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GKA deel 1 college 5
 

GKA deel 1 college 5

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    GKA deel 1 college 5 GKA deel 1 college 5 Presentation Transcript

    •  
    • Hematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy Cartier, Hacein-Bey-Abina, Von Kalle, Fischer, Cavazzana-Calvo and others Science (2009) 326: 818 – 823
      • Demyelination
      • Defect in ALD protein
        • ATP-binding cassette transporter
        • ABCD1 gene
        • Peroxisomal protein
        • Lipid degradation in oligodendrocytes and microglia
      • Two boys treated
        • HSC-Lentivirus
      Inserted Nov 2009
    • Hematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy Cartier, Hacein-Bey-Abina, Von Kalle, Fischer, Cavazzana-Calvo and others Science (2009) 326: 818 – 823
      • Demyelination
      • Defect in ALD protein
        • ATP-binding cassette transporter
        • ABCD1 gene
        • Peroxisomal protein
        • Lipid degradation in oligodendrocytes and microglia
      • Two boys treated
        • HSC-Lentivirus
      Inserted Nov 2009
    • Hematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy Cartier, Hacein-Bey-Abina, Von Kalle, Fischer, Cavazzana-Calvo and others Science (2009) 326: 818 – 823
      • Demyelination
      • Defect in ALD protein
        • ATP-binding cassette transporter
        • ABCD1 gene
        • Peroxisomal protein
        • Lipid degradation in oligodendrocytes and microglia
      • Two boys treated
        • HSC-Lentivirus
      Inserted Nov 2009
    • Genetische therapiën
      • Anti-sense therapie
      • Triplex-strategie
      • Gentherapie
      • RNAi
      • Gen-repair
        • Via oligonucleotide
        • Via zink-vinger geïnduceerde klieving
    • RNA interference; RNAi Pomerantz 2002, Nature Med 8, 659-660
      • RNA interference, RNAi
        • siRNA
          • Small interfering RNA
      • Sequence-specific
      • Degradation of mRNA
        • Cellular mRNA
        • Viral mRNA (HIV?)
        • Function for the cell?
          • Defense?
          • Control of gene expression
            • Lin4-Lin14
      • Useful for therapy?
    • Different small RNAs Großhans and Filipowicz, Nature 451, 2008, 414-416
      • Inserted 15-2-2008
    • Different small RNAs Großhans and Filipowicz, Nature 451, 2008, 414-416
      • Inserted 15-2-2008
    • Different small RNAs Großhans and Filipowicz, Nature 451, 2008, 414-416
      • Inserted 15-2-2008
    • Can RNAi be a therapy? Stevenson, Nature Rev Imm 3, 2003, 851-858
      • Large dsRNAs (>60 nucleotide pairs) 
        • IFN: interferon response
          • RNaseL
            • Degradation RNA
          • Induction PKR
            • Protein kinase RNA-regulated
          • Shut-off protein synthesis
            • Non-specific
      • DICER: RNase
      • RISC: RNA-induced silencing complex
      Viral (m)RNA
    • HIV life cycle Stevenson, Nature Rev Imm 3, 2003, 851-858
    • siRNA inhibits HIV infection
      • Novina et al. 2002, Nature Med. 8, 681-686
      • HIV binds receptors
        • CD4
        • CCR5 or CXCR4 (chemokine receptors)
      • Targeting RNAi against
        • Cellular mRNAs
          • Required for viral replication
        • Viral mRNAs
          • Incoming RNA
          • Produced mRNA
    • How to make RNA? Stevenson, Nature Rev Imm 3, 2003, 851-858 One promoter
    • How to make RNA? Stevenson, Nature Rev Imm 3, 2003, 851-858 One promoter Two promoters
    • How to make RNA? Stevenson, Nature Rev Imm 3, 2003, 851-858 One promoter Two promoters Viral vector: adeno, HIV
    • Factors influencing effect of RNAi Stevenson, Nature Rev Imm 3, 2003, 851-858
      • Mutation of HIV-RNA
        • Loss of complementarity, required for RNAi
      • Virus in vesicles
      • Viral RNA partly inaccessible
    • Factors influencing effect of RNAi Stevenson, Nature Rev Imm 3, 2003, 851-858
      • Mutation of HIV-RNA
        • Loss of complementarity, required for RNAi
      • Virus in vesicles
      • Viral RNA partly inaccessible
      • How to deliver?
    • Delivery to brain cells Nature 448, 2007, 33-34
      • Use of the acetylcholine receptor to insert dsRNA duplexes
      Kumar et al ., Nature 448, 2007, 39-43, Transvascular delivery of small interfering RNA to the central nervous system Inserted July 10, 2007 ========