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

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

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

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

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

Collar; Pig

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

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

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

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

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

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