Lecture 16: Cancer Genetics and Gene Therapy Flashcards
gene therapy
- the delivery of therapeutic genes into patient’s cells
- goals is to correct genetic disease conditions caused by faulty genes
translational medicine
translating scientific discoveries into effective therapy
what is the criteria for gene therapy?
- the gene or genes involved in causing the disease have been identified
- the gene can cloned or synthesized in the lab
what is the only gene therapy approved for diseases?
somatic cells
-enhancement, germline, and stem cell are not
ex vivo gene therapy
- cells from a person with a genetic condition are removed
- treated in a lab
- translated back
- no immune response rejection
in vivo gene therapy
- therapeutic DNA introduced into affected cells
- the challenge is restricting delivery to desired cells
- off target gene delivery is a problem
viral vectors in gene therapy delivery strategies
DNA viruses, RNA viruses
non-viral gene therapy delivery strategies
cationic polymers, dendrimers, cell penetrating peptides
adenoviruses
- used in early gene therapy trials
- capable of carrying large number of genes
- there is a disadvantage because humans produce antibodies against adenoviruses, which would make the therapy ineffective
how does adeno-associated viruses work as gene vecotrs?
- the vector is DNA
- RNA is translated into protein in the cytoplasm
what are you making in gene therapy vectors?
-AAV particles (gene therapy vectors)
what are the resulting vectors when making gene therapy vectors?
- are non-replicating because they do no have rep or cap genes
- they can infect target tissue and express their genes, but are defective to make more virus particles
rAAV
recombinant AAV, these are replication incompetent
where is cancer largely caused?
somatic cells
-only 5% of cancers are associated with germline mutations
cancer: genetic disease
-genomic alterations with cancer include single-nucleotide substitutions, chromosomal arrangements, amplifications, and deletions
cancer: genetic disease at somatic level
- results from mutated gene products ir abnormally expressed genes
- mutations affect multiple cellular functions
what two fundamental properties do cancer cells have?
- abnormal cell growth and division
- metastatic spread
benign tumors
- result from unregulated cell growth that forms a multicellular mass
- removed by surgery, causing no serious harm
malignant tumors
-results from metastisized cells invading other tissue and causing life threatening problems
clonal origin
all cancer cells in primary and secondary tumors are clonal
-by clonal, this is meaning originated from common ancestral cell that accumulated numerous specific mutations
what does cancer require?
- multistep mutations
- age-related incidence of cancer indicated that cancer develops from accumulation of several mutagenic events in single cell
- incidence of most cancers rises exponentially with age
- independent and random mutations are necessary for cell to become malignant
carcinogens
- cancer causing agents
- delay between exposure to carcinogen and appearance of cancer is an indication of the multistep process
tumorigensis
- development of a malignant tumor
- result of two or more genetic alternations
- progressively release cells from normal controls on cell proliferation and malignancy
interphase
- interval between mitotic division
- cell grows and replicates its DNA
cells that stop proliferating eneter G0
- do not grow or divide but are metabolically active
- cancer cells are unable to enter G0 and cycle continously
- cells in G0 are stimulated to reenter cell cycle by external growth signals
- signal transduction initiates gene expression that propels cell out of G0 and back into cell cycle
G1/S, G2/M, and M checkpoints
- 3 distinct checkpoints where the cell monitors external signals and internal equilibrium
- cells decide whether to proceed to the next stage of the cell cycle
CDKs (cyclin-dependent kinases)
- regulation of cell-cycle progress is mediated by cyclins and cyclin-dependent kinases
- regulate synthesis and destruction of cyclin proteins
proto-oncogenes
genes whose products promote cell growth and division
proto-oncogenes encode
- transcription factors that stimulate expression of other genes
- signal transduction molecules that stimulates cell division
- cell cycle regulators that move cell through cell cycle
oncogenes
- is a proto-oncogene mutated or aberrantly expressed
- has gain-of-function alteration
- contributes to development of cancers
- only one allele needs to be mutated or misexpressed to contribute to cancer
tumor suppressor genes
regulate cell-cycle checkpoints and initiate process of apoptosis
mutated tumor-suppressor genes
- are unable to respond to cell-cycle checkpoints or undergo apoptosis
- this leads to more mutations and the development of cancer
apoptosis
- programmed cell death
- occurs when DNA or chromosomal damage is too severe to repair
- cells halt process through cell cycle
- prevents cancer
- eliminates cells not contributing to final organism
steps in apoptosis
- fragmentation of nuclear envelope
- disruption of internal cellular structures
- dissolution of cell into small, spherical apoptotic bodies
- engulfing of apoptotic bodies by phagocytic cells