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 understandingof 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 2005Patient Safety andDose Escalation studyLow dosesuccessfully completed

Gene Therapy

Problems

1. Gene can disseminateto whole body

2. Can we get enoughwhere 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)

CommittedMK-progenitor cell

Multipotent progenitor cell

Platelet-sheddingmature 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