Gene therapy on horizon for ASD families
Gene therapy on horizon for ASD families
We were all born with a hole in the septum, the thin membrane that separates the left and right atrial chambers. The hole shunts fetal blood away from still-undeveloped lungs. It usually closes shortly after birth, within the first week of life.
Once in every 1,500 live births in the United States, the hole never closes. In that case, blood passes from the left side of the atrium to the right side; instead of the normal process of blood returning from the lungs after being collected in the left atrium and passing to the left ventricle. As a result, patients aren’t getting enough blood in their left ventricle. When the chamber squeezes, it doesn’t squeeze enough blood into the circulation to provide adequate oxygenated blood to the rest of body. Children with atrial septal defect (ASD) become cyanotic.
Human molecular geneticist Jon Seidman, MD, of Harvard Medical School recently announced the discovery of gene mutations responsible for ASD.1 To scope the gene mutations’ role in ASD and determine the disorder’s inheritance pattern, he analyzed the DNA of a five-generation, 32-member extended congenital heart disease family, of which 17 survive. The family members who harbor this NKX2-5 mutation have a septal defect, Seidman wrote. Individuals with a surgically repaired septum usually do quite well. In other circumstances, they have electrical conductance defects and require a pacemaker to maintain a strong, steady heartbeat.
"In this extended family," Seidman wrote, "every living member required a pacemaker. The surprising thing is that many of them had the devices installed before they went on to have surgery to repair the hole."
It has been previously hypothesized that it was the surgical repair itself that led to the destruction of the electrical conductance system, requiring a pacemaker. "That may be true in many instan-ces," Seidman allowed, "but in this family, it ap-pears not to be. There are individuals here who had a conduction defect well before they showed any signs of a septal defect. . . Not all individuals with septal defects have conduction disease, certainly one could imagine screening the NKX2-5 gene of patients with septal defects to see if they have gene mutations, and . . . develop conduction disease. I just don’t know if the low number of cases will make it worthwhile."
Further down the road, Seidman foresees the potential for gene therapy in individuals with septal defects is real if you can identify the inadequate proteins in the septum. "You could imagine turning those genes on, stimulating septal formation — providing a treatment for people with this condition." "Of course," he concluded, "that’s sort of a pipe dream right now."
Reference
1. Schott J, Benson DW, Seidman JG, et al. Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science 1998; 281.
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