Naked DNA gene therapy used to non-invasively cure heart disease

It would be hard to think of a more arresting experience than waking up in the middle of your own open heart surgery. While many patients make an excellent recovery, the body does not readily forget the trauma of this now familiar procedure. A softer, more creative approach to treating damaged hearts has recently been developed by Amit Patel at the Utah School of Medicine. Patel just injected a smart, gene therapy bomb comprised of naked DNA into the ailing heart of actor Ernie Lively — and Lively, who is doing great, scarcely skipped a beat.

To reach the heart, Patel uses a catheter to access the main cardiac vein, or coronary sinus. Once there, he inflates a balloon to halt the flow of blood, effectively isolating the area. A high dose of naked DNA — DNA that is stripped of any extra bits, like histones — that codes for a protein called SDF-1 is then delivered. This SDF-1, which stands for stromal cell-derived factor, is a potent attractant both for stem cells circulating in the bloodstream, and for those developing in the bone marrow. Stromal cells, which manufacture SDF-1, are the creative force which knit together our fibrous connective tissues. The problem is they do not make enough of this SDF-1 under normal conditions, nor do specifically deliver it in just the right places for repair of a mature heart.

In contrast to other gene therapies that have had trouble in the past, the introduction of SDF-1 into cells was done without the assistance of a virus. Viral vector methods still hold great promise because of their ability to target specific cell types, and to integrate into specific spots in the genome. However, to date, there are still too many unknowns for introducing their use into standard practice. Furthermore, the remnant viral components still present in the vector sequence tend to draw unwanted attention from the immune system.

During embryogenesis, SDF-1 plays a “chemotactic” role for lymphocyctes. That just means it acts to attract cells in a concentration-dependent manner by virtue of its molecular identity. Specifically, it directs the migration of blood cell precursors from the liver of the fetus, to the bone marrow, and also instructs the formation of the larger blood vessels.

In the biomedical world, the number, or sometimes the percentage, of the cells that take up the DNA is known as the yield. The yield for these experiments, if we can still call treatments by that name, is not precisely known. Neither are the precise mechanisms of uptake and integration within the cell known here either. Fortunately, a lot of work as far as figuring out the perfect recipe for “transfecting” raw DNA into cells is now being done by neuroscientists trying to control brain cells with light. In fact, the heart has also recently emerged as an ideal target for optogenetic control. The most efficient methods involve using femtosecond laser beams to open transient pores in the cell membrane, and then delivering an additional chemical agent (typically a peptide cocktail known as Nupherin) to form an access channel in the nuclear wall.

Femtosecond lasers, split into multiple independent beams by MEMS-based spatial light modulators, and directed to individual cells as fast as the operator can target them on an imaging screen, is state of the art tech. That won’t be done in the OR anytime soon. It seems however that Ernie’s heart is doing well with a simple brute-force local injection, and that the procedure can be declared a success. Still, a powerful bioactive protein like SDF-1 still needs to be applied with caution. Its effects, and the that of the other molecular players with with it associates are still incompletely known.

Intriguingly, one of the close associates of SDF-1, TNF (tumor necrosis factor) has just been reported to be intimately involved with he transmission of learned experience directly through breast milk, to a mother’s offspring. As exotic as that may sound, that is the system we are dealing with here, and we best start trying to better understand it if we hope to trade scalpel for needle.

Now read: Regenerated human heart tissue beats on its own, leads towards replacement hearts and other organs