GENE THERAPY: A brief overview

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Presentation transcript:

GENE THERAPY: A brief overview D. Bunker TAS USANZ 2014

Overview What is it How can it be achieved Transfection Transduction Adeno-associated viral vectors Example  achieving transplant tolerance Gene therapy in prostate cancer research

Gene therapy - on the rise

What is it? Using genes to treat or prevent disease Methods: Expression Repair Silencing

How do we get genes in? All methods require getting new genes in i.e. transfer of genetic material using a vector Transfer accomplished by: Transfection (non-viral) Transduction (viral)

Transfection p c + pDNA GAG HSR - - Variable, low-level expression Physical  injection, sonoporation Chemical  Ca-Phos-DNA Electrical  ‘electropores’ Synthetic Vectors  lipopolyplex vehicles pDNA p c - + - GAG HSR Variable, low-level expression

Transduction Use of a virus to confer uptake of the transgene into host DNA Stable, high-level expression Figure: http://theresagk12.files.wordpress.com/2011/07/signal-transduction-by-audre-geras.jpg

Adeno-associated virus (AAV)

Adeno-associated Virus (AAV) REPICLATION DEFECTIVE  requires helper virus for replication ‘NON-PATHOGENIC’ Infects DIVIDING AND QUIESCENT CELLS EXTRACHROMOSOMAL or INTEGRATES IN A PREDICTABLE PATTERN

AAV genomics

Recombinant AAV (rAAV) Recombinant AAV  can influence the structure of the virus to express what you want where you want with maximum efficiency

Example – Transplant tolerance

Normal allograft function without immunosuppression Clinical impetus Operational tolerance : Rejection driven by MHC mismatches: if we can tolerise to donor antigens can we prevent the rejection process? Normal allograft function without immunosuppression

Liver tolerance effect Propensity to induce tolerance to neoantigens Can gene transfer of donor MHC to recipient liver confer tolerance?

Murine Skin Allograft Model IA IE B10 k 178.3 k,b Control group: 178.3  naïve B10.BR recipients Experimental group: 178.3  B10.BR recipients given rAAVKb 5x 1010 vgc day 0, transplanted day 7

Kb Transduction rAAVKb 5x1011 vgc via penile vein  rapid, high-level, stable hepatic expression of Kb on hepatocytes B10.BR rAAVKb C57BL/6

No significant inflammatory infiltrate after rAAVKb 5x1011 vgc Non-immunogenic No significant inflammatory infiltrate after rAAVKb 5x1011 vgc CD4 CD8 B220 F4/80

Tolerance to Allografts Transplanted Day 0 rAAVKb confers tolerance to allografts control MST 16 days, rAAVKb treated mice harvested at day 250 Day 250 post transplant

Role in Prostate Cancer

www.clinicaltrails.gov

Gene Therapy for Prostate Cancer Goals: Enhance cure rate of primary therapy Treatment option for metastatic disease/hormone resistant Use of adenoviral vectors selective for PCa cells Delivery routes Modes of action: Oncolytic vs. Radio-sensitisation (adenovirus replication inhibits DNA repair pathways  susceptible to radiation) Local therapies  lack of sustained efficacy Metastatic therapies  poor therapeutic efficacy

Examples: Phase III ProstAtakTM suicide gene therapy (Advantagene) ProstAtak™ + EBRTx for intermediate-high risk localized prostate cancer Outcome: DFS, PCSS, OS Phase II: prolonged Tcell activation against PCa cells and 75% decrease in recurrence ?First vaccine against cancer recurrence

Conclusion Novel strategy for addressing many types of disease Main roles roles are in single gene disorders, immunotherapy and cancer Expanding role in prostate cancer research (Clinical adenoviral gene therapy for prostate cancer. Hum Gene Ther. 2010 Jul;21(7):807-13)