Update on Gene Therapy

1. Update on Gene Therapy Dr. Nicola Stoner Specialist Principal Pharmacist Cancer Research UK & Oncology Unit Oxford Radcliffe Hospitals NHS Trust November 18th, 2003

2. Introduction • Gene therapy background • Vectors • Gene therapy strategies • Patient monitoring • Regulatory bodies • Considerations when handling gene therapy in clinical setting • QC Pharmacists National Guidance & HSE Guidance • Gene therapy procedures • The Future

3. Definition of Gene Therapy Introduction into the human body of genes or cells containing genes foreign to the body for the purposes of prevention, treatment, diagnosis or curing disease

4. Cancer HIV Cardiac Hereditary Other UK Gene Therapy by Disease 1993-2002

5. Gene therapy strategies • Single gene replacement • Inhibit dominant oncogene expression • Augment deficient tumour suppressor genes • Suicide genes • kill infected cells (deliver toxin or toxin gene) • bystander effect • make infected cells susceptible to drugs

6. The Bystander Effect Bystander Cell Death Gene Therapy Cytokines

8. ABC’s of Gene Therapy Access Binding DNA Cytoplasmic Transport Expression Function

9. Types of Vectors for Gene Transfer • Plasmid DNA • Retroviruses • Adenoviruses • Adeno-associated vectors • Vaccinia/fowlpox vectors • Poxviruses • Herpes virus • Salmonella

12. Patient Monitoring • Cellular migration studies - if cells are transfected ex vivo and re-administered to patient • Assessment of immune responses to vector and antibody responses to transgene product • Studies of duration of transgene expression and cellular survival

13. Patient Monitoring • Vector dissemination studies including shedding and germ line transmission • Replication Competent Virus (RCV) Testing • e.g., RCR testing • Long-term and potentially life-long monitoring

14. Regulatory Bodies • HSE (2000) A guide to the Genetically Modified Organisms (Contained Use) Regulations • Medicines & Healthcare Products Regulatory Agency (MHRA) • Gene Therapy Advisory Committee (GTAC) • Local Genetic Modification Safety Committee • Biological Safety Officer

15. Considerations When Handling Gene Therapy In Clinical Settings • Classification of risk • Biological containment level • Routes of exposure • Minimise staff exposure, risk to patient and contamination of environment • Integrity of product • Regulatory bodies and accepted national practice • Standard operating procedures (SOPs) • Risk assessment

16. Risk Assessment • Risk classification and containment • HSE guidelines on essential information to be included • Risk to humans and the environment • Identification of harmful effects • Characteristics of proposed activity • Severity and risk of potential effects • Control measures needed • Disposal methods

17. QC Pharmacists - National Guidance on Handling Gene Therapy Products (1) • It is recommended that gene therapy products should not be manipulated in clinical areas • uncertain effects of specific genes on normal human cells • the potential for operator sensitisation on repeated exposure • the potentially infective nature of some products.

18. QC Pharmacists - National Guidance on Handling Gene Therapy Products (2) • Plasmid DNA and DNA Complexes • Manipulate in existing non-cytotoxic facilities • Ensure adequate segregation from other products • Viral Vectors • Products to be considered infective • Dedicated negative pressure isolator or type 2 safety cabinet (in a dedicated room) • External ventilation

19. Health and Safety Executive (HSE) Guidance • Draft guidance • Internal HSE Review • Discussion required with RPSGB, MHRA

20. Cancer Research UK Medical Oncology Unit gene therapy trials • 16-bedded inpatient facility • 8 gene therapy clinical trials 1998-2003 • Containment level one facilities • Vectors included • inactivated retrovirus • adenovirus • herpes simplex virus • Vaccinia

21. Standard Operating Procedures (SOP’s) • Preparation of biological safety cabinet • Dispensing guidelines • Administration to patient • Waste disposal • Accidental spillage • Accidental product exposure • Nursing care of patient

24. Waste Disposal Procedure • All disposable materials in linbins • All sharps placed in a yellow sharps box, which is placed in linbin • Linbin sealed and collected by GM licenced contractor • Bedding is treated as infectious if there is a spill • Non-disposable items cleaned with Virkon2%.

26. Summary • Gene therapy background • Vectors • Gene therapy strategies • Patient monitoring • Regulatory bodies • Considerations when handling gene therapy in clinical setting • QC Pharmacists National Guidance & HSE Guidance • Gene therapy procedures • The Future

27. Conclusion: Gene Therapy Challenges • Place in Therapy • Preparation • National Guidance • Dosing • Monitoring for Efficacy • Monitoring for Toxicity • Long Term Effects • Ethical

28. The Future • “Our Inheritance, Our Future: Realising the Potential of Genetics in the NHS” whitepaper June 2003 • New EC Clinical Trials Directive 2004 • European Pharmacopoeia - implementation of standard quality control measures for gene therapy products

29. Further information • HSE (2000) A Guide to the Genetically Modified Organisms (Contained Use) Regulations • Http://www.hse.gov.uk • Www.doh.gov.uk/genetics/gtac • Http://cis.nci.nih.gov/fact/7_18.htm • Email: nicola.stoner@cancer.org.uk

30. Useful References • Simpson, J., Stoner, N.S. (2003) Implications of Gene Therapy to Pharmacists, Pharmaceutical Journal 271(7259):127-130. • Stoner, N.S., Gibson, R.N., Edwards, J. (2003) Development of procedures to address Health and safety issues in the administration of gene therapy Within the clinical setting. Journal of Oncology Pharmacy Practice 9:29-35. • Brooks, G. Gene Therapy -The use of DNA as a Drug (2002), Pharmaceutical Press, London. • Stoner, N.S. (Oct. 2002) Considerations for Cancer Pharmacists Undertaking Gene Therapy Clinical Trials, BOPA Newsletter.