Please enable JavaScript.

Coggle requires JavaScript to display documents.

GENE DELIVERY (Regulation/ FDA (Pre-clinical Trial (Animal selection…

- - - - Pharmacological response to expressed gene
      - Sensitivity of the species to the biological actions
      - Viral vector: permissiveness/susceptibility to
        infection by, and replication of vector.
      - animal models of disease
    - - toxicological study
        
        Vector-Specific Considerations
        
        Non-viral vector
        
        Replication-deficient viral vectors
        
        Replication-competent oncolytic vectors
        
        Microbial vectors used for gene therapy
        
        Overall Safety Considerations
        
        Transgene Considerations
        
        local versus systemic expression
        
        level and duration of expression
        
        acute versus chronic effects
        
        Ex vivo Genetically Modified Cells
        
        Biodistribution Considerations
      - pharmacological study
        proof-of-concept
        
        effective dose range
        
        route of administration / targeting efficiency
        
        timing of product administration
        
        dosing schedule
        
        Characterization of the putative MOA or hypothesized biological activities of the investigational CGT product
    - - change in manufacturing
      - toxicity study
  - - - Dose Exploration (capture effective biologic activity rather than dose-limiting toxicity)
      - Feasibility of administration/ manufacturing
      - Activity Assessments
        
        potential efficacy, including specialized assessments of gene expression, immunologic changes and standard tumor responses
    - - prolonged biologic activity i(ntegration of the therapeutic gene into the host genome,
        
        duration of safety assessments
      - Assess potential delay risk
        
        Q2. preclinical study results show persistence of vector sequences
        
        Q1. duration of safety assessments
        
        Q3. Are vector sequences integrated
        
        Q4. vector have potential for latency and reactivation
- - - - Severe Combined Immune Deficiency (ADA-SCID)
      - Chronic Granulomatus Disorder (CGD)
    - - Hemophilia
      - Thalassemia
      - Sickle cell disease
  - - - Suicide gene therapy
        
        cytosine deaminase/5-fluorocytosine
        
        herpes simplex virus/ganciclovir gene
        
        Adenovirus Vector
        
        Modification: first-generation/ E1/E4-deleted
        
        increased vector doses due to decreased contamination with high levels of replication-competent adenovirus were performed. Link Title
      - Immunotherapy gene therapy/ Cytokine
        
        activate the immune system
        
        Pros: lower toxicity, higher local concentrations, much longer persistence of the cytokine, and advantages relating to cytokine secretion by the tumor cell itself.
        
        R: systemic
      - Corrective gene therapy
        therapeutic genes into cancer cells to adjust the deranged gene profile and consequently moderate or stop cell proliferation
        
        Replacement of Tumor Suppressors
        (use a gene therapy vector to encode a tumor-suppressor protein in tumor cells that is mutated or absent)
        
        Tumor-based p53 therapy
        (p53 inactivation found in 50% cancer case)
        Link Title
        
        Targeting p53 itself
        
        reintroduce wild-type p53
        
        replication-defective adenovirus vector
        
        5 more items...
        
        retrovirus-mediated vector
        
        1 more item...
        
        To eliminate mutant p53
        
        E1B-deleted adenovirus vector (ONYX-015)
        
        1 more item...
        
        Targeting Other p53 Family Members
        
        targeting p73 and p63
        
        adenovirus-mediated vector
        
        1 more item...
        
        FUS1 replacement.
        
        miRNAs
        short, non-coding endogenous RNA, which silence the gene functions by targeting messenger RNA (mRNA) through degradation or translation repression
        
        Benefit: miRNAs can also target the tumor-promoting stromal cells
        
        let-7
        
        miR-15a/16
        
        miR-17/20
        
        miR-221/222
        
        miR-34 families
        
        Non-viral vector
        Pros: ability to condense miRNA & non-specifically enter the cell
        
        Liposomes
        
        Cons: toxicity, nonspecific uptake, and unwanted immune response, inefficiency
        
        6 more items...
        
        control of their molecular composition, simplified manufacturing, modification and analysis, tolerance for cargo sizes, and relatively lower immunogenicity
        
        Polyethylenimine (PEI)
        
        polyurethane-short branch polyethylenimine (PU-PEI)
        
        2 more items...
        
        Dendrimers
        
        Pros: defined architecture and a high ratio of surface moieties to molecular volume
        
        poly(amidoamine) (PAMAM) >> more efficiency
        
        Poly(lactide-co-glycolide) (PLGA)
        
        Pros: allow the release of miRNA over time; can protect nucleic acids from degradation, achieve high loading capacities, and afford multiple surface modifications
        
        penetratin modified PLGA
        
        2 more items...
        
        nona-arginine modified PLGA
        
        2 more items...
        
        Natural polymers
        
        Atelocollagen
        
        2 more items...
        
        protamine
        
        1 more item...
        
        Inorganic materials
        
        Pros: monodispersed particle size and good optical properties, high payload, low cytotoxicity and robust miRNA transfection capacity
        
        R: systemic
        
        silica-based nanoparticles
        
        1 more item...
        
        RGD modified ultrasmall
        magnetic nanoparticles
        
        1 more item...
        
        Viral Vector
        
        lentiviruses
        
        R: systemic
        
        Cons: integrate their own reverse transcribed DNAs into the host cellular genome, which may lead to insertional mutagenesis and activation of oncogenic pathways.
        
        adenoviruses/ AAV
        
        Pros: keep their own genomes in episomal form. less toxicity
        
        exosomes (nano-sized lipid vesicles, produced and released by virus-infected cells)
        
        pros: increased targeting efficacy
        
        Cons: immunogenic and more difficult to scale up manufacturing
      - Modulation of resistance gene therapy
      - Anti-angiogenic Gene therapy
      - Toxin Gene Therapy
- - - - Retrovirus (RV)
      - Lentivirus (LV)
      - Adenovirus (AV)
      - Adeno-associated virus (AAV)
      - Herpes simplex virus (HSV)
      - Human foamy virus (HFV)
      - Pox virus (PV)
      - Alphavirus
    - - Physical
        
        Naked DNA
        
        Gene gun
        
        Electroporation
        
        Hydrodynamic
        
        Ultrasound
        
        Magnetofection
      - Chemical
        
        Cationic liposomes
        
        Cationic polymers (PLL)
        
        Cationic polymers (PEI)
    - - deliver gene to a specific cell type
      - accommodate foreign genes of sufficient size
      - achieve the level and duration of trans-genic expression sufficient to correct the defect
      - non-immunogenic and safe
- - - - surgical
      - percutaneous
      - US and computed tomography guided
      - catheters
      - intratumoral injection
      - pros: higher bioavailability, reduced toxicity, good fo readily accessible primary tumors such as melanoma, breast cancer or cervical cancer.
        Link Title