Reversing heart defects through gene therapy involves the transfer of genes into defective cells or organs to correct a functional abnormality. By Michael Lim

IMAGINE that if your heart cannot pump well, has clogging of the blood vessels or has a disruption of the electrical system caused by a genetic effect and the defect can be reversed, it will be a dream come true. The pursuit of this dream is slowly being realised through gene therapy which involves the transfer of genes into defective cells or organs to correct a functional abnormality.

Vehicle for transportation of genes

Genes can be transferred into defective cells by passive or active methods. A simple passive way is to expose the defective cells to genetic material (“DNA”) and flood the surrounding milieu of the defective cells with the genetic material hoping that some of the genetic material may be taken up into the cells. While producing large amounts of genetic material is not difficult, the process is inefficient and uptake of genetic material is only seen in a small proportion of cells.

A more active process involves loading the genetic material into viruses. When these viruses infect the cells, genetic material carried by the viruses is transferred to the infected cell and incorporated into the cell. Viruses that have been used more effectively for the heart include adenoviruses and adeno-associated viruses. The main problem with using viruses to transport genetic material is the ability of the body’s immune system to recognise these viruses as foreign and start producing antibodies to neutralise the effects of the viruses. In this respect, the body seems to be more tolerant of adeno-associated viruses.

Delivery routes

Even with effective genes and good vehicles to transport the genes, the genes still have to be delivered to the right place. One way is to infuse the genetic material into the heart by inserting a catheter or plastic tubing from the leg artery or wrist artery to the opening of the heart arteries. In this way, the genetic material or viruses will be infused through the catheter into the vessels of the heart and allow homogenous exposure of the heart muscle cells to the genetic material. As the genetic material can pass through the circulation without being taken up by the cells in the heart, this is not an efficient method. It is nevertheless safe and does not require surgery. Most other techniques of delivering the genetic material involve surgery to get access to the heart muscle and the genetic material or viruses are either injected into the heart muscle or applied as a film on the exterior surface of the heart by literally painting a thin layer on the heart surface. The main disadvantages of these surgical techniques is that it cannot be applied in routine clinical practice as it requires open heart surgery.

Gene therapy for heart disease

Coronary artery disease (CAD) or blockage of heart arteries remains a major cause of death. Although advances in medicine have reduced the risk of death and prolonged survival in patients with CAD, there is nevertheless a group of patients who have severe CAD which cannot be optimally managed with medication and is not amenable to treatment by bypass graft surgery or balloon angioplasty. As a result of severe diffuse blockage of the arteries leaving many areas of the heart muscle without sufficient blood flow, various biological agents such as Vascular Endothelial Growth Factor (VEGF) and Fibroblast Growth Factor (FGF) which can induce the growth of new blood vessels, have been used in studies. Though animal studies have been able to demonstrate the growth of new vessels with infusion of genes, Phase 3 human studies with VEGF and FGF have failed to demonstrate consistent significant benefit and hence it will be some time before gene therapy will be used routinely in CAD.

Heart failure or impaired heart pump function is a common cause of death and hospitalisation in an ageing population. It is estimated that for those with heart failure, only 50 per cent will remain alive after five years. Phase 2 human studies using viruses that can encode sarcoendoplasmic reticulum calcium-ATPase 2a (SERCA2a), which transfers calcium from different parts of the cell, and gene therapy using Stromal Derived Factor – 1 (SDF-1) , which activates stem cells, have also shown promising results. The greatest benefit for gene therapy in those with impaired heart function will be those with no evidence of muscle scarring but the heart pump capability remains poor. The analogy will be a car which has a working engine but has a flat battery. Gene therapy can potentially improve the heart pump function by providing it with a working “battery”.

The third main area where there has been considerable research has been the treatment of life-threatening abnormal heart rhythms. Most of the gene therapy studies have been on animals and it will be some time before human trials will be performed. The results appear promising but the most effective method for delivering the genetic material appears to be painting a film of the genetic material with or without viral carriers onto the surface of the heart. Hence, significant challenges remain.


Just in case one thinks that gene transfer presents a “magic bullet” solution for heart conditions, there are certain limitations. Whether it is genetic material directly or carried by viruses, the body’s immune system will recognise them as foreign proteins and mount an immune response to subdue these foreign proteins. The result will be reduced effectiveness of the gene transfer or worse still, the battle between the body’s antibodies and these viruses may have unintended consequences such as inflammation. To overcome some of these limitations, viruses have been modified to increase their efficiency for delivering the carried genetic material. This may suggest that we have finally overcome the challenges of delivering genes into defective cells. However, viruses being very small particles, have limited carrying capacities and hence there is only limited space within the virus for a small amount of additional genetic material for it to carry to the defective cell.

So far, improving the heart muscle pump by gene therapy appears to have the best potential for successful human therapy. For those with weak hearts, there is finally some light at the end of tunnel.