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Gene Therapy (1) (Gene Based Therapies (Types (Somatic Gene Therapy…
Gene Therapy (1)
Gene Based Therapies
Types
Gene Expressing Technologies
Gene Silencing Technologies
Somatic Gene Therapy
Transfer DNA section to body cells except reproductive cells
Non-transferrable to future gen
Germline Gene Therapy
Transfer DNA section to reproductive cells
Transferrable to future gen
Cure
Gene Augmentation Therapy
Insert functioning gene into cell with non-functioning gene
Cell functions normally
Gene Inhibition Therapy (Fig 48)
Use blocking gene to block faulty gene in the cell
Cell functions normally
Treat infectious diseases, cancer, inherited disease
Gene Therapy to kill cells
Suicide Gene Concept (Fig 49)
Immunotherapy (Fig 50)
Gene Types
Tumor Suppressor Gene (Fig 47)
Purpose
Directly/Indirectly prevent cell division/apoptosis
Mutation
Cancer
Type
p53 Gene
"Guardian of the Genome"
Block Tumor Formation
Activates proteins to stop cell division & repair corrupted DNA
Retinoblastoma (Rb Gene)
Proto-oncogene
Protein
Stimulate/Enhance Cell Division
Mutation
Oncogene
Protein
Inhibit Cell Death
Examples
PDGF
erb-B
Recombinant DNA Technology
Nucleic Acid Therapy
Possibilties
Insert new functional genes
Correct faulty genes
Antisense Tech
Crisper Cas9 Tech
Stop/Block mutated gene function
RNAi
siRNA
miRNA
Purpose
Rectify Inherited Diseases
Hemophilia
Muscular Dystrophy
Cure Acquired Diseases
HIV/AIDS
Ebola
Cancer
Delivery Systems
RNA Viruses (Retrovirus)
HIV
MuLV
Genetic Material
RNA
Pros
Insert genes into host chromosome
Permanent Effect
Transfer Genetic Info to Daughter Cells
Example
HIV
Cons
Insert Genes Randomly
Needs active dividing host cell
Modified Virus may mutate & cause serious disease
DNA Viruses
Adenoviruses
Non enveloped Particle
Genetic Material
Linear Double Stranded DNA Molecules
Cons
Temporary Gene Expression
Low Efficiency
Multiple Dose Required
Gene does not integrate into host genome
Does not transfer genetic info to daughter cells
Temporary Effect
Pros
Does not need active dividing host cell
Successful Treatment
Functional Protein
Mechanism
Same as Virus
Adeno-Associated Viral Vector (AAV)
Genetic Material
Linear Single Stranded DNA molecules
Insertion at Chromosome 19 of Host Genome
Pros
Non-Pathogenic
Does not trigger immune response
Cons
Infect non-dividing cells like neurons
Low Gene Loading Efficiency
Low Transfection Efficiency
Require Multiple Dose
HSV
Non-Viral Vectors
Liposomes
Naked DNA
Peptide Delivery System
Liposome-Polycation Complexes
Diseases
Huntington's Disease
Progressive Brain Disorder
Uncontrolled movements, emo, inability to think
40 glutamine repeats
Cystic Fibrosis (Fig 45)
Missing CTT Phe-508 DNA bases/Codon from CFTR gene (Fig 46)
Mutations in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene on Chromosome 7
Recessive genetic disease
Both copies
Carrier
1 Mutated Gene Copy
Cancer Development
Endogenous Sources of ROS => Tumor Promotion => Mutations => Cancer
Delivery Method
Viruses (Fig 51)
In Vivo
Genes transferred into cells while still in patient
Ex Vivo
Cells removed from patient => Gene modified in vitro => Cels transferred back into patient
Therapy Methods
Conventional
Agents
Small Molecules
Peptides
Proteins
Agonists
Antagonists
Purpose
Relieve symptoms/target disease
Cons
Effect stops once drug stopped
Pro
No Ethical Issue
Gene
Agents
DNA
RNA
Purpose
Cure disease cause
Pro
Permanent
Passdown to next gen
Germline Gene Therapy
Cons
Major Ethical Issue
Human Genome Project
2003
Single Gene Mutation
Can cause disease like cancer
Clinical Trials
Diseases
Highest: Cancer
Lowest: Inflammatory
Vectors
Highest: Adenovirus
Lowest: Herpes Simplex Virus
Genetic Info
Principle
DNA encodes miRNA => Protein (DNA => RNA => Protein)
Viral Vectors: Mimicking Nature => Replicates by inserting its genes into host cell's genome (Fig 52)