Harvard Stem Cell Institute (HSCI) researchers at Massachusetts General (MGH) and Boston Children’s hospitals (BCH) have used a relatively new gene-editing technique to create a promising strategy for blocking HIV from invading and destroying patients’ immune systems.
According to the report published on this research, the scientists used a technology known as CRISPR Cas ― clustered regularly interspaced short palindromic repeat-activated cells ― 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.
The work, led by Chad Cowan and Derrick Rossi, associate professors in Harvard’s Department of Stem Cell and Regenerative Biology, was published in the November 6 issue of the journal Cell Stem Cell.
The researchers believe this new approach to HIV therapy might be ready for human safety trials in less than five years. However, they pointed out 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 development to be applicable in the areas of the world that have been the hardest hit by the epidemic.
HIV specifically targets T cells, which make up 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 same procedure used to transplant blood stem cells into leukemia patients ― to give rise to HIV-resistant immune systems.
In their Cell Stem Cell paper, Rossi and Cowan showed they could edit β2M out of T-cells and CCR5 out of hematopoietic stem/progenitor cells (HSPCs) efficiently, predictably, and precisely. They further showed that edited HSPCs could go on to produce the normal portfolio of blood and immune cells.
“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. He added 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. 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 1 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.”
According with Harvard Gazzete, what makes this work especially promising is that it may create a way to do for a large number of patients what was done for Timothy Ray Brown, the “Berlin patient.” Physicians in Berlin gave Brown, who was suffering from both HIV/AIDS and leukemia, a transplant of bone marrow harvested from someone with a rare genetic defect that left the person free of the CCR5 receptor. For the six years since he received the transplant, Brown reportedly has been HIV free, and is thought to be the only patient ever “cured” of HIV/AIDS. If successful, the gene therapy treatment proposed by Cowan and Rossi might accomplish the same thing.
Through: Harvard Gazette