Biomedicine Xagena

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People infected with HIV: gene editing of CCR5 in autologous CD4 T cells

CCR5 is the major coreceptor for human immunodeficiency virus ( HIV ). Researchers have investigated whether site-specific modification of the gene ( gene editing ), in this case, the infusion of autologous CD4 T cells in which the CCR5 gene was rendered permanently dysfunctional by a zinc-finger nuclease ( ZFN ), is safe.

Twelve patients in an open-label, nonrandomized, uncontrolled study of a single dose of ZFN-modified autologous CD4 T cells, were enrolled.

The patients had chronic aviremic HIV infection while they were receiving highly active antiretroviral therapy. Six of them underwent an interruption in antiretroviral treatment 4 weeks after the infusion of 10 billion autologous CD4 T cells, 11 to 28% of which were genetically modified with the ZFN.

The primary outcome was safety as assessed by treatment-related adverse events. Secondary outcomes included measures of immune reconstitution and HIV resistance.

One serious adverse event was associated with infusion of the ZFN-modified autologous CD4 T cells and was attributed to a transfusion reaction.

The median CD4 T-cell count was 1517 per cubic millimeter at week 1, a significant increase from the preinfusion count of 448 per cubic millimeter ( P less than 0.001).
The median concentration of CCR5-modified CD4 T cells at 1 week was 250 cells per cubic millimeter. This constituted 8.8% of circulating peripheral-blood mononuclear cells and 13.9% of circulating CD4 T cells.

Modified cells had an estimated mean half-life of 48 weeks.

During treatment interruption and the resultant viremia, the decline in circulating CCR5-modified cells ( −1.81 cells per day ) was significantly less than the decline in unmodified cells ( −7.25 cells per day ) ( P=0.02 ).

HIV RNA became undetectable in one of four patients who could be evaluated. The blood level of HIV DNA decreased in most patients.

In conclusion, CCR5-modified autologous CD4 T-cell infusions are safe within the limits of this study. ( Xagena )

Tebas P et al, N Engl J Med 2014; 370:901-910