Seminar Gentherapie SS 2011 Somatische Gentherapie und

Seminar Gentherapie SS 2011 Somatische Gentherapie und

Seminar Gentherapie SS 2011
Somatische Gentherapie und genetische Immunisierungen
1. Üb 15.04.2011
Übersicht Gentherapie, molekularbiologische Grundlagen, Hilfsmittel der
Gentherapie
2. Gh 29.04.2011
Retrovirale Vektoren
• Blaese RM 1995 - T Lymphocyte-Directed Gene Therapy for ADA SCID -- Initial
Trial Results After 4 Years.
• Ott MG 2006 - Correction of X-linked chronic granulomatous disease by gene
therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or
SETBP1.
• Mitsuyasu RT et al. Phase 2 gene therapy trial of an anti-HIV ribozyme in
autologous CD34+ cells Nat Med. 2009 Mar;15(3):285-92
3. St
6.05.2011
HIV und Lentivirale Vektoren
• Luo et al.: Engineering human hematopoietic stem/progenitor cells to produce a
broadly neutralizing anti-HIV antibody after in vitro maturation to human B
lymphocytes Blood 2009 113: 1422-1431
• ter Brake O et al. Lentiviral vector design for multiple shRNA expression and
durable HIV inhibition. Mol Ther. 2008 Mar;16(3):557-64.
• Levine BL et al. Gene transfer in humans using a conditionally replicating
lentiviral vector. Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17372-7.
4. Tb 13.05.2011
Adenovirale Vektoren
• Roberts DM - Hexon-chimaeric adenovirus serotype 5 vectors circumvent preexisting anti-vector immunity. Nature 2006 May 11;441(7090):239-43
• Freytag et al.: Phase I study of replication-competent adenovirus-mediated double
suicide gene therapy for the treatment of locally recurrent prostate cancer. Cancer
Res. 2002 Sep 1;62(17):4968-76
• Khuri FR et al.: A controlled trial of intratumoral ONYX-015, a selectivelyreplicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients
with recurrent head and neck cancer. Nat Med 2000 Aug;6(8):879-85.
5. Gh 20.05.2011
Nicht-virale Gentransfersysteme
• Hojman P et al. Sensitive and precise regulation of haemoglobin after gene transfer
of erythropoietin to muscle tissue using electroporation Gene Therapy (2007) 14,
950–959
• Zhang G et al. Tissue specific cytotoxicity of colon cancer cells mediated by
nanoparticle-delivered suicide gene in vitro and in vivo Clin Cancer Res. 2009 Jan
1;15(1):201-7
6. St
27.05.2011
Hilfsmittel der Gentherapie; Wirkmechanismen
• Goyenvalle A et al.: Rescue of Dystrophic Muscle Through U7 snRNA-Mediated
Exon Skipping. Science: 306: 1796-99.
• Samakoglu et al., A genetic strategy to treat sickle cell anemia by coregulating
globin transgene expression and RNA interference Nat Biotechnol 24:89-94.
• Hanna J et al. Treatment of sickle cell anemia mouse model with iPS cells
generated from autologues skin. Science 318,1920 (2007)
7. Tm 10.06.2011
Gentherapeutische Ansätze zur Therapie von Tumorerkrankungen
• Klein C et al.: Comparative Analysis of Genetically Modified Dendritic Cells and
Tumor Cells as Therapeutic Cancer Vaccines. JEM 2000, 1699-1708.
• Dossett ML et al. Adoptive immunotherapy of disseminated leukemia with TCRtransduced, CD8+ T cells expressing a known endogenous TCR. Mol Ther. 2009
Apr;17(4):742-9
8. Tm/Gh
24.06.2011
weitere virale Vektoren (HSV-1, AAV, MVA)
• LaVail MM et al.: Ribozyme rescue of photoreceptor cells in P23H transgenic
rats: Long-term survival and late-stage therapy. Proc.Natl.Acad.Sci. 2000;
97:11488-93.
• Mineta T et al.: Attenuated multi-mutated herpes simplex virus-1 for the treatment
of malignant gliomas. Nat Med 1995 Sep;1(9):938-43.
9. Tb 01.07.2011
Genetische Immunisierungsstrategien
• Hansen SG et al. Effector memory T cell responses are associated with protection
of rhesus monkeys from mucosal simian immunodeficiency virus challenge. Nat
Med. 2009 Mar;15(3):293-9
• Barouch DH et al.: Control of Viremia and Prevention of Clinical AIDS in Rhesus
Monkeys by Cytokine-Augmented DNA Vaccination. Science 290: 486-492.
• Buchbinder et al.: Efficacy assessment of a cell-mediated immunity HIV-1
vaccine: a double-blind, randomized, placebo-controlled, test-of-concept trial.
Lancet 2009; 372: 1881-1893
10. Gh 8.07.2011
Risiken der Gentherapie
• Raper SE et al.: A Pilot Study of In Vivo Liver-Directed Gene Transfer with an
Adenoviral Vector in Partial Ornithine Transcarbamylase Deficiency. Hum Gene
Ther 2002 Jan 1;13(1):163-75.
• Cavazzana-Calvo M et al.: Gene Therapy of Human Severe Combined
Immunodeficiency (SCID)-X1 Disease. Science 288: 669-672.
Üb= Überla
Tb= Tenbusch
St= Stang
Tm= Temchura
Gh= Ghulam