Human blood stem cells genetically 'edited'

Harvard Stem Cell Institute (HSCI) researchers at Massachusetts General (MGH) and Boston Children's hospitals (BCH) for the first time have used a relatively new gene-editing technique to create what could prove to be an effective technique for blocking HIV from invading and destroying patients' immune systems.

This is the first published report of a group using CRISPR Cas technology to efficiently and precisely edit clinically relevant genes out of cells collected directly from people, in this case human blood forming stem cells and T-cells.

Though the researchers that believe this new approach to HIV therapy might be ready for human safety trials in less than five years, they themselves offered three strong points of caution:

The first and most obvious is that they could run into unexpected complications; the second is that the history of the HIV/AIDS epidemic is littered with "cures" that turned out not to be; and finally, even if this new approach works perfectly, it will require additional developments to be applicable in the areas of the world that have been the hardest hit by the epidemic.

The work, led by Chad Cowan, and Derrick Rossi, associate professors in Harvard's Department of Stem Cell and Regenerative Biology, is featured on the cover of today's issue of the journal Cell Stem Cell.

HIV specifically targets T cells, a principal portion of the blood-based immune system, and enters via a gene receptor called CCR5 that serves as a doorway into the cells. Once inside the T cells, HIV replicates and kills off the host cells, leaving patients at the mercy of a variety of opportunistic infections.

Using the CRISPR Cas gene-editing technology, the Cowan and Rossi teams knocked the CCR5 receptor out of blood stem cells that they showed could give rise to differentiated blood cells that did not have CCR5. In theory, such gene-edited stem cells could be introduced into HIV patients via bone marrow transplantation, the procedure used to transplant blood stem cells into leukemia patients, to give rise to HIV-resistant immune systems.

"We showed that you can knock out CCR5 very efficaciously, we showed that the cells are still functional, and we did very, very deep sequencing analysis to show that there were no unwanted mutations, so it appears to be safe," Cowan said, adding that "there is obviously much more work to do.

"The next step is animal trials in collaboration with the Ragon Institute at Mass General," Cowan said. "There are excellent mouse models you can give a human immune system and then infect with HIV. We can give our cells to the mice and see if they're protected from HIV." Once those studies are completed, and if they are successful and complications do not arise, the next step would be to apply to the U.S. Food and Drug Administration to launch phase I human trials, which are designed solely to test the safety of new treatments. Cowan said it is too early to predict how soon such trials might begin.

David Scadden, a hematologist/oncologist who is both co-director of HSCI and director of the Center for Regenerative Medicine at MGH, called the new work "a tremendous first step in editing out what makes human cells vulnerable to HIV. It makes possible the idea that a person's own immune cells can attack HIV without being susceptible to it. Since this was done in stem cells, the entire immune system may be durably brought to bear on the virus. That's a powerful concept.

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Human blood stem cells genetically 'edited'