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CRISPR yields new potential “bubble boy” gene therapy

Stanford scientists and collaborators have harnessed CRISPR to replace the mutated gene underpinning the devastating immune disease, SCID-X1.

About 1 in 50,000 baby boys are born with no immune cells -- they have no way to molecularly protect themselves. The disease, called X-linked severe combined immunodeficiency, or SCID-X1, is more commonly known as the "bubble boy" disease because if babies born with SCID-X1 are not secluded in a hygienic "bubble," they could contract an infection and die.

Now, through the gene-editing technology CRISPR-Cas9, Stanford scientist Matthew Porteus, MD, PhD, professor of pediatrics, is leading the charge for a new type of treatment that harnesses the particular class of stem cells that gives rise to immune and blood cells. In people with SCID-X1 these cells are robbed of their immune cell-generating abilities due to a mutation in a single gene called ILR2 gamma.

For years, the "gold standard" treatment for SCID-X1 was a bone marrow transplant, which would equip the patients with new stem cells that can give rise to blood cells and immune cells. The problem was, a bone marrow transplant is finicky business -- a perfectly-matched donor is not always available, and even when they are, the procedure can trigger a host of complications.

Porteus' approach takes a different angle, using the cells of the SCID-X1 patients themselves.

Our story explains:

Porteus uses CRISPR-Cas9 to create a double-stranded break in DNA to insert a healthy copy of the ILR2 gamma gene in the stem cells that create immune cells.

Using the gene-editing system, scientists tweaked cells from six people with SCID-X1 and then transplanted those cells into mouse models of SCID-X1. Those mice were then not only able to make their own immune cells, but many of the edited cells retained something called 'stemness,' meaning that they maintained their ability to continually create new cells.

The preclinical result, which successfully restored function to the ILR2 gamma gene, seems promising, said Porteus.

"To our knowledge, it's the first time that human SCID-X1 cells edited with CRISPR-Cas9 have been successfully used to make human immune cells in an animal model," said Mara Pavel-Dinu, PhD, a member of the research team.

What's more, Porteus and Pavel-Dinu did not observe any harmful side effects from the CRISPR-based treatment. The mice are functionally normal, and after genetic analysis, the researchers confirmed that gene editing was successfully restricted to only the ILR2 gamma gene with no accidental side edits.

A paper describing the work was published online in Nature Communications.

Porteus said he is optimistic that if larger preclinical studies prove promising, the therapy could be piloted in human patients in the next several years through the Stanford Center for Definitive and Curative Medicine.

Photo by Marc Sendra Martorell

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