Transient gene therapy may help youngsters with premature ageing

A rose will bloom, it then will fade.  Alas, not so for those afflicted with Hutchison-Gilford Progeria Syndrome (HGPS). Their lives skip the blooming stage.  Within a few months of birth their growth is stunted and they begin to show the hallmarks of ageing. Their skin loses its elasticity and their hair falls out. As teenagers they resemble tiny, gnomish octogenarians, with prominent eyes, pinched noses, receding jaws and veins protruding through thin transparent skin. The average age of death is 13 – usually from a heart attack or stroke.

Cardiologist John Cooke is trying to help those with the disease by at least slowing the ageing and stiffening of their blood vessels. His approach involves rejuvenating this tissue by delivering transient gene therapy using messenger RNA for a gene called telomerase. Since messenger RNA does not hang around, the technique avoids the pitfalls of gene therapy, like inadvertently triggering cancer.

The results of his research, published this week in the Journal of the American College of Cardiology, show the successful rejuvenation of cells in the test tube from youngsters with HGPS.

“It brings tears to my eyes to see these kids but despite the fact they’re trapped in the body of an 80-year-old,” he says. “They’re not bitter. They are intelligent and hopeful. They want to count the stars.”

The efforts of Cooke and colleagues based at the Houston Methodist Research Institute in Texas won’t just benefit children with progeria; there are potential pluses for most of us who are also likely to die of heart disease.

The cells of those afflicted with HGPS have a shortened life span. Compared to normal cells, they multiply fewer times before becoming senescent cells that are no longer able to rejuvenate through dividing. The fault lies with the worn-down tips of their chromosomes, known as telomeres.  In normal cells, the telomeres are much longer.

This is all a consequence of the LMNA mutation that is the underlying cause of HGPS. It impairs the way DNA is housed in the nucleus,  buckling the appearance of the nucleus and also meaning the DNA cannot be properly maintained – particularly the vulnerable ends, which fray. Cells with seriously frayed telomeres become senescent. They no longer divide or respond to the environment in a normal way, and ooze inflammatory factors. In the case of the endothelial cells that line the blood vessels, Cooke says, this means they don’t line up against the shear stress and they become stickier, attracting plaque.

For several years Cooke has wondered whether it might be possible to restore ageing endothelial cells to a more youthful state by repairing the telomere ends – not just in youngsters with HGPS but everybody.

The enzyme telomerase is designed to do this job; but delivering a hard copy of the gene to the cells is probably a bad idea: cancer cells often rely on activating telomerase.

So Cooke opted for giving the cells a soft copy – the messenger RNA that carries the same information as the gene but doesn’t hang around. It is sort of like a flimsy photocopy of an important manuscript. 

The just-published study was a proof of concept. The Houston researchers took skin cells from 17 youngsters with HGPS aged one to 14 and grew out cells called fibroblasts. (It’s much harder to extract endothelial cells that line the blood vessels). In 12 of the patients, the fibroblasts showed abnormally short telomeres. Five of the younger patients (aged eight years or less) had normal length telomeres – something that surprised the researchers. When the scientists added the messenger RNA of the telomerase gene, the cells with short telomeres kicked back into replicating again. On the other hand, the cells that had normal length telomeres showed no response.

The study suggests that the delivery of the telomerase messenger RNA is able to rejuvenate fibroblast cells. It presumably might do the same for the endothelial cells and blood vessels of youngsters with HGPS. The next step, Cooke says, is to work on techniques to deliver the telomerase messenger RNA into the body, perhaps using nanoparticles.