Ten weeks after investigators implanted the genetically engineered human stem cells into mice, tissue repair and function, as measured by the heart’s ability to pump blood, was twice that of controls. This improvement persisted for at least 20 weeks after implantation.
“This study brings us one step closer to a clinical application for stem-cell therapy,” said Sadia Mohsin, Ph.D., lead author of the study and post-doctoral research scholar at San Diego State University in California. “Since patients with heart failure are normally elderly, their cardiac stem cells aren’t very healthy. We were able to modify these stem cells, obtained from heart failure patients, to be healthier so that they could be transplanted into the heart and survive and thrive.”
Researchers used cardiac stem cells from patients receiving mechanical assist device pumps to help their failing hearts. They then genetically engineered the cells to express a protein, known as Pim-1, which naturally occurs in response to heart damage. Using molecular technology, they attached this protein to another, derived from jellyfish, which glows fluorescent green so that Pim-1 expression was clearly visible.
2. A one-dose method for delivering gene therapy into an arterial wall effectively protects the artery from developing atherosclerosis despite ongoing high blood cholesterol. The promising results, published July 19 in the journal Molecular Therapy, came from research in rabbits.
In atherosclerosis, fatty lesions called plaques form on the inner lining of blood vessels. Plaque growth narrows arteries, thereby restricting blood flow and causing chest pains and other symptoms. Plaques sometimes rupture. The resulting blood clots can spur heart attacks or strokes.
Gene transfer would move the production of the therapeutic “drug” (in this case a therapeutic gene) directly to the site of atherosclerosis development: the blood vessel wall. The approach maximizes delivery of the drug to the artery wall and minimizes side effects in the rest of the body, the research team noted.
The deployed gene produces a protein that is likely responsible for the beneficial effects of high-density lipoprotein, or HDL, commonly known as good cholesterol.
This substance is apolipoprotein A-1, or apoA-1. It pumps out harmful cholesterol from the scavenger-type cells that ingest fats and congregate in early atherosclerotic lesions.
ApoA-1 appears to remove cholesterol from the lesions and is capable of transporting it to the liver, where it can be excreted from the body.
Lack of a suitable vector to transfer apoA-1-manufacturing genes into the cells lining the arterial wall has hampered the progress of this approach. Normally apoA-1 is produced by cells in the liver, stomach and intestine and enters the artery wall only after circulating through the blood.
The UW researchers successfully used a helper-dependent adenovirus (HDAd) as the vehicle to transfer a genomic clone of rabbit apo-A1 into the carotid artery. This large blood vessel sends oxygenated blood to the brain. After the vector was infused into the artery, the gene was taken up almost exclusively by the cells in the thin layer that lines the carotid’s inner surface and is in contact with circulating blood.
At two weeks, atherosclerosis in the carotid artery, as measured by lesion size and lipid content, was minimal and similar in fat-fed rabbits with or without gene therapy. Between weeks two and four, disease measurements increased in control arteries, but were stable or decreased in treated ones.
A lengthier study of chow-fed rabbits revealed that apo-A1 production from a treated artery continued for at least 48 weeks after a single dose of gene therapy.