It seems like from a galaxy far, far away, but research published today has demonstrated the safety of a new way to treat HIV by directly editing a patient's cells.
The study, which appears in the New England Journal of Medicine, involved only 12 HIV-positive people, but it is a milestone in HIV research.
CD4 T-cells, or “helper cells,” are the cells targeted by HIV. The subsequent damage to the immune system is what causes AIDS.
For the purposes of the study, scientists extracted such cells from the subjects and 'edited' their genetic makeup to artificially create a type of HIV immunity that has in previous research been identified in about nine percent of people of European descent.
How Did They Do It?
CCR5 is a protein that is expressed on a CD4 cell gene known as Delta 32, and its expression is what allows HIV t o find a cell and infect it.
Scientists have known for some time that people with a mutation on one CCR5 Delta 32 allele have protection against HIV. Those with a mutation on both alleles are believed to be completely immune to the virus.
Timothy Ray Brown, known as “The Berlin Patient,” underwent a stem cell transplant in 2007 to treat acute myeloid leukemia (AML). Doctors discovered that he had a CCR5 Delta 32 mutation on one allele, so they searched for a bone marrow donor who also had the mutation. They found one, and after the transplant Brown was functionally cured of his preexisting HIV infection.
Only one percent of the population is believed to have the CCR5 Delta 32 mutation on both alleles. But researchers at the University of Pennsylvania Penn Center for AIDS Research have ushered in a new era by finding a way to artificially create the mutation on at least one allele.
Pointing the 'Finger' At a Cure
They have been able to do this using artificial enzymes called zinc finger nucleases (ZFNs), explained Bruce L. Levine, associate professor of cancer gene therapy and the director of the Clinical Cell and Vaccine Production Facility at Penn.
He told Healthline that by teaming up with Sangamo BioSciences, developer of the ZFNs, researchers were able to create a technique that worked like “molecular scissors” to insert the desired mutation. “By targeting the Delta 32 portion, you can disrupt the expressions of the CCR5 protein on the surface of the cell, locking out HIV, or removing the doorknob,” Levine said.
When researchers put the modified cells back into the patients, not only did they persist, but viral loads also dropped, even in the four of six patients taken off of life-saving antiretroviral therapy (ART) for three months.
"In the cell therapy and gene therapy community, we've always been believers in what we do or we wouldn't be working on it,” Levine said. “There has been a paradigm shift in biotechnology and pharma to go this way. Up and down the board it's a very different way of delivering a new therapy.”
One patient, who already had a CCR5 Delta 32 mutation on one allele, had a completely undetectable viral load even after being taken off of ART. Per research protocol, he went back on ART, so it is impossible to compare his outcome to that of the Berlin Patient.
One adverse outcome was reported in the study. One patient was taken to the emergency room because he felt ill 24 hours after the injection of the modified cells.
An 'Important First Step'
All of the participants were injected once with 10 billion T-cells between May 2009 and July 2012, with between 11 and 28 percent of the cells believed to be genetically modified. While blood T-cell counts dropped when ART was stopped four weeks after the infusion, the modified T cells disappeared at about one-third the typical daily rate.
Meanwhile, the modified cells continued to be found in gut-associated lymphoid tissue in the intestines, which is known to be a reservoir of HIV infection.
In an accompanying editorial also published today in the New England Journal of Medicine, Dr. Mark Kay of the Stanford University School of Medicine and Dr. Bruce Walker of Howard Hughes Medical Institute at Harvard University called the research an important first step. Further studies demonstrating safety and potential long-term efficacy are needed, they wrote.
“The potential future of gene knockout by ZFNs and other techniques is not restricted to HIV infection. There are now methods that can be used not only to inactivate a gene but also to make specific nucleotide changes in a specific site in the genome and gene addition,” Kay and Walker wrote.
But is it realistic to expect that such therapies will be affordable and widely available anytime soon?
Levine said that many people scoffed when stem cell transplants were first being developed, calling it a “boutique therapy” that would never become common practice.
“A year ago last January, the one millionth stem cell transplant took place," Levine said. "It happened over time. I don't see the impossibility of bringing this type of therapy into wider practice.”