLB1 gene causing their condition, Weinstein’s team injected normal copies of the gene via a virus into cerebrospinal fluid in the backs of the children’s necks. The virus then circulated around their brains and spinal cords, delivering the new genes.
The brains of children with GM1 gangliosidosis usually progressively shrink, but the younger child has displayed normal brain growth since the gene therapy. Both have also learned to walk and talk, which only some children with the condition ever achieve and then lose the ability as their illness progresses. The older child has shown improvements, but not to the same extent as the younger one, possibly because he had more severe disease to begin with.
None of the three gene therapies has caused any serious side effects to date.
The only known treatment with the same effectiveness is a stem cell transplant. This requires a matched donor, which can be hard to find.
Stem cell transplants also run the risk of graft-versus-host disease, a potentially life-threatening complication that occurs when the transplanted cells attack the recipient’s own cells.
In the early 2000s, gene therapies fell out of favour after some people receiving them developed leukaemia, but this was related to the particular mouse virus used to deliver the genes into cells, says Mamcarz.
Most groups now use an inactivated form of HIV to deliver the genes. It has been gutted so “it’s just like a shell for carrying the genes into cells”, says Mamcarz. It appears safe so far and there is no risk of them catching HIV, but all children who receive this virus will be carefully monitored for at least 15 years to check for increased cancer risk, which is a requirement of the US Food and Drug Administration for all gene therapies.
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Article amended on 30 May 2022
This article has been amended to correct the date the infants with X-SCID started receiving gene therapy.
