The first clinical trial has shown that gene-editing can be safely used in humans to target HIV infections.
Once an HIV infection is established, the only treatment is to use combinations of drugs to suppress active infection; this does not eradicate the virus, and if treatment is stopped then active growth of the virus rapidly resumes. There have been reported successes in eliminating the virus from newborns with rapid anti-viral drug treatment, but none in older people.
Gene or genome editing is a method of gene therapy that precisely inserts, removes or replaces a selected genetic sequence or sequences to a target genome using genetically engineered enzymes to introduce targeted, sequence specific breaks in the target DNA. Typically this would be correcting or ameliorating a genetic defect – for example, providing healthy copies of a disease-associated dysfunctional gene. Technical approaches include the recent CRISPR method and the older zinc-finger nuclease method.
Now for the first time a clinical trial has demonstrated the safe application of zinc-finger nucleases in humans, showing apparent effectiveness in the treatment of HIV infections in 12 people without significant side-effects. This approach built on earlier observations that humans with a natural variant in the CCR5 gene, which encodes the main co-receptor by which HIV enters human immune cells, are protected from infection.
Results published in The New England Journal of Medicine report that researchers inactivated the normal CCR5 genes in immune cells from twelve infected patients receiving highly active antiretroviral therapy (HAART) using engineered a zinc-finger nuclease before reintroducing the immune cells; between 11 and 28% of the re-infused cells incorporated the inactivating mutation.
After four weeks, six of the patients stopped receiving the normal HIV therapy; all showed a slower return to active HIV infection than would be expected. Four remained without therapy for twelve weeks, and of these one one patient did not show detectable virus levels throughout the trial. This individual turned out to be heterozygous for the protective CCR5 delta 32 mutation, which appeared to boost the therapeutic effect of the gene.
Although the trial was small, and the therapy had limited effects and some undesirable side-effects, the demonstration of general safety and apparent proof-of-principle shows promise for the eventual development of related therapies that could reduce or perhaps even remove the need for lifelong, continuous drug treatment to suppress spread of the virus. Researchers have also pointed out that it is a safer and more practical approach than the only current example of successful HIV gene therapy, which involved a complete bone marrow transplant from a donor with the protective genetic variant.