Genes to mend a broken heart

Sydney researchers have used gene therapy to experimentally transform skin cells into a novel type of muscle cell that could rejuvenate damaged hearts and correct abnormal heartbeats.

The multi-institution team, lead by Dr Eddy Kizana, of the Children's Medical Research Institute (CMRI), inserted two genes into dermal fibroblasts that transformed them into electrically excitable skeletal muscle cells.

But the transformed cells share the special ability of cardiac muscle cells to couple electrically with their neighbours and respond in unison to the electrical impulses that drive heartbeat.

Although the experiments were conducted in vitro, Dr Ian Alexander, head of gene-therapy research at CMRI, believes fibroblast cells present in cardiac muscle could be reprogrammed in situ, to repair damage caused by heart attacks, or to correct heart arrhythmias without an implanted pacemaker.

Kizana developed the gene-therapy technique during his PhD studies at CMRI. He is now doing postdoctoral research with world-leading molecular cardiologist Professor Eduardo Marvan at Johns Hopkins University in Baltimore, Maryland, to develop a large-animal model for the therapy.

Alexander said the genes are delivered by a retrovirus - a lentivirus - that integrates the two transgenes into the DNA of the fibroblast cells.

"One of the genes, myo-D, acts as a master switch that reprograms the fibroblast to take on a skeletal-muscle phenotype," he said.

"The second is the connexin-43 gene, a gap-junction gene that allows adjacent cells to couple electrically. Between them, the two genes create a facsimile of a cardiac muscle cell."

Alexander said the joint project, involving researchers from CMRI, the Westmead Children's Hospital, the Westmead Hospital Department of Cardiology, and Sydney University, was exploring the possibility of repairing conduction defects in the heart.

Skin fibroblasts are involved in skin-repair processes, and also repair damaged heart muscle, creating scar tissue in the process. The new technology could transform the fibroblasts in scar tissue into skeletal muscle cells that would behave in the same way as cardiac muscle cells.

"The heart is made primarily of cardiac muscle cells, most of which are dedicated to pumping functions, and all of them can propagate electrical currents," he said.

"But specialised cells act as the wiring for the heart, responding in a coordinated manner to create the heartbeat. There are many aberrant pathways - with this technology we could create new pathways from scratch, or deliver genes to scar tissue to change its phenotype, so they would facilitate the passage of electrical impulses."

While pacemakers could be a good remedy for heart arrhythmias, pacemakers eventually wore out and required replacement - younger patients might require several operations in a lifetime.

"With extensive research, it may be that gene therapy can give a patient's own cells the capacity to be repaired for life."

Children born with congenital heart blockages, or heartbeat abnormalities, could also benefit, he said.