CRISPR, the gene-editing technique, went 1-for-2 in a real world tryout, showing safety and successful engraftment of edited cells in a patient with HIV infection, but with no clinical benefit, researchers said.
Hematopoietic stem and progenitor cells edited with CRISPR-Cas9 technology were successfully transplanted into a 27 year-old man, and even showed evidence of replication, reported Hongkui Deng, PhD, of Peking University in China, and colleagues, writing in a brief report in the New England Journal of Medicine.
But the transformed cells remained a minority in the patient’s bone marrow — less than 10% — and viral rebound was seen when antiretroviral therapy was stopped, they noted.
HIV can be eradicated following allogeneic transplantation with hematopoietic stem and progenitor cells with a CCR5 mutation, the authors said, similar to the “Berlin patient” and the more recent “London patient.” Both achieved sustained HIV remission following allogeneic hematopoietic stem-cell transplantation.
In this study, the male patient had both HIV infection and acute lymphoblastic leukemia. A donor was selected who was human leukocyte antigen (HLA) compatible, and the donor cells were edited with CRISPR to knock out the CCR5 gene, which encodes a HIV coreceptor that allows viral entry into host cells. Gene-editing efficiency of the stem cells and progenitor cells was 17.8%, the authors noted.
Deng and colleagues said that after 19 months, the patient’s leukemia was in remission and had achieved full donor chimerism, and that the patient continues to receive ART for HIV infection.
‘Positive and Negative Study’
Both the London and Berlin patients received stem cell transplants from donors with CCR5 mutations, which researchers noted as being key to their successes. But neither of those cases involved using CRISPR gene-edited cells, said Satish Pillai, PhD, of the University of California San Francisco, who was not involved with the research.
Pillai described the study by Deng and colleagues as both a positive and negative study — negative for the field of HIV cure research, as the patient did not achieve HIV cure, but “a huge step forward” for the CRISPR field.
“One huge question floating around in the field is that CRISPR is a very powerful tool to use in the laboratory, but does it really have a clinical future,” Pillai told MedPage Today. “This may open the floodgates to show that CRISPR-Cas9 gene editing is clinically relevant and clinically applicable. It’s a bigger story for the gene-editing field than it is for the HIV field.”
While the procedure did not cure or make much of an impact in the patient’s HIV, Pillai pointed out that data suggested that “no harm was conferred to an individual when you engraft CRISPR gene-edited cells.”
Furthermore, he noted that 19 months later, the authors continued to see evidence of CRISPR cells, suggesting they don’t have “a massive survival disadvantage,” though they did not become dominant. Pillai also pointed out that the authors found “bona fide evidence of differentiation” — meaning that the gene-edited precursor cells were able to produce new cells needed to do work throughout the body. There was also no evidence of “off-target” effects, meaning no additional mutations.
“One of the biggest concerns associated with CRISPR is even if you get rid of the CCR5, it will induce mutations where you don’t want them,” Pillai noted, adding that based on this data, there was no concrete evidence of off-target editing.
Pillai also noted the low efficiency of the gene editing, less than 20%, and speculated that if the efficiency was higher, off-target effects could have occurred. He also cited the low efficiency as being a major limitation of the study.
An accompanying editorial by Carl June, MD, of the University of Pennsylvania in Philadelphia, also highlighted the “rapid translation of advances in basic science to phase 1 trials.” He said that experiments at his institution with genome-edited CD4 T cells required 5 years from proof-of-concept experiments in animals to trials involving humans. However, it has only been 2 years for this Chinese trial since the first animal studies.
“This may be an indication that the regulatory environment in China permits more rapid translation than that in the United States,” June wrote. “In a larger sense, it is likely that the time frame for the developmental cycle for engineered cellular therapeutics will be shorter than the traditional pharmacuetical development timescale.”
June added that other techniques for HIV eradication may be more “complementary or more scalable,” such as using CRISPR-Cas9 gene-editing to excise HIV proviral DNA from the host genome in the hopes of eliminating the latent reservoir.
The authors disclosed no conflicts of interest.
June disclosed being the scientific founder of Tmunity Therapeutics, a biotech dedicated to developing engineered T cells for therapy of cancer, infections (including HIV), and autoimmunity. He has founders stock but no income from Tmunity.