LA JOLLA, California — Geneticists have been able to modify the immune system to confer resistance to HIV infection.

The technique involves harvesting a patient's T-cells, using genome-editing techniques to disrupt the gene that controls the receptor used by HIV to infect those cells, and returning the modified cells to the patient, Fyodor Urnov, PhD, from Sangamo BioSciences in Richmond, California, explained here at the Future of Genomic Medicine VIII.

The hope is that the edited cells will establish a permanent reservoir of HIV-resistant immune cells, he said.

In effect, the therapy mimics the natural mutation that confers HIV resistance in some people. The mutation came to light when a man named Timothy Brown, known as "the Berlin patient," was apparently cured of HIV infection after a bone marrow transplant from a donor who had the mutation.

"You start with a naturally occurring variation, and then you aim to recapitulate it to create a disease-protective genotype and then a phenotype in a clinical setting," Dr Urnov said.

He presented updated data from a phase 2 trial, the early results of which were published in the New England Journal of Medicine (2014;370:901-910). In the study, the researchers edited T-cells to modify the gene that encodes for CCR5, the coreceptor exploited by HIV to infect immune system cells.

I'm thrilled to report that we have done this in more than 70 individuals, and the treatment has been well tolerated so far.

With an established genome-editing technique, the team used DNA-snipping enzymes — called zinc-finger nucleases — to mimic the naturally occurring CCR5-delta32 mutation, which causes the expression of a truncated and nonfunctioning form of the CCR5 protein.

The targeted section of DNA cleaved by the zinc-finger nucleases then undergoes a self-repair process, or nonhomologous end joining, leaving behind a T-cell with a nonfunctioning but otherwise healthy form of CCR5. The modified autologous cells are then reinfused into the patient.

"I'm thrilled to report that we have done this in more than 70 individuals, and the treatment has been well tolerated so far. I'm also delighted to report that the genome-edited cells persist over time," Dr Urnov said. "We have observed persistence of the cells in our subjects out to 4 years."

They saw a lasting increase in T-cell counts, even after a planned interruption of antiretroviral therapy. In one patient, the viral load decreased to below the level of detection even before the resumption of antiretrovirals.

"I can now disclose that we have observed long-term viral control in four subjects," Dr Urnov reported.

The team is using the same genome-editing technique to modify hematopoietic stem cells ex vivo, with the goal of treating hemoglobinopathies such as sickle-cell anemia and transfusion-dependent beta-thalassemia.

But there are concerns about the unintended consequences of genome editing.

Frankenstein's Mosaic?

"If you're going insert some gene changes — let's say to reduce a hemoglobinopathy in bone marrow cells or cystic fibrosis pulmonary cells — what happens to the rest of the cells throughout the body? Are they affected in some way, or is the insertion only temporary?" Irwin Jacobs, MD, a retired internist from Del Mar, California, asked after the presentation.

Dr Urnov acknowledged that genetic therapy creates genetic mosaics.

If there are immunologic or physiologic ramifications, we need to monitor and mitigate them should they become an issue.

"I think it's unequivocally the case that we have created a mosaic human being, which is kind of striking. This is something we have to be conscious of. If there are immunologic or physiologic ramifications, we need to monitor and mitigate them should they become an issue," he said.

Some patients who have received therapeutic bone marrow transplants have only partial engraftment, with only about 25% of their bone marrow coming from the donor, yet they remain disease-free for decades, Dr Urnov reported.

"If a human being can live for a decade with only 25% of her or his bone marrow being genetically cured and be disease-free, it gives us confidence that should we obtain such an outcome with genome editing, this chimeric situation will be manageable," said Dr Urnov.

The work described by Dr Urnov is supported by Sangamo BioSciences, and Dr Urnov is an employee of the company. Dr Jacobs has disclosed no relevant financial relationships.

Future of Genomic Medicine (FoGM) VIII. Presented March 6, 2015.