Jim Riley, a microbiologist at the University of Pennsylvania in Philadelphia, was skeptical at first when he learned 10 years ago that scientists at Sangamo BioSciences wanting to use genome editing technologies to treat patients with HIV.
What was being planned by the Sangamo researchers was indeed remarkable. Their aim was to not only control the symptoms of HIV/AIDS, but to directly change the genes of adults who were HIV positive to remove their susceptibility to the virus. One of main the ways HIV enters immune cells, including helper T cells and macrophages, involves latching onto a cell-surface protein called CCR5 (C-C chemokine receptor type 5). A small percentage of people – about 10% of those of European descent – have a deletion that eliminates 32 nucleotides from the gene that encodes CCR5. The resulting receptor is cut and impossible for the virus to grab. What this means is that homozygous people – those who inherited the mutation from both parents – are basically resistant to the most frequently transmitted strain of HIV.
To reproduce this desirable trait, scientists at the biopharmaceutical company Sangamo based in Richmond, California, have been working with academic researchers all over the United States, including Riley (once he overcame his initiate skepticism) and his team at the University of Pennsylvania. The project utilizes one of the more established tools of genome engineering, ZFN (zinc-finger nuclease) technology. SB-728, Sangamo’s product, carries a set of engineered protein parts called zinc fingers that cohere to certain sites within the CCR5 gene. These zinc fingers are connected to a nuclease enzyme that can cut the DNA. Riley’s team demonstrated in 2008 that SB-728 can specifically and efficiently cut out a chunk of the CCR5 gene in cultured human T cells.
These findings provided teasing proof of concept that such genome editing might supply real protection for patients.
Berlin and yonder
There is a medical precedent for believing that this method will work against HIV. In the 1990s, while studying in Berlin, Germany, US student Timothy Ray Brown became infected with HIV. About 10 years later, he developed acute myeloid leukemia. The situation got even worse when his initial two courses of chemotherapy resulted in kidney failure. Doctors then discontinued his antiretroviral drugs, which resulted in his viral load starting to climb. However, amazingly, it was this combination of HIV and leukemia that was Brown’s salvation.
He received a stem-cell transplant at Charité in 2007, a huge teaching hospital in Berlin. These blood stem cells were carefully chosen for him. Doctors also screened possible donors homozygous for the CCR5 mutation. Following radiation therapy, the blood stem cells received by Brown, and from which his T cells developed, were hence immune to HIV. Brown was soon in remission after a few rounds of treatment. His T cell levels improved and he has stayed disease free without requiring antiretroviral drugs.
Into the clinic
Between 2011 and 2013, researchers used SB-728 to edit genomes of helper T cells received from 12 volunteers who were HIV positive. The cells were then cultivated by the researchers and transplanted back into the participants. All 12 of them experienced an improvement in their T cell count and all of them established a small but stable subpopulation of immune cells with modified CCR5 genes. Some patients saw transient reductions in their viral load after treatment with antiretroviral drugs was suspended to see whether the gene edits worked on their own.
However, the amount of cells that have to have their CCR5 genes modified to keep HIV away is unclear. A totally modified T cell population would be difficult, but it may be possible to have protection even with quite a small proportion of modified cells, according to gene therapy researcher Hans-Peter Kiem, at the Fred Hutchinson Cancer Research Centre in Seattle.
Kiem believes that the vital factor for building immunity against HIV is grafting – the level to which transplanted cells absorb themselves into the tissues of the recipient’s body. Him and his team are separately exploring whether SB-728 might do better if it is applied haematopoietic stem cells, instead of a few varieties of fully developed immune cells.
However, cultivation and modification of stem cells is more difficult than that of T cells. Using stem cells also results in more serious side effects for patients, who will have to have an aggressive course of chemotherapy before treatment.
Hopefully genome editing will have benefits for all sorts of other diseases in the future.