'Gene editing' shows promise as HIV therapy

New technology allows safe build-up of army of modified T cells to repel virus.

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HealthDay News -- Immune cells of HIV positive patients can be safely genetically engineered to resist infection, decreasing the viral loads in some patients no longer taking antiretroviral drugs and even dropping the viral load to undetectable levels in others, study findings indicate.

The treatment approach, dubbed "gene editing," is an attempt to mimic the natural resistance to HIV demonstrated in patients with the delta32 gene deletion for CCR5, a molecule the virus uses to enter target cells.

Although the process was safe, most patients who then stopped HIV treatment saw a relapse in the virus, Pablo Tebas, MD, from the University of Pennsylvania in Philadelphia, and colleagues reported in the New England Journal of Medicine.

The open-label study involved 12 patients with HIV, in whom the virus was completely suppressed by highly active antiretroviral therapy. The researchers removed CD4-positive T cells from the patients and used what are called zinc-finger nucleases (ZFN) to edit the cellular genome.

All participants got an infusion of 10 billion of their own modified T cells. Four weeks after infusion, six of the patients then underwent an interruption in antiretroviral treatment (cohort one) and the other six remained on treatment to serve as a control group (cohort two).

At week one, the median CD4 T-cell count was 1,517 cells/mm³, which was significantly increased from the preinfusion count of 448 cells/mm³ (P<0.001).

At week one, the median CCR5-modified CD4 T-cell count was 250 cells/mm³, which constituted 8.8% and 13.9% of circulating peripheral-blood mononuclear cells and circulating CD4 T cells, respectively.

The modified cells had an estimated half-life of 48 weeks. The decline in circulating CCR5-modified cells was significantly less than that of unmodified cells during treatment interruption and the resultant viremia.

Most of the patients who stopped patients developed HIV viremia, with the exception of one patient, who was later found to have had one copy of the delta32 mutation previously. People who naturally inherit two copies of the mutation are almost completely immune to HIV, the researchers noted.

In this patient, HIV viral load remained undetectable for several weeks, then spiked to 6,247 copies/ml, before declining below the level of detectability by the time therapy was re-started.

In most patients, the blood level of HIV DNA decreased. Furthermore, in these patients the median decline in the modified cells was about 1.81 cells per day, significantly less than the 7.25 unmodified cells that were lost daily (P=0.02).

There was one serious adverse event that was associated with ZFN-modified autologous CD4 T-cell infusion, which was attributed to a transfusion reaction.

"Our study supports the feasibility of targeted genome editing to introduce a disease-resistance allele," the researchers wrote.

In an accompanying editorial, Mark Kay, MD, PhD, of Stanford University School of Medicine in Stanford, Calif. and Bruce Walker, MD of Massachusetts General Hospital in Boston, called the study "an important step forward," but cautioned that more study is needed to determine the treatment's potential clinical utility.

References

  1. Tebas P et al. N Engl J Med 2014; 370: 901-910.
  2. Kay M, Walker BD. N Engl J Med 2014; 370: 968-969.
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