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Gene therapy success in children with rare immunodeficiency

An investigational gene therapy for a rare, life-threatening inherited immunodeficiency disorder has been found to safely restore the immune systems of infants and children.

Rare immunodeficiency

Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is an inborn error of metabolism. It is caused by mutations in the ADA gene that impair the activity of the adenosine deaminase enzyme. It specifically results in the accumulation of adenosine and deoxyadenosine, and the inhibition of DNA synthesis and repair. Those affected by ADA-SCID have profound lymphocytopenia and also impaired immune function. As a result, without treatment, patients can die from infection by the age of 2 years.

Patients can be treated with enzyme replacement therapy, yet this does not fully reconstitute the immune function and must be taken for life. A haematopoietic stem-cell transplantation is a more definitive treatment. However, finding a HLA-matched donor can be difficult. There is also the risk of graft-versus-host disease.

Lentiviral gene therapy

In this paper, published in the NEJM, researchers have reported on a new investigational gene therapy composed of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with a self-inactivating lentiviral vector encoding human ADA. There were three studies – 2 conducted in the US and one in the UK – involving 50 patients with ADA-SCID. Previous gene therapy approaches for this condition have used gamma retroviruses. Some patients have subsequently developed leukaemia due to the vector activating genes that control cell growth. In this study, researchers designed the lentiviral vector to avoid this outcome and enhance the effectiveness of gene delivery.

In all studies, overall survival was 100% up to 24 and 36 months. Most participants acquired and retained robust immune function following gene therapy. To be more specific, after two years, event-free survival was 97% in the US studies and 95% in the UK study. There were only two participants for whom the gene therapy did not restore long lasting immune function. Most importantly, the gene therapy was safe overall. There was no evidence of leukoproliferative complications and no autoimmunity. Most adverse events were low grade.

These findings provide hope for a more effective and long-term treatment for infants and children with ADA-SCID.

 Anthony Fauci, Director of NIAID, stated:

“These findings suggest that this experimental gene therapy could serve as a potential treatment option for infants and older children with ADA-SCID.

Importantly, gene therapy is a one-time procedure that offers patients the hope of developing a completely functional immune system and the chance to live a full, healthy life.”

Image credit: By andriano_cz –