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8/6/2019 8 Gene Therapy Alison M Beaney
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Gene Therapy - Problems and
Challenges
Alison M. Beaney
Regional Quality AssuranceSpecialist
North-East and Yorkshire
Helapet Aseptic Study Day 2008
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Gene Therapy Background to Gene Therapy
P
otentialB
enefits Perceived Hazards and Risks
Regulations
Implications for
Phar
macy Aseptic Units
Future?
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Gene Therapy Definition
The deliberate introduction of genetic material intohuman somatic cells for therapeutic, prophylacticor diagnostic purposes
Addition of EXTRA genes
Aim is to cure disease (or at least help the patient)
First introduction of gene-
modified cells into a patientwas in 1989
First gene therapy product approved formarket in 2004
Still very experimental and early in its development
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PTQA April 2008 4
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Gene Therapy Vectors Vectors deliver genes to cells
Therapeutic gene(Transgene)
TherapeuticproteinVector for efficient gene delivery
Transcription
Translation
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Gene Therapy Strategies1) Gene Replacement
Replace faulty genes with normal genes
Corrects inherited genetic errors Provides a missing function
Monogenic diseases e.g. cystic fibrosis,haemophilia, X-SCID
2) Gene Addition Delivers genes to provide a new function
Polygenic diseases e.g. cancer
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Were trying to make a mousecontraceptive vaccine for pest control
Used modified mousepox virus as
vehicle for transporting antibodies
into mice Inserted gene to create IL-4
(interleukin 4) to boost production
Surprise !!
totally suppressed the "cell-mediated
response which combats viral
infection
Mousepox 100% lethal
2001
8
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December 19, 2007
Boy gets leukaemia after gene treatment
to cure bubble baby syndrome
3 year-old with X-linked severe combined immunodeficiency
(X-SCID) - immune system fails to develop
Treated with genetically modified virus to correct the faulty DNA
that causes X-SCID
Inserting the replacement DNA activated another gene that
promotes cancer
Now an acknowledged risk of gene therapy
Also seen in 4 / 11 patients in a French trial
One has died while 3 are in remission
Retrovirus vector
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Regulations governing the handling
of gene therapy vectors
No additional regulations governing the
handling of Non-Infectious vectors
Non-viral & Non-bacterial
Viral vectors are Genetically Modified
Genetically Modified Organisms
(GMOs)
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Genetic Modification Genetic modification is officially defined
as the alteration of genetic material
(DNA or RNA) of an organism by means
that could not occur naturally through
mating and/or recombination
A guide to Genetically modified organisms (Contained Use)
Regulations 2000. Health and Safety Executive
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Regulations governing the handling
of gene therapy viral vectorsTwo sets of Regulations:
GMO (Contained Use) Regs 2000, HSE
All possible barriers (physical, biological or chemical) arein place to limit contact of the GMOs with humans and theenvironment
GMO (Deliberate Release) Regs 2002, DEFRA
All appropriate measures are taken to avoid damage to
the environm
ent from
the escape or release from
hum
ancontrol of GMOs
aimed at laboratories (difficult to interpret clinically)
no reference to product or patient safety
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Additional Regulations that apply to
Gene Therapy Clinical TrialsProtection of the Patient Gene Therapy Advisory Committee (GTAC)
Established 1993, Department of Health
UK national research ethics committee (REC) forgene therapy
Ethical acceptability for human gene therapy
Scientific merits
Potential benefits and risks
Patient flagging and long termmonitoring
Advice to UK health Ministers on developments ingene therapy research
Applies to ALL GENE THERAPY CLINICAL
TRIALS using viral and non-viral vectors
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Containment Measures Required
IsolatableLab Suite
MicrobiologicalSafety Cabinet
Gloves ProtectiveClothing
Class 1
Level 1
NO NO NO YES Requires first use ofpremises notification to
HSEClass 2Level 2
NO RiskAssessment
R/A
R/A YES Minimum requirement forany human bloodorclinical samples.
Requires HSE notification
Class 3
Level 3
YES YES YES YES
+ Footwear
Requires HSE notification
Class 4
Level 4
YES YES YES YESCompletechange of
clothing andfootwear on
entry and exit
Requires HSE notification
Containment Levels for GMOs
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Guidelines on Handling GMOs
in Pharmacy QA of Aseptic Preparation Services (4th Edn.)
Appendix 6 Gene Therapy
Scientific Advisory Committee on Genetic
Modification (SACGM), Part 6,Guidance on the use of genetically modified
micro-organisms in a clinical setting
European Association of Hospital Pharmacists (EAHP)Guidance on the Pharmacy Handling of Gene Medicines
Rules and Guidance forPharmaceutical
Manufacturers and Distributors 2007
No Specific Guidance
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APPENDIX 6 -
GENE THERAPY
Facilities
Documentation
Labelling
Training
Asepticprocessing
Cleaning
Storage
Transport
Waste
Disposal
Spillage
16
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Facilities Gene therapy should not be manipulated in
clinical areas
Basic Principles - Containment
- Knowledge/ understanding /skill- Validated procedures
Persons handling the product should be masked and gloved
All disposable equipment and materials used for prep & admin
- handled as biohazardous
Dedicated facilities required -ve pressure isolators orClass IIBSC
+ve pressure room or lobby
Contain
ment level > 2
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Clean roo
msuitedesigned to
provide protection
to the cleanroom
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Aseptic Manipulation
Doses Calculation/dilutions/multiple dilutions
Needle stick injury risk
Units
Particle Units/ml (PU/ml)
Plaque Forming Units/ml (PFU/ml)
Infectious particle Units/ml (IU/ml)
Gene Transfer Units/ml (GTU/ml)
Stability
Container compatibilities - Plastic/glassadhesion
Expiry date - Time to administration from thawing
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Decontamination Cleaning
Virucidal detergents (validated against GT vectors)
Cleaning Validation
Specific Detectionm
ethods needed for virusesthat are virus specific and highly sensitive
Waste Disposal
On site validated autoclave for re-usable
equipment Inactivation on-site forClass 3 vectors
Validated autoclave
Incineration
Disinfectant treatment
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Spillage
Specific to GT vector
Spillage kit Contents ( gloves, masks, aprons, goggles,
disposable shoe covers, virucidal detergents,
absorbent material, disposable forceps &
biohazard incineration bag)
Positioned in all GT handling areas
Notification to HSE
Accidental Exposure
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Risk Assessment Assess each product individually
Cytolytic viruses
Non-cytolytic viruses
Replication competent
Replication deficient Class I, II orIII
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What will the Future bring? Dedicated facilities
Automation?
The first gene medicine in Europe could belicensed in 2008
Licensed closed-system gene therapy products
Use of gene therapy as an adjunct to standardtherapy e.g. Radiotherapy & Chemotherapy
Vector development e.g. Targeted vectors (viral & non-viral)
Bacterial vectors
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Additional Information Gene Therapy Advisory Committee (GTAC)
http://www.advisorybodies.doh.gov.uk/genetics/gtac/index.htm
Gene therapy trials worldwide. Provided by the Journal of gene medicinehttp://82.182.180.141/trials/index.html
A guide to Genetically modified organisms (Contained Use) regulations2000. Health and Safety Executive
Genetically Modified Organism (Deliberate Release) Regulations 2002[GMO(DR)]. Department for the Environment, Food and Rural Affairs (DEFRA)http://www.opsi.gov.uk/si/si2002/uksi_20022443_en.pdf
Quality Assurance of Aseptic Preparation Services Fourth Edition.A.M.Beaney. Pharmaceutical Press 2006. Appendix 6. Gene Therapy.
EU Clinical Trials Directive.http://www.wctn.org.uk/downloads/EU_Directive/Directive.pdf
Implications of gene therapy for hospital pharmacists. Simpson.J, Stoner.N. www.pjonline.com/pdf/articles/ pj_20030726_genetherapy.pdf
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Additional Information Cancer gene therapy: from science to clinical trials. Searle. P.F, Spiers. I,
Simpson. J, James. J.D. Drug Delivery Systems and Sciences 2002, 2 (1), 5-13.
Standards for gene therapy clinical trials based on pro-active risk
assessment in a London NHS Teaching Hospital Trust. Bamford, K.B.,Wood, S., Shaw, R.J. QJM 2005, 98, 75-86. www.qjmed.oupjournals.org
Progress in Gene Therapy are hospital pharmacies the next barrier?Simpson, J. Hospital Pharmacist, 2006, 13 (8), 266http://www.pjonline.com/pdf/hp/200609/hp_200609_comment.pdf
Cancer Biotherapy. An Introductory guide. Young, A. Rowett, L. Kerr, D.Oxford University Press 2006
Scientific Advisory Committee on Genetic Modification (SACGM), Part 6,Guidance on the use of genetically modified microorganisms in a clinicalsetting. http://www.hse.gov.uk/biosafety/gmo/acgm/acgmcomp/part6.pdf
European Association of Hospital Pharmacists (EAHP) Guidance on thePharmacy Handling of Gene Medicines. http://www.ejhp.eu/