Stem cells and gene therapy to repair the damaged heart: will it work and is it right?

1. Stem cells and gene therapy to repair the damaged heart: will it work and is it right? John Martin Professor of Cardiovascular Medicine University College London

2. Small molecules Industry funded Heavily regulated Mechanisms understood Extensive toxicology performed Intellectual property obvious Industry total control

3. Gene therapy Venture capital funded Heavily regulated Mechanism understood Very extensive toxicology Intellectual property less obvious but possible Control shared - biotech/academia

4. Stem cell therapy Difficult to fund Less regulated Mechanisms not understood Little toxicology Intellectual property difficult Academia can control

8. Gene therapy trials failed 1. because of lack of understanding of basic biological problems 2. lack of safety 3. and small, uncontrolled trials

12. Collar; Pig

13. TRINAM: EMEA orphan drug status FDA orphan drug status and fast track status October 2005 Patient Safety and Dose Escalation study Low dose successfully completed Ark Therapeutics

14. Gene Therapy Problems 1. Gene can disseminate to whole body 2. Can we get enough where we want it? Solution 1. Local gene therapy 2. Use a reservoir

17. Embryonic stem cells The whole body Specialised tissue (e.g. heart, blood vessels) Bone marrow stem cells Repair of the organ (e.g. in heart, repairs heart) Resident stem cells

18. Use of autologous cells in large randomised control trials in patients with: • Acute myocardial infarction • Late presentation myocardial infarction • Heart failure (both ischaemic and dilated) • Use of autologous cells in small clinical mechanistic studies • Studies to test use of cytokines

19. Stem Cell Research Plan at Barts and UCL 3 protocols approved by ethics committee Acute myocardial infarction Ischaemic Heart Failure Dilated Cardiomyopathy (Total recruitment of 700 patients)

20. Expression of introduced gene in cells originated from stem cells GENE TRANSFER (green protein) Gene transfer to stem cell Thrombopoiesis of haematopoietic progenitors Multipotent progenitor cell Committed MK-progenitor cell Immature MK Platelet-shedding mature MKs