Researchers have used base editing to correct the mutation that causes a rare immune disorder. A one-off gene therapy could potentially be used to treat the condition known as CD3δ severe combined immunodeficiency (CD3δ SCID) according to a new study published in Cell.
A rare condition
CD3δ SCID is a severe immunodeficiency disorder that presents at birth, characterised by a lack of T-cells and inability to fight infection. Currently there is only one effective treatment – bone marrow transplant – and those who go untreated often do not live past infancy. The condition is caused by a mutation in the CD3D gene that leads to the presence of an erroneous stop codon, halting T-cell production.
Although the disease is rare, with such limited treatment options, it is vital that research is prioritised. With this in mind, the authors, some of whom have successfully used gene editing to treat genetic conditions in the past, pursued base editing to treat CD3δ SCID. Faced with a new challenge, senior author Donald Kohn sought advice from expert scientists, eventually developing a mechanism that successfully corrected the mutation in human derived stem cells.
Base editing involves the precise alteration of one nucleotide, contrasting with strategies such as CRISPR that require both strands of DNA to be cut. The technique is highly efficient and much less error-prone than other methods.
In the current study, the researchers used an adenine base editor (ABE) to correct the disease-causing point mutation. ABEs are capable of chemically altering nucleotides such that an adenine-thymine base pair becomes a cytosine-guanine pair. The researchers tested the editor in patient-derived stem cells, and the CD3D mutation was successfully corrected 71% of the time.
To further test the efficacy of the base editor and to analyse the knock-on effects of the correction, the team experimented with thymic organoids. When the base corrected stem cells were transplanted into the lab grown tissues, the organoids were capable of producing fully matured T-cells. This was the first true indication that this technique could be used to correct the pathogenic mechanisms underpinning CD3δ SCID. In a final test, the stem cells were transplanted into mice, where they persisted long term. This result indicates that base edited cells could be provided as a one-off treatment for the condition, delivering effective, long-term results.
A team effort
As the disease is so rare, there were many challenges associated with the study, namely in obtaining enough patient derived stem cells. The technique was also an entirely new venture for the Kohn lab, and as such, the team had to consult many prominent scientists – including base editing pioneer David Liu.
Despite the difficulties associated with the project, the team continued with their goal of developing a cure for the condition. Speaking of her desire to make a difference, first author Grace McAuley stated: “My goal was help get this therapy to the clinic as fast as was safely possible.” Co-senior author Gay Crooks praised the team effort: “This project was a beautiful picture of team science, with clinical need and scientific expertise aligned. Every team member played a vital role in making this work successful.” The team are working towards a clinical trial using the technology, taking us one step closer to a life-changing treatment for this severe condition.