Gene Editing

Our research is focused on editing the HLA gene in the peptide binding groove in order to change its ability to bind specific peptides associated with disease. In preliminary studies, we designed a specific mutation in DRB1 to alter the K71 residue found in DRB1*04:01 (an RA-susceptibility allele) to E71, which is found in RA-resistant alleles (e.g., DRB1*01:03 and *04:02); this mutation eliminated collagen binding and the preferential binding of citrullinated peptides. Thus, a single amino acid substitution renders the arthritogenic peptide-binding profile of DRB1*04:01 nearly identical to that of the resistant allele, DRB1*04:02. Although a DRB1-mismatched hematopoietic stem cell transplant to replace DRB1*04:01 could be used to treat RA, the risk of graft-versus-host disease is too high for this to be a viable strategy. However, an autologous hematopoietic stem cell transplant could treat RA by preventing antigen-presenting cells from binding and presenting arthritogenic peptides to T cells.

 

We are assessing the potential of the CRISPR-Cas9 system to specifically edit genomic DRB1*04:01 to DRB1*04:01K71E in human hematopoietic stem cells while preserving their “stemness.” We propose that performing “plastic surgery” on the patient’s HLA molecule by editing a single amino acid in the HLA gene will introduce the necessary change in DRB1 to halt the progression of RA, while also being safe and avoiding rejection.  These studies will provide an essential preclinical evaluation of this novel mode of immunotherapy for the treatment of RA, as a prelude to performing HLA gene editing in humans. Our research will be the first attempt to treat an autoimmune disease by editing individual amino acids within the patient’s own stem cells. If successful, this approach would create entirely new clinical avenues for the treatment of a variety of autoimmune diseases such as multiple sclerosis, Type I diabetes and ankylosing spondylitis.

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We have provided FDA-Approved stem-cell therapies to over 2,000 patients