Blaese awardee is developing a gene editing strategy to treat XLA

As the IDF Research Grant Program applicant with the highest-scoring application, this year’s Michael Blaese Research Grant Award goes to Dr. Donald Kohn, distinguished professor at the University of California, Los Angeles (UCLA), and director of the UCLA David Geffen School of Medicine Human Gene and Cell Therapy Program. Kohn's name may be familiar, as he has devoted his career to developing gene therapy for PIs, including adenosine deaminase deficient severe combined immunodeficiency (ADA-SCID) and leukocyte adhesion deficiency-I (LAD-1). IDF’s grant will help him move that work into the age of gene editing for a PI that has been difficult to address with traditional gene therapy—X-linked agammaglobulinemia (XLA).

In his previous work, Kohn introduced a working copy of a gene into patients’ blood-forming, or hematopoietic, stem cells using a type of gene therapy vector that inserts the gene at somewhat random sites in the cells’ DNA. That works well for genes like adenosine deaminase that don’t require tight control over where and when they are turned on versus off. 

In contrast, Kohn said, “Mother Nature controls the expression of [the BTK] gene very precisely,” referencing the gene, Bruton's tyrosine kinase (BTK), that is disrupted in XLA. Typically, such tight control relies on the DNA surrounding a gene. If a tightly controlled gene is inserted in another place and loses its DNA context, it can cause problems. In fact, using a traditional vector to introduce BTK in mice causes abnormal cell growth and division of white blood cells, which can lead to cancer. 

For this reason, Kohn has been working on a more precise approach for XLA. Instead of just plopping a working copy of BTK down somewhere in cells’ DNA, he is using gene editing with CRISPR/Cas9 to insert BTK just in front of the nonworking copy in each cell. Kohn’s lab has already shown that the approach works in human cell lines and non-XLA stem cells without any troubling side effects.

Kohn plans to use the IDF grant to gather additional pre-clinical data he hopes will dovetail with ongoing experiments in mice—testing the BTK gene editing strategy in hematopoietic stem cells from individuals with XLA. 

Not only will Kohn test the ability of these edited cells to make the BTK protein, he also plans to infuse the edited cells into a mouse model of XLA. “If we can show they grow as far as normal donors’ [cells] do in those models, and show the mouse model parallel approach leads to vaccine response, we think that’ll be good evidence to get to clinical trial,” he said. He hopes to start clinical trials in two to four years if everything goes well.

Kohn’s also thinking about how to get a therapy like this to patients following setbacks over the past year in the gene therapy commercial market. 

“Is commercialization by pharma the only model? Or can, for example, [the therapy] continue to be made at a university but reimbursed by insurance?” he wondered. “It’s getting so that the science isn’t what’s limiting. The financial, the regulatory [issues] are becoming the rate-limiting issues.”

In discussing his IDF-supported research, Kohn remarked that he was especially honored to be named the Blaese awardee. “I started as a fellow in Mike’s lab. I joined Mike in 1985, and one of the first things he said to me was ‘How would you like to work on gene therapy for your fellowship?’ And I thought, wow, that sounds cool,” Kohn said. “It’s always with me, the lessons I learned with him, so it’s really nice to get this award in his name.”