Since its debut in 2012, CRISPR-based gene editing has taken the scientific world by storm. From disease modeling to prenatal screening, the innovative platform has been hyped and hailed as the ultimate scientific multi-tool—capable of revolutionizing the treatment of human disease. In the flood of headlines and hyperbole, it can often be hard to determine what’s real, and most importantly, what it really means for patients.
Take the case of HLA-derived therapies: some suggest that the marriage of CRISPR with HLA could open the door to new therapies and the potential elimination of immunogenicity. For example, CRISPR could one day be used to create universal stem cells, eliminating the need for HLA-matched donor banks. (HLA, short for human leukocyte antigens, are proteins or markers on most cells, which are used by the immune system to recognize which cells belong in the body and which don’t). What’s the reality?
“CRISPR and other gene editing technologies can be used to eliminate HLA or other genes that contribute to alloreactive responses,” said Caleb Kennedy, Ph.D., senior manager of Bioinformatics Research at Be The Match BioTherapies®. But the elimination of HLA, while it may one day be possible, would come with a significant downside, as well.
“Although we tend to focus on HLA for histocompatibility and matching, it’s important to remember that HLA is often considered the most medically relevant locus in the human genome,” said Caleb. “Besides matching donors and patients, HLA is implicated in specific disease associations—for example, Celiac disease—drug response, and molecular ancestry.”
In this sense, HLA-derived immunotherapies may prove to have distinct advantages over CRISPR-edited immunotherapies when it comes to certain forms of cancer or virus-associated diseases, which sometimes result from stem cell and solid organ transplants.
“Just like with preemptive vaccination, HLA is critical because it presents disease-specific antigens to the patient’s immune system, producing durable therapeutic effects,” said Caleb. “By honing in on a single antigen-HLA complex, these therapies may require only a single match to target specific antigen-presenting cells and reduce or eliminate the risk of GVHD.” Thanks to donor registries like the Be the Match Registry®, researchers and drug developers are able to source from thousands of HLA variants, including rare phenotypes.
“In the end, there’s considerable speculation,” said Caleb. “CRISPR will continue to advance, but the exact clinical applications are unclear. HLA is playing an important role in treating patients, and I expect that to continue.”