Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV
| Autor: | Gwendolyn Binder-Scholl, Ronald G. Collman, Michael Kalos, Ian Frank, Philip D. Gregory, Geoff Nichol, Bruce L. Levine, S. Kaye Spratt, Dale G. Ando, Michael C. Holmes, Pablo Tebas, Winson Tang, Gabriela Plesa, Shelley Wang, Gary Lee, Carl H. June, David Stein, Martin Giedlin, Wei-Ting Hwang, Richard T. Surosky |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Adult
CD4-Positive T-Lymphocytes Male Lymphocyte Transfusion Blood transfusion Receptors CCR5 medicine.medical_treatment HIV Infections Blood Transfusion Autologous Immune system Antiretroviral Therapy Highly Active Medicine Humans Lymphocyte Count Adverse effect business.industry fungi Rectum HIV General Medicine Genetic Therapy Middle Aged Viral Load Zinc finger nuclease Combined Modality Therapy Genetically modified organism Clinical trial Immunology DNA Viral RNA Viral Female business Viral load |
| Zdroj: | The New England journal of medicine. 370(10) |
| ISSN: | 1533-4406 |
| Popis: | 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.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.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 (P0.001). 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.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.). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|