Researchers at the Garvan Institute of Medical Research have found three patients with a severe genetic immunodeficiency disorder that have spontaneously repaired the harmful variants in their DNA.
Immunodeficiency and somatic reversion
Primary immunodeficiencies (PIDs) or inborn errors of immunity (IEI) are monogenic immune deregulatory conditions. They are caused by mutations in single genes that compromise the function of the immune system.
Somatic reversion is the spontaneous repair of a pathogenic germline genetic variant. This results in the improvement of the defective molecular phenotype in progeny cells. Specifically, this repair can lead to restoration of either expression or function of the wild-type allele and protein. As the immune system is a regenerating system, somatic reversion provides the opportunity for somatically corrected cells to replace the pre-existing immune repertoire if they have a selective advantage. Somatic reversion has been associated with milder clinical phenotypes in patients with numerous PIDs.
DOCK8 deficiency, due to biallelic inactivating mutations in DOCK8, results in a combined immunodeficiency. This is characterised by severe bacterial, viral and fungal infections, as well as allergic disease and some cancers.
In this study, published in Journal of Clinical Investigation, researchers identified three patients with DOCK8 deficiency that have repaired their faulty genes through somatic reversion. Using sophisticated genetic, molecular, cellular and functional analyses, the team explored the immune cells of these patients.
The patients had all been suffering from infections and rashes since birth. Yet, began experiencing significant improvements in their clinical features, despite the absence of significant treatments. The researchers observed that acquisition of DOCK8 expression due to somatic reversion in multiple lymphocyte subsets restored defective lymphocyte signalling, survival and proliferation. It also restored CD8+ T cell cytotoxicity, CD4+ T cell cytokine production and memory B cell generation.
DOCK8 deficiency affects hundreds of patients globally. Without interventions like bone marrow transplants or these rare somatic reversion cases, 50% of patients die before they turn 20 years old.
These findings emphasise the value of treating inherited immunodeficiencies with gene therapy. Gene therapy has shown to be successful in treating a small number of genetic diseases. However, it is currently not available to DOCK8 deficiency.
Professor Stuart Tangye, co-senior author, stated:
“What our study suggests is that introducing even a few healthy cells into those patients with rare genetic conditions may be an effective treatment, if these cells multiply over time, and are therefore a promising potential therapy in the future.”
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