Four years ago, a newborn was transferred to NewYork-Presbyterian/Morgan Stanley Children's Hospital for treatment of a severe arrhythmia. The full-term infant boy had normal heart structure but a prenatal history significant for fetal bradycardia of unclear etiology. There was no family history of arrhythmias, long QT syndrome, or sudden death. "The baby was having multiple episodes of ventricular tachycardia daily," recalls Wendy K. Chung, MD, PhD, Director of the Division of Clinical Genetics at NewYork-Presbyterian/Columbia. "He was arresting at least once a day, and had such a malignant type of arrhythmia that within the first month of life he had a defibrillator implanted and required defibrillation several times a month."
The infant was diagnosed with congenital long QT (LQT-3) causing extreme QT prolongation. The condition resulted from a de novo mutation in the heart's sodium channel and possibly a common polymorphism in a critical heart potassium channel. This particular form of the syndrome, while less common, is more lethal. Evidence has shown that mutations in ion channels may contribute to sudden infant death syndrome and other cardiac arrhythmias in newborns. "It is very unusual to see symptomatic long QT syndrome in a newborn," notes Dr. Chung. "It generally presents in children or in adults."
There are at least 12 genes associated with long QT syndrome and hundreds of mutations within these genes have been identified. Mutations in three of these genes account for about 70 to 75 percent of long QT syndrome cases. LQT-3 is caused by mutations in SCN5A, the gene coding for the sodium (Na+) ion channel protein, NaV1.5. Evidence has shown that frequency, severity, and treatment of SCN5A mutations may be distinct from other forms of long QT syndrome. "Generally, Na+ channel blockers - such as mexiletine and flecainide - are effective in treating LQT-3 patients due to preferential inhibition of mutant Na+ channel activity," says Dr. Chung. "However, in this particular newborn, conventional drug therapy was ineffective."
Having diagnosed the baby's condition as genetic, Dr. Chung and her colleagues partnered with researchers, including Robert S. Kass, PhD, Chairman, Department of Pharmacology at Columbia University, in an effort to develop a therapy that would stop the refractory arrhythmias. From a skin sample they created beating heart cells in a dish in the laboratory that had the baby's entire genetic make-up, including the infant's mutant ion channel. They investigated the efficacy of three compounds - flecainide, mexiletine, and ranolazine - in correcting the biophysical dysfunction that provoked his arrhythmia in the past to see which drug might work best to stop his arrhythmias.
"Based on both his genetic diagnoses and the results of our tests, our goal was to be able to customize his medication," says Dr. Chung. "We essentially conducted clinical trials in a dish with skin cells converted to a type of all-purpose stem cell called induced pluripotent stem cells, which were made into cardiac myocytes. Using patch clamp analysis, which allowed us to study the ion channels in cells, we tried different ways of pacing his heart rate at the cellular level. This was not a trivial thing and took us over a year of experiments - going from bedside to bench and back again. But it provided us with proof of concept for a better model of personalized medicine - one in which a person's own cells can be used to determine which treatments should not be used and those that might work best for a particular condition."
Their research, reported in the December 2007 issue of PLoS ONE, revealed significant changes in channel biophysics, and detected subtle differences in drug action in correcting mutant channel activity, which, together with the known genetic background and age of the patient, contributed to the distinct therapeutic responses observed clinically. "The results of our study provide further evidence of the grave vulnerability of newborns with Na+ channel defects and suggest that both genetic background and age are particularly important in developing a mutation-specific therapeutic personalized approach to manage disorders in the young," says Dr. Chung.
The work of Drs. Chung, Kass, and their colleagues demonstrated that induced pluripotent stem cells (iPSCs) offer an unprecedented opportunity to investigate the pharmacology of disease processes in therapeutically and genetically relevant primary cell types in vitro and uncovered a novel method to evaluate treatment for heritable arrhythmias. The painstaking endeavor led to the first-time report of the application of iPSC technology to correlate basic pathophysiologic in vitro studies with medical treatment of an individual patient with a complex disease phenotype that was initially resistant to medical therapy.
"These arrhythmias are caused by inherited mutations in genes coding for ion channels and/or ion channel-related proteins expressed in the heart," says Dr. Kass. "Our work has contributed to an understanding of gene-specific risk factors caused by mutation-induced changes in heart ion channel activity, and to the development of a mutation-specific approach to manage these disorders. Implicit in this use of patient-specific iPSCs for disease modeling and drug screening is the promise of applying these cells to develop more individualized therapies to treat the patient from whom the cells are derived."
To translate information gleaned from their work back to the patient, the researchers developed three teams of basic scientists charged with establishing iPSC-derived beating cardiomyocytes from the child and his parents. These teams were not involved in the patient's care or clinical decisions, but interacted regularly with his clinical cardiologist to provide results from the in vitro model and to discuss correlation with response to treatment with standard FDA-approved drugs and electrical pacing therapy.
"Analysis of the molecular pharmacology of ion channels expressed in cardiomyocytes differentiated from these iPSCs revealed the mechanistic basis for the resistance to therapy. They also correlated with clinical responses to a simplified therapeutic approach that has effectively controlled arrhythmic activity in the patient," says Dr. Chung.
Now nearly four years old, the child that Dr. Chung met in his first weeks of his life has all the protective devices and medications in place to help keep his arrhythmia at bay. He has remained free of any ventricular arrhythmias or shocks for eight months, in marked contrast to the average of 100 arrhythmias per month observed prior to the initiation of this study.
"We believe this to be the first clinical translation of iPSC technology to a patient's care," notes Dr. Chung. "The results of our study strongly support consideration of in vitro iPSC studies as a new method for optimization of personalized medicine. This first-in-man clinical application of iPSC technology to help understand response to therapy in an individual patient provides a proof-of-principle for personalized medicine employing iPSC model systems."