So gene therapy administered during the operation can extend bypass life

Extending the life of the bypass, the operation that saves the heart when the coronary arteries close, by intervening in the biological behaviour of the implanted vessels. This is the idea behind the first gene therapy administered during a heart bypass. The first patient in the world to receive it was a 73-year-old man in Scotland's Golden Jubilee University National Hospital.

Bypass allows blood flow to the heart to be restored by bypassing blocked arteries, using vessels taken from other parts of the body to act as a graft, i.e. a 'bridge' to the blocked arteries. In most cases, veins taken from the leg (usually the great saphenous vein) are used because they are readily available and simple to implant. In the case of the 73-year-old British man, gene therapy was added to the bypass, which consists of carrying the TIMP-3 gene into the vein before implanting it as a graft. The new gene therapy aims to make the vessel more stable and resistant right from the start by affecting its biological behaviour before it is implanted in the heart. The researchers are thus attempting to overcome one of the main limitations of the bypass procedure: once connected to the heart, the veins have to withstand much higher pressure than they are designed for, which in time leads them to shrink and reduce blood flow, until they lose their function. This is a frequent complication, which can lead to the reappearance of symptoms, new hospitalisations and, in the most serious cases, further operations.

The strategy adopted is innovative in its mode and timing of administration. After the vein is taken from the patient's leg, the vessel is treated ex vivo, i.e. outside the body, immediately prior to implantation. The treatment uses a viral vector that carries the gene for the TIMP-3 (Tissue Inhibitor of Metalloproteinases-3) protein within the cells of the vascular wall. TIMP-3 is a protein involved in regulating tissue remodelling and controlling the activity of metalloproteinases, enzymes that contribute to the thickening and degeneration of the vascular wall. The mechanism leads to expression of the gene in graft tissue that induces an increase in TIMP-3 protein production in the graft to counteract the processes that lead to vessel narrowing and occlusion, prolong functional by-pass duration well beyond current standards, and reduce the incidence of failure.

The intervention was carried out to complement the PROTECT trial, the result of more than 20 years of translational research into the role of TIMP-3 in vascular remodelling, within academic research and the public health system. The trial has been supported by the Medical Research Council and the British Heart Foundation, with support from national infrastructure dedicated to advanced therapies, including the Cell and Gene Therapy Catapult and several university programmes. The trial is still at an early stage and further confirmation will be needed to demonstrate its safety and clinical efficacy; but it is an important innovation, opening up new possibilities for the use of gene therapy in the cardiovascular field for which there are currently no approved gene therapies. The more traditional strategies tried out, such as therapeutic angiogenesis developed in past years to improve heart perfusion, have not led to the expected clinical results. Today, however, the field is moving towards more targeted approaches, thanks, for example, to the genetic editing of key cardiovascular risk genes, such as PCSK9, and the correction of cardiomyopathies of genetic origin. Several studies on rare inherited heart diseases have entered or are entering the clinical phase, with results expected in one to two years.