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Hematopoietic stem cell based gene therapy for HIV diseases

Hematopoietic stem cell based gene therapy for HIV diseases. Dong Sung An, M.D., Ph.D Associate professor UCLA School of Nursing UCLA AIDS Institute. Long-term goals Advance stem cell based gene therapy research. Develop a new therapy for cure for HIV infected individuals.

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Hematopoietic stem cell based gene therapy for HIV diseases

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  1. Hematopoietic stem cell based gene therapy for HIV diseases Dong Sung An, M.D., Ph.D Associate professor UCLA School of Nursing UCLA AIDS Institute

  2. Long-term goals • Advance stem cell based gene therapy research. • Develop a new therapy for cure for HIV infected individuals.

  3. Limitations in the current treatment for HIV infection • No cure. • Rapid rebound of viremia if patients stop medication. • Everyday life long medication • Treatment adherence is difficult. • Side effects. • Medication costs ($100,000-$400,000 for one patient’s life). • Emergence of multi-drug resistant HIVs. • Limited treatment access world wide. • No vaccine

  4. A Man is Cured of AIDS Photo Credit: http://pozmagazine.tumblr.com/

  5. HIV entry into CD4 T lymphocytes is mediated by the chemokine CCR5 receptor

  6. Natural HIV resistance by CCR532/32 mutation CCR5 32/32 homozygous mutation 1% in Caucasian population No CCR5 expression Naturally protected from HIV-1 infection

  7. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation Hutter et.al. N Engl J Med. 2009 Feb 12;360(7):692-8. Acute Myeloid Leukemia Patient (HIV+) CCR5-32/ 32 BM Donor (HIV-) Bone Marrow transplant This “Berlin Patient” was cured from HIV. Nearly 100% replacement with the CCR5 negative donor cells. HAART was discontinued after BM transplant. HIV RNA and DNA became undetectable at 68 days post-transplant and remained negative for 5 years. http://www.nytimes.com/1998/06/21/magazine/the-berlin-patient.html?pagewanted=all

  8. A novel HIV cure therapyDevelop a hematopoietic stem cell based gene therapy for long term control or HIV cure by a single treatment

  9. Develop anti-HIV gene therapy strategies using autologous hematopoietic stem cells

  10. RNA interference (RNAi) siRNA (20nt) CCR5 mRNA AAAAn RNAi Induce sequence specific mRNA degradation Remove CCR5 from cell surface Inhibit HIV infection

  11. Stable CCR5 knock down by RNAi to confer resistance to R5 tropic HIV-1 infection CCR5 Lentiviral vector CCR5 mRNA shRNA Qin XF, An DS, Chen ISY, D Baltimore, PNAS, 2003

  12. Modeling RNAi-mediated CCR5 knockdown in NOD/SCID humanized BLT mouse CCR5 shRNA (EGFP) Irradiation NOD/SCID Hu BLT mouse Human CD34+ Stem cells No shRNA (mCherry)

  13. Efficient CCR5 down regulation in EGFP+ CD4+ T cells in the humanized BLT mouse model Thy/Liv Bone Marrow Spleen Lymph Node Lung Small Intestine LPL CCR5 EGFP mCherry Shimizu. S et. al. Blood 2010

  14. Selective advantage of EGFP+ CCR5 knock downCD4+ T cells in peripheral blood CCR5 shRNA no shRNA CCR5 tropic HIV-1 HIV-1 NFNSX SL9 (R5) HIV-1 NL4-3 (X4) Unpublished

  15. Mr. Timothy Brown “Berlin Patient” The man was cured of HIV I will I promise to develop a cure therapy for HIV patients!

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