Back in February, I blogged about a patient who received a bone marrow transplant, from an HIV-immune donor, that cured both his leukemia and AIDS.  I mentioned that while bone marrow transplants were impractical as a primary treatment for AIDS, I suggested that perhaps gene therapy tactics could be employed to achieve the same effect.  For the first time, scientists at Sangamo BioSciences have shown that this may actually be possible.

HIV infects white blood cells by latching onto two protein receptors, CD4 and CCR5.  Scientists noticed that people with a defect in the CCR5 gene (a 32-bp deletion) are incapable of making the CCR5 receptor and are highly resistant to HIV infection.  Unlike with other genetic defects, these people appear otherwise healthy.  If an HIV patient’s own white blood cells could be removed, their CCR5 genes mutated, and the cells returned to the body, then the patient would be protected from further infection.  The virus would not be eradicated from the patient’s body, but the HIV would be unable to attack more white blood cells so that the patient’s immune system would remain intact to fight off other infections.

The primary problem with such a technique, however, has been an issue of gene targeting: how do you inactivate the CCR5 gene without disrupting the rest of the genome?  Scientists have found  a pair of proteins that can help them do just that.  Zinc finger proteins are exceptionally good at binding to DNA.  In addition, they can be designed to bind to very specific sequences of DNA.  A type of enzyme, called a restriction endonuclease, can cut DNA.  Scientists have hitched these two protein types together to create the molecular equivalent of a heat-seeking missile:  the zinc fingers home in on and attach to a sequence in the CCR5 gene while the restriction enzyme damages the DNA in that gene only.  Cells come armed with machinery for patching damaged DNA, but the repair process eliminates some of the information needed to make the CCR5 protein.  The end result is a shorter, defective CCR5 protein which cannot guide HIV into the cell.

Scientists at Sangamo BioSciences have used this approach to inactivate the CCR5 gene in a type of differentiated white blood cell called a T cell.  The company has progressed to clinical trials with HIV patients and has so far found that the genetically altered T cells survive and function normally while the amount of virus detected in patients decreases.  Because T cells eventually die, however, the company is also in the process of modifying blood stem cells, called Hematopoietic Stem Cells (HSCs), in much the same way.  If the company succeeds in modifying HSCs, then any new white blood cell made in a patient’s body would be immune to attack—the treatment would need to occur only once for life-long protection to be realized.