Identification of Rare Mutation May Lead to Heart Repair Gene Therapy

Identification of the mutation responsible for an exceedingly rare type of heart defect in infants may pave the way for a gene therapy approach for regenerating adult heart tissue damaged by heart attack or disease.

Investigators at Johns Hopkins University (Baltimore, MD, USA) had been examining the hearts removed from two infant siblings during heart transplant surgery. Initial findings were that cells in the heart muscle (cardiomyocytes) were continuing to divide despite the fact that the infants had passed the age by which such cell division has normally terminated. The investigators established that the infants' genomes contained two abnormal copies of the ALMS1 gene. The same mutation was then found in five infant patients, including two sets of siblings, at the Hospital for Sick Children (Toronto, Canada).


The investigators reported in the March 4, 2014, online edition of the journal Nature Communications that the ALMS1 gene mutation caused a deficiency of the Alström protein that impaired the ability of the heart cells to stop dividing. In a genetically engineered mouse model, animals that lacked the ALMS1 gene displayed increased cardiomyocyte proliferation at two weeks postnatal compared with wild-type littermates. Furthermore, cultured cardiomyocytes divided abnormally after exposure to siRNA (short interfering RNA) that blocked expression of the ALMS1 gene.

“This study offers hope that we can someday find a way to restore the ability of heart cells to divide in response to injury and to help patients recover from many kinds of cardiac dysfunction,” said senior author Dr. Daniel P. Judge, associate professor of cardiology at Johns Hopkins University. “Things usually heal up well in many parts of the body through cell division, except in the heart and the brain. Although other work has generated a lot of excitement about the possibility of treatment with stem cells, our research offers an entirely different direction to pursue in finding ways to repair a damaged heart.”

“The children who helped us recognize the importance of this gene were born with a rare condition that leads to heart failure and many other problems, such as diabetes, obesity, blindness, and deafness,” said Dr. Judge. “Now we hope to apply these discoveries to help millions of others with heart disease.”

Related Links:
Johns Hopkins University
The Hospital for Sick Children