1. Gene Therapy Trials for PID:A Nursing Perspective Jin Hua Xu-Bayford Clinical Nurse Specialist Gene Therapy Email: xuj@gosh.nhs.uk The child first and always

2. Outline of talk What is Gene Therapy Gene Therapy trials at GOSH What are the procedures Entry criteria Ethical/Safety Issues Preparation of the family Post gene therapy follow up monitoring

3. Gene Therapy Advisory Committee (GTAC) definition of Gene Therapy "The deliberate introduction of genetic material into human somatic cells for therapeutic, prophylactic or diagnostic purposes."

4. Two Types of Gene Therapy Somatic gene therapy involves introducing a “good “ gene into targeted cells with the end results of treating the patient-not the future children Germline gene therapy involves modifying the genes in egg or sperm cells, which will then pass any genetic changes to future generations as well

5. Trials under taken at GOSH X-Linked Severe Combined Immunodeficiency (SCID-X1), now it is closed Adenosine Deaminase Deficiency (ADA- SCID) X-Linked Chronic Granulomatous Disease (X-CGD)

7. Entry criteria for the trials

8. Trial Entry Criteria for SCID-X1 Molecularly confirmed diagnosis No MSD, MFD or fully matched MUD GTAC approval Parental/guardian voluntary consent

9. Entry Criteria for X-CGD Molecularly Confirmed diagnosis X-CGD At least one severe infection needing hospital treatment, or sever inflammation due to CGD No MSD, MFD or fully matched MUD GTAC approval Parental/guardian voluntary consent

10. Entry criteria trial for ADA Molecularly Confirmed diagnosis of ADA- SCID Failure of PEG-ADA No HLA identical family donor GTAC approval Parental/guardian voluntary consent

11. How parents choose GT vs BMT Percentage of survival following gene therapy is greater than following a MUD SCT. Fear of chemotherapy Fertility issues for the child Shorter hospitalisation with gene therapy Safer treatment, at least in the short term

12. Decision making GT remains a largely experimental and innovative treatment Currently undergoing clinical trials with PID One centre in the UK is treating Children using this form of therapy Rapidly expanding field Media attraction / publicity

13. Preparation of the family Begins once a diagnosis of ADA or X-linked SCID has been established Tissue typing for family to search a MFD Medical team approaching GTAC-seek approval for gene therapy Consultation with immunology and BMT consultants Independent consultation

14. Other factors Availability of the vector Laboratory resources to prepare the cells Theatre space for the child to have a bone marrow harvest Availability of UCLH laboratory for CD34 selection Availability of a bed on the appropriate unit

15. Administration of Gene Transduced cells Apply principles of BM/ PBSC infusion Via blood giving set Over 30-40 minutes Ensure appropriate cover prescribed( Chlorphenamine & Hydrocortisone) Less likely to react as own cells given back Usually on a Friday afternoon

16. Patients treated at GOSH X-SCID (10 patients) ADA SCID (3 patient) X-CGD (2 patients)

17. Immune reconstitution post gene therapy 4-6 weeks, natural killer (NK) cells start recovering Approx 12 weeks, T-cells start recovering Approx 6 months, CD4 should be reaching 300

18. Risks and side effects of Gene Therapy 3 Paris patients developed T cell Leukaemia 2/3 were the youngest patients (<3 months) 2 patients in remission and 1 died

19. Ethical / Safety Issues GTAC - Gene Therapy Advisory Committee Not germ line (eggs and sperm) gene therapy -only somatic cells (body cells) are corrected Theoretical risk of harm from virus Risk of malignancy- insertional mutagenesis DoH health record flagging Informed consent Unknown risks as novel procedure

20. Parental Support Numbers of children being treated remain very small Parents support parents MDT offer information and support Medical and nursing experiences

21. Balancing clinical risk and benefit

22. 6th October 2006