Tailored gene therapy approach could replace drug treatments for HIV patients
February 3, 2013
One of the biggest problems in treating HIV patients is the amount of daily individual medications it takes to keep the virus at bay. In a new study, scientists at the Stanford University School of Medicine have engineered a new approach to tailored gene therapy that they say makes key cells of the immune system resistant to attack from the HIV virus, which may eventually lead to the removal of life-long dependencies on drugs for patients living with HIV.
The drug treatment regime for HIV is intended to block the reception of the virus at different stages of the replication process. Unfortunately, the virus itself is known to mutate and that’s why a selection of medications, known as highly active antiretroviral therapy (HAART), is required to stave off potentially fatal infections. Researchers at Stanford have added to previous experiments by cutting and pasting a series of HIV-resistant genes into the immune cells that are targeted by the virus, known as T-cells, thereby simulating the HAART treatment through genetic manipulation.
Typically, HIV enters T-cells by latching onto one of two surface proteins known as CCR5 and CXCR4. However, a small number of people carry a mutation in CCR5, making them more resistant to HIV. The results of this are exemplified by the now-famous Berlin Patient, a leukemia sufferer with the HIV virus, who received a bone-marrow transplant and was subsequently cured of HIV, thanks to the donor carrying the mutated CCR5 gene.
This new study builds on previous work by scientists at Sangamo BioSciences in California who developed a technique using a protein that recognizes and binds to the CCR5 receptor gene, genetically modifying it to mimic the naturally resistant version. This technique uses a protein that can break up pieces of DNA, known as a zinc finger nuclease, to effectively inactivate the receptor gene.
The Stanford researchers have now used the same nuclease to create a break in the CCR5 receptors' DNA, within which they pasted three genes known to hold back the virus. The technique of placing these genes in one site is known as “stacking.” The study also states that, “Incorporating the three resistant genes helped shield the cells from HIV entry via both the CCR5 and CXCR4 receptors. The disabling of the CCR5 gene by the nuclease, as well as the addition of the anti-HIV genes, created multiple layers of protection.”
This form of tailored gene therapy, which blocks both the CCR5 and CXCR4 has not been achieved before. The stacked “triplet” of anti-HIV genes created an effective barrier of more than 1,200-fold protection for the CCR5 gene and more than 1,700-fold for the CXCR4 (based off an unaltered T-cell), which is a much higher success rate than tests with only one or two alterations. Comparatively, the unaltered T-cell became infected within 25 days.
However, the technique is not without drawbacks. A concern is that creating a break in one part of the cell may lead to an unintended break elsewhere, which may cause cancer or other cell aberrations. The study also says that “It’s possible the cells won’t like the proteins they’re asked to express, and won’t grow.”
Those challenges aside, the news is promising for the development of delivering individually tailored, virus resistant T-cells to an infected patient. Because the method will be on a patient-by-patient basis it will be time consuming, and though it will not kill the virus, it may free patients of the need to take strong antiretroviral medications that keep their immune system from collapsing. The researchers hope to begin clinical trials within three to five years.
The study appears in the Jan. 22 issue of Molecular Therapy.
Source: Stanford School of Medicine