Base Editing Shows Promise for Treating Rare Immune Disorder

Research led by the University of California, Los Angeles, shows base editing could be used to treat a rare immune disorder known as CD3 delta severe combined immunodeficiency (SCID).

Writing in the journal Cell, the authors describe using base editing, a new and more precise version of gene editing than CRISPR, to correct the genetic mutation causing the immune disorder in human stem cells.

CD3 delta SCID is caused by a mutation in the gene CD3D that stops production of the CD3 delta protein. This protein is essential for the development of T immune cells from stem cells in the blood. Without CD3 delta, babies are unable to make these essential immune cells and often die within the first two years of life from infections they are not able to fight off.

Bone marrow transplant is currently the only treatment for these children, but can cause potentially fatal adverse events such as graft vs host disease, as well as other treatment-related toxic effects.

Donald Kohn, a professor at UCLA and lead author on this paper, and his team have previously developed successful gene therapies for similar immune disorders including other forms of SCID. This research is the result of a collaboration between Kohn and Nicola Wright, a pediatric hematologist and immunologist at the Alberta Children’s Hospital Research Institute in Canada, who was looking for a better treatment option for children with CD3 delta SCID.

“Grace proposed we try base editing, a very new technology my lab had never attempted before,” said Kohn, in a press statement.

For the study, the team used adenine base editing to restore the function of the CD3D gene in autologous hematopoietic stem and progenitor cells (HSPCs), which produce T cells in the blood. mRNA encoding an adenine base editor and a guide RNA was delivered to cells extracted from a patient with CD3 delta SCID and across three experiments was able to correct around 71% of the cells to enable them to produce a normal version of the CD3 delta protein.

In a follow-up experiment the corrected cells were added to lab-grown organoids mimicking the human thymus organ, where T cells are produced in the body. The corrected cells were able to produce healthy, functional T cells.

“Because the artificial thymic organoid supports the development of mature T cells so efficiently, it was the ideal system to show that base editing of patients’ stem cells could fix the defect seen in this disease,” said Gloria Yiu, a UCLA clinical instructor in rheumatology, who was also a co-first author of the study.

In a third part of the research, the corrected cells were injected into a model mouse to assess their longevity and they showed the cells remained functional for four months after implantation, suggesting they could correct the genetic fault long-term.

The research is still at an early stage, but the investigators are now planning a clinical trial for infants with this condition from Canada, Mexico and the U.S.