UCLA researchers correct mutation causing IPEX

A team of researchers have developed a method for modifying blood stem cells to reverse the genetic mutation that causes a life-threatening autoimmune syndrome called IPEX. 

IPEX stands for Immunodysregulation Polyendocrinopathy Enteropathy X-Linked Syndrome, and refers to a lethal syndrome that manifests with early onset, insulin-dependent diabetes mellitus, severe diarrhoea, dermatitis and failure to thrive. As it is an X-linked syndrome and the defective gene is carried on the X chromosome, should a females’ X chromosome contain the defective gene, there is still another X chromosome present with a functioning gene. However, as males have only one X chromosome, they are affected by the condition.

Most affected children die within the first two years of life. 

The condition is caused by a mutation that prevents the FoxP3 gene from making a protein that is needed for blood stem cells to produce T-cells.

These T-cell keep the immune system working properly, and without them the immune system would attack itself.

The team of researchers conducted in vivo tests on mice, and added a normal copy of the FoxP3 gene to blood stem cells – those that can produce all blood cell types. This approach corrected the genetic mutation in mice with a version of IPEX similar to the human version, and also restored immune regulation.

Dr Donald Kohn led the team, and used a viral vector to carry the genetic information to the nucleus of the cell, without causing an infection. They engineered the vector used so it only turned on regulatory T-cells, and not other cells.

“It’s exciting to see how our gene therapy techniques can be used for multiple immune conditions,” said Dr Kohn, a Professor of Paediatrics and Microbiology, Immunology and Molecular Genetics at the David Geffen School of Medicine at UCLA and member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “This is the first time we’ve tested a technique that targets an autoimmune disorder, and the findings could help us better understand or lead to novel treatments for other autoimmune conditions such as multiple sclerosis or lupus.”

All of the mice treated were virtually free of the IPEX symptoms shortly after the treatment.

“It’s incredibly important that we only create regulatory T-cells that have the non-mutated FoxP3 gene,” said Katelyn Masiuk, a student in the ULCA physician-scientist degree program and the study’s first author.

“We found that if the FoxP3 protein is turned on in blood stem cells, the whole blood system functions abnormally. We realised that we needed a vector that only made FoxP3 in the regulatory T-cells made from the blood stem cells, but not in the blood stem cells themselves or other types of blood cells they make.”

Prof Kohn mentioned that to treat humans, blood stem cells would be removed from the bone marrow of patients with IPEX. Then the FoxP3 mutation would need to be corrected in the lab using the IPEX-targeting vector.

The patients would then receive a transplant of their own corrected blood stem cells, which should provide a continuous life-long supply of regulatory T-cells.

The research was published in the journal Cell Stem Cell.