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24 Cards in this Set

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What is gene replacement therapy?
The replacement of a defective gene w/ a normal copy of the same gene. Tech diff to achieve b/c targeted insertion is inefficient
What is gene augmentation theray?
The transfer of a normal copy of a gene into a cell that has a defective copy of the gene. Mucheasier to achieve b/c targeted insertion is inefficient
What is gene regulation therapy?
The use of antisense DNA oligonucleotides, small inactivating RNA (siRNA) or shall hairpin (shRNA) to inactivate specific mRNA. Organ or tissue specific inactivation of a particular mRNA is hard to achieve
What are some candidate diseases for gene therapy?
Genetic: SCID, hemophilia, CF, thalassemias, sickle cell,inherited emphysema. Acquired: Cancer, Parkinson's, Alzheimer's, atherosclerosis, asthma)
Approaches to gene transfer?
ex vivo: cells w/ defective gene removed form patient, gene transferred into cells, cells transplanted back into patient. in vivo: gene transfer directly into patient
Vehicles for gene transfer?
Viral vectors (most common) & non-viral
Advantages & disadvantages for viral vectors?
Advantages: effeciency, targeting specificity. Disadvantages: difficult to prepare, limit on size of gene, immunogenic
Charac of retrovirus as vector
23%. 7kb insert, used ex vivo. Advan: stable integration & efficient. Disadvan: infects dividing cells only & random integration
Charac of lentovirus as vector
0.8%. 7kb insert, HIV. Advan: No host immune response, stable integration. Disadvan: not widely used
Charac of herpesvirus as vector
3.2%. 150kb insert. Target neuronal cells. Advan: infects non-dividing cels, large genome. Disadvan: not widely used, possible expression latency
Charac of adenovirus as vector
25% Most commonly used, 30kb insert. Advan: easy to prepare, infects nondividing cells. Disadvan: doesn’t integrate into host genome, stim immune response.
Charac of Adeno-assoc virus as vector
4%. 4.5kb insert, stable integration, prefers chrom 19. Advan: stable integration & non-pathogenic. Disadvan: difficult to prepare & small genome
Charac of non-viral vectors?
naked DNA, liposomes, 26% of clinical trials
Advantages & disadvanages for non-viral vectors?
Advan: easy to prepare, not immunogenic, no limit on size of gene. Disadvan: lack of targeting specificity
Process to prepare vial vector?
Remove viral genes-> insert therapeutic gene w/ promoter & other reg of expression-> package & prolif in mamalian cell line-> purify viral vector-> treat patient
Disease symptoms & genetic of CFTR?
Most common fatal auto recessive disease in whites. Inc viscosity of secretions. Most common defect is 3 nucleotide deletion-> loss of single AA (delta508). Chrom 7
Status if CF gene therapy?
Normal copies of CFTR will correct CF cell in culture-> 1st gene therpay in humans-> 9 CF gene therapy centers-> 5 clinical trials (3 liposomes, 1 adenovirus, 1 AAV)-> 2 Phase II trials (AVV vectors improves ling fcn)
Future of CF gene therapy?
Modify therapy to prevent immune response, improve vectors, extend effects of treatment, & expand therapy to other organs
Types of hemophilia?
Hem A: x-linked, FVIII deficiency. Hem B: X-linked, FIX deficiency (most common)
Charac of hemophilia?
Uncontrollable bleeding & joint damage. Severe (<1% normal clottinf factor): Treated w/ wkly injections of blood proteins (expensive). Can get Hepatitis C or HIV. Moderate: 1-5% clotting, needs fewer injections
Status of hemophilia gene therapy?
FVII (A) & FIX (B) genes cloned. Successful in animals but FVIII I higher antigenic. Phase II & III trial for FIX (AAV)-> inc circ FIX & required fewer injects for 6mths
Future of hemophilia gene therapy?
Improve vectors, reduce immunogenic response (esp FVIII), determine best admin rout & target cell
Protocal types w/ most approved clinical trials?
Cancer, vascular disease (atherosclerosis), mongenic (CF, SCID), & infectious (HIV)
1st commercial gene therapy product?
Gendicine (2005)-AV serotype expresses p53-> treat head & neck squamous cell carcinoma