Download gene therapy in medicine

GENE THERAPY IN AIDS
PRESENTED
BY
PAIROAJ VONGHATHAIPAISARN
MASTER DEGREE STUDENT
OF
MAHIDOL UNIVERSITY
CONTENT
-INTRODUCTION
-GENE THERAPY IN MEDICINE
-GENE THERAPY IN AIDS
-GENE DELIVERY
-CONCLUSION
GENE THERAPY IS A TREATMENT OR
PREVENTION OF DISEASE BY GENE
TRANSFER
EDWARD TATUM GIVE THIS CONCEPT
SINCE 1966
GENE THERAPY IN MEDICINE
-POTENTIAL REVOLUTION IN MECICINE
-AIMED AT TREATING OR ELIMINATING THE
CAUSES OF DISEASE
GENE THERAPY IN MEDICINE
-ORIGINALLY WAS ENVISIONED AS A MEANS TO
TREAT DISEASES ARISING FROM SINGLE GENE
DEFECTS
-FAILURE TO SYNTHESIZE A PARTICULAR
PROTEIN OR TO SYNTHESIS OFF AN ABNORMAL
PROTEIN
GENE THERAPY IN MEDICINE
-NOW GENE THERAPY ADAPT TO USE IN
ACQUIRED DISEASE SUCH AS AIDS,
MALIGNANCIES AND CARDIOVASCULAR DISEASE
-GENE THERAPY FOR ACQUIRED DISEASE HAS
PROCEEDED FASTER THAN FOR INHERITED
DISORDER
GENE THERAPY IN MEDICINE
-THE EARLIEST HUMAN GENE TRANSFER
EXPERIMENTS BEGAN IN 1989
-NO THERAPEUTIC EFFECT
-SHOWED ONLY SAFETY AND MANY OF
TECHNICAL DIFFICULTIES
GENE THERAPY IN AIDS
-TODAY, DRUG THERAPY IN AIDS ONLY
CONTROL NOT CURE DISEASE
-ADMINISTRATION SCHEDULES
-SIGNIFICANT TOXICITY
-SO CONTINUING NEED FOR NEW OR
INNOVATIVE THERAPIES INCLUDING GENE
THERAPY
GENE THERAPY IN AIDS
1.INTRACELLULAR IMMUNIZATION
2.RIBOZYMES
3.TRANSDOMINANT MUTANT
4.TROJAN HORSE
THE HIV LIFE CYCLE AND
POINTS OF INTERVENTION
1.TAT
-KEY PLAYER IN THE EARLY STAGES OF HIV
RNA SYNTHESIS
2.REV
-SECOND KEY REGULATOR CAUSES SHIFT IN
THE TYPE OF HIV m RNA PRODUCE TO LONGER
TRANSCRIPTS
BINDING REGION ON TO HIV m RNA
-TAT---> TAR (TRANS-ACTIVATION RESPONSE-ELEMENT)
-REV-----> RRE (REV-RESPONSE ELEMENT )
*TAT + TAR -->> POTENT ACTIVATION OF VIRAL GENE
EXPRESSION BY INDUCING TRANSCRIPTIONAL
INITIATION AND ELONGATION
*REV + RRE -->> STRONG ACTIVATES HIV BY
FACILITATING THE EXTRACELLULAR TRANSPORT OF
UNSPLICED OR SINGLY SPLICED m RNA
RHIBOZYME
RHIBOZYME ARE RNA MOLECULES THAT
CONTAIN ANTISENSE SEQUENCE FOR
SPECIFIC RECOGNITION AND A RNA-CLEAING
ENZYMATIC ACTIVITY
SEVERAL FEATURES OF RZs MAKE THEM
ATTRACTIVE FOR HIV GENE THERAPY
-SIMPLICITY OF DESIGN
-LACK OF IMMUNOGENICITY OF RNA
-POSSIBILITY OF DESIGNING MULTIPLE RZS
AGAINST CONSERVED REGION OF VIRAL GENOME
TWO TYPE OF RZS THAT HAVE BEEN
USED MOST EXTENSIVELY ARE HAIRPIN
AND HAMMERHEAD
HAIRPIN Rz REQUIRING A GUC AT THE
CLEVAGE SITE
HAMMERHEAD Rz REQUIRING A NUH (WHERE
“N” DENOTES ANY BASE AND “H” DENOTES A,
C OR U)
RHIBOZYME APPLICATION IN AIDS
TAGET RNA : HIV -I
Rz TYPE
: HAIRPIN HAMMERHEAD
MODE OF DELIVERY AND RESULTING
PHENOTYPE
: RETROVIRUS DELIVERY OF A VARIETY OF
HIV Rzs
: INHIBITOR VIRAL REPLICATION 10-1000 FOLD
IN T-CELL, T-CELL LINES AND CD34 STEM
CELL PROGENY
TROJAN HORSE
IS AN ANTI-HIV RNA THAT CONTAINS
AN HIV-PACKAGING SIGNAL COUPLED
TO AN ANTI-HIV NUCLEIC ACID.
TRANS-DOMIANAT MUTANT (PROTEIN)
TRANSDOMINAT PROTEIN ARE PROTEINS
THAT HAVE ALTERED AMINO ACID THAT
RENDER THE MUTANT PROTEIN CAPABLE OF
DISRUPTING THE FUNCTIONS OF THE WILDTYPE PROTEIN
LTR
CMV IE
REV M10
LTR
REGULARTORY PROTEIN : TAT, REV
STRUCTURAL PROTEIN : Gag AND Env
(PREVENT LIBERATION OF VIRION OR
LEAD TO THE RELEASE OF DEFECTIVE
PARTICLES THAT CANNOT INFECT NEW
TARGET CELLS
INTRACELLULAR IMMUNIZATION
(INTRABODIES)
INTRABODY : AN ANTIBODY THAT IS
PRODUCED INTRACELLULARY BY
GENETIC ENGINEERING TO MAKE THE
ENGINEERED CELLS RESISTANT TO VIRAL
INFECTION
THESE ARE Ig - DERIVED MOLECULES
THAT COMBINE HIV-SPECIFIC VARIABLE
REGIONS WITH AN ALTERED
IMMUNOGLOBULINE CONSTANT REGION
DOMAIN THAT RESULTS IN THE
MOLECULES BEING RETAINED INSIDE
THE CELL.
INTRABODIES AGAINST : TAT, REV,
REVERSE TRANSCRIPTASE AND
ENVELOPE EPITOPE
ANOTHER FORM : RNA DECOY , SUICIDE
GENE, ANTISENSE NEUCLEIC ACID
GENE DELIVERY
-VIRAL VECTOR
-NON VIRAL VECTOR
CONCLUSION
THANK YOU VERY MUCH