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Update on Gene Therapy. Dr. Nicola Stoner Specialist Principal Pharmacist Cancer Research UK & Oncology Unit Oxford Radcliffe Hospitals NHS Trust November 18th, 2003. Introduction. Gene therapy background Vectors Gene therapy strategies Patient monitoring Regulatory bodies

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slide1

Update on Gene Therapy

Dr. Nicola Stoner

Specialist Principal Pharmacist

Cancer Research UK & Oncology Unit

Oxford Radcliffe Hospitals NHS Trust

November 18th, 2003

slide2

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
slide3

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

slide4

Cancer

HIV

Cardiac

Hereditary

Other

UK Gene Therapy by Disease

1993-2002

slide5

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
slide6

The Bystander Effect

Bystander

Cell Death

Gene

Therapy

Cytokines

slide8

ABC’s of Gene Therapy

Access

Binding

DNA

Cytoplasmic

Transport

Expression

Function

slide9

Types of Vectors for Gene Transfer

  • Plasmid DNA
  • Retroviruses
  • Adenoviruses
  • Adeno-associated vectors
  • Vaccinia/fowlpox vectors
  • Poxviruses
  • Herpes virus
  • Salmonella
slide12

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
slide13

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
slide14

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
considerations when handling gene therapy in clinical settings
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
slide16

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
qc pharmacists national guidance on handling gene therapy products 1
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.
qc pharmacists national guidance on handling gene therapy products 2
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
health and safety executive hse guidance
Health and Safety Executive (HSE) Guidance
  • Draft guidance
  • Internal HSE Review
  • Discussion required with RPSGB, MHRA
slide20

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
slide21

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
slide24

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%.
slide26

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
slide27

Conclusion: Gene Therapy Challenges

  • Place in Therapy
  • Preparation
  • National Guidance
  • Dosing
  • Monitoring for Efficacy
  • Monitoring for Toxicity
  • Long Term Effects
  • Ethical
the future
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
slide29

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
slide30

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.