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N Engl J Med. 2014 Mar 6;370(10):901-10. doi: 10.1056/NEJMoa1300662.

Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV.

Author information

1
From the Perelman School of Medicine, University of Pennsylvania, Philadelphia (P.T., I.F., M.K., R.G.C., G.B.-S., G.P., W.-T.H., B.L.L., C.H.J.); Albert Einstein College of Medicine, Bronx, NY (D.S.); and Sangamo BioSciences, Richmond, CA (W.W.T., S.Q.W., G.L., S.K.S., R.T.S., M.A.G., G.N., M.C.H., P.D.G., D.G.A.).

Abstract

BACKGROUND:

CCR5 is the major coreceptor for human immunodeficiency virus (HIV). We 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.

METHODS:

We enrolled 12 patients in an open-label, nonrandomized, uncontrolled study of a single dose of ZFN-modified autologous CD4 T cells. 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.

RESULTS:

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<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.

CONCLUSIONS:

CCR5-modified autologous CD4 T-cell infusions are safe within the limits of this study. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00842634.).

PMID:
24597865
PMCID:
PMC4084652
DOI:
10.1056/NEJMoa1300662
[Indexed for MEDLINE]
Free PMC Article
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