This could be a step toward controlling HIV without the daily use of antiviral drugs. It also marks the first study — published in this week’s New England Journal of Medicine – to report the modification of an exact spot in human DNA, ushering in the age of gene editing.
Researchers used an “editing tool” developed by Sangamo BioSciences of Richmond, Calif. The tool consisted of natural proteins called zinc finger nucleases that recognize specific DNA sequences and can be used like molecular scissors to introduce intentional genetic mutations.
It’s much more specific than the older way of doing gene therapy, which relied on disabled viruses to carry and dump genes randomly into a cells’ DNA.
“The ability to edit the human genome has been a prayer ever since we first understood that genes control biology,” said Sangamo CEO Edward Lanphier, who founded the company in 1995. “But we’ve moved beyond the concept of gene replacement, which was the idea behind gene therapy. Gene editing is much safer and more effective.”
Sangamo is working on zinc finger-based approaches to treat and possibly cure hemophilia, Huntington’s disease, and sickle-cell anemia, which are all caused by a single defective gene. The firm also supplies ready-made and custom-made zinc finger proteins to scientists around the world.
The Penn study, led by gene-therapy pioneer Carl June and funded by both the federal government and Sangam, aimed to recreate the genetic variations in some people who are either partially or completely immune to HIV.
One such gene variant keeps T cells, which are disease-fighting blood cells that HIV attacks, from making a receptor (a sort of cell doorway) that HIV uses to break in and attack the body. About 10% of Caucasians have inherited one copy of this gene variant, making them resistant to HIV infection and about 1% have two copies – one from each parent – making them immune to HIV.
To replicate this invulnerability, June’s team removed T cells from 12 HIV-infected patients who were taking standard antiviral drugs and used the zinc fingers editing tool to delete the doorway receptor gene. The modified T cells were then multiplied and each patient received a transfusion of roughly 10 billion.
To see whether these modified cells might be fighting HIV, the researchers interrupted standard drug therapies for three months in six patients with healthy T cell counts and observed that blood levels of HIV decreased in four of the patients, falling to an undetectable level in one man.
Some of the modified T cells were found to concentrate in the patients’ guts, where HIV builds a stockpile. Current drugs reduce the ability of HIV to reproduce but can’t completely eliminate it from the body because of this reservoir.
“We believe the only effective way to functionally cure HIV is to get the immune system to reduce the reservoir,” Lanphier said.
Whether or not this early effort at gene editing leads to a functional cure for HIV, experts say the gene editing technology is game-changing in the fight against disease.
“Gene therapy had a lot of hype and the expectations were unrealistic; it still has no approved therapy,” said June. “But I think we’re on the threshold. We now know it’s possible to do genetic editing with exquisite precision at levels with therapeutic relevance.”