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Similar to the way the caps on the ends of a shoelace prevent it from fraying, telomeres—regions of repetitive DNA sequences and a protein structure—protect the tips of chromosomes from damage.

Every time our cells divide, telomeres lose a bit of that DNA. Eventually, telomeres become so short that they can no longer keep dividing and the chromosomes lose their protection. When there's a significant decline in the number of cells that can divide, tissues and organs lose their capacity to undergo the renewal processes that support healthy function. Telomeres naturally shorten as we age, but in people with telomere biology disorders (TBDs) such as dyskeratosis congenita, this process is accelerated.

The critical role that telomeres play in aging and age-related disease has long made them a target of research. Recent work at Boston Children's continues to expand our understanding of telomeres and is laying the foundation for new approaches to TBDs.

A one-and-done approach to lengthening telomeres

For more than a decade, Suneet Agarwal, MD, Ph.D., co-program leader of Boston Children's Hematopoietic (Stem) Cell Transplant Program, has looked for a way to lengthen telomeres and turn back the cellular aging process. Much of his lab's work has focused on telomerase, an enzyme that builds back shortened telomeres: Could we manipulate telomerase to support telomere maintenance, potentially opening the door to new TBD treatments? The question sparked Agarwal and his colleague Neha Nagpal, Ph.D., to investigate further.

Advances in chemical engineering have led to enhanced synthetic RNAs with therapeutic uses. However, some RNA classes pose engineering challenges due to their size and function. Telomerase RNA component (TERC) is a long non-coding RNA that has been shown to extend telomere length in human stem cells.

To address TERC RNA's complex structure and other challenges, Nagpal and Agarwal have developed an enzymatic method that can stabilize RNAs of any size. They've also demonstrated that this form of engineered TERC (eTERC) can function within human cells—and appears to have a lasting, targeted effect.

After introducing eTERC into different types of cells, the team found that just one exposure appeared to increase telomere length in human stem cells, which lasted about 69 days—the equivalent of years of human life. What's more, eTERC left normal cell mechanisms intact. A paper on this work in Nature Biomedical Engineering.

"What's nice about this is that we can give telomeres a temporary boost that doesn't disrupt other natural cell processes," explains Agarwal. "It has one specific effect in cells and then it's gone."

Up next: finding a way to deliver eTERC to cells beyond the lab. Agarwal suspects that will involve a combination of approaches, such as nanotechnology and small molecule agents. He's optimistic that such an innovation is possible.

"At Boston Children's," he says, "we will develop and test every one of these strategies until we have effective treatments for TBDs."

Unraveling the genetics of telomere disease

Other teams at Boston Children's are focused on investigating the genetic underpinnings of TBDs. Studies have previously identified variants in genes that regulate telomere length, maintenance, structure, and function. However, those genetic variants can have wide-ranging effects in terms of TBD symptom severity, age of symptom onset, and which organs are affected.

For example, some people who carry variants in TBD-associated genes develop severe childhood-onset bone marrow failure, while others develop pulmonary fibrosis or liver disease as adults. Still others may never develop symptoms at all.

"People with variants in TBD-associated genes want to know whether they will develop severe disease," explains Vijay Sankaran, MD, Ph.D., a physician-scientist at Dana-Farber/Boston Children's Cancer and Blood Disorders Center. "But different families can have different mutations and members can be affected differently, even within the same family."

Sankaran and his team, led by MD-Ph.D. student Michael Poeschla, theorized that those differences might be the result of TBD-causal genetic variants combining with common genetic variations associated with telomere length in the general population. Using samples from the large UK Biobank, they developed polygenic scores to provide an estimate of this combined effect and then applied that estimate to various patient cohorts.

In work in the Journal of Clinical Investigation, they found that both rare, high-impact gene mutations and common, small-effect genetic variants seem to independently impact TBD development and severity.

For instance, people with severe, early-onset TBD tended to have polygenic scores that were linked to shorter telomeres. This suggests that many common genetic variants that slightly affect telomere length—not just one rare genetic variation—influence whether, or how severely, someone develops a TBD. It may also explain why relatives with the same rare variation experience differences in TBD development.

While it's too early to say whether the findings could be used clinically, Sankaran hopes that they will pave the way to future research and a better understanding of TBDs, as well as other genetic disorders with similar challenges.

"Families with rare genetic variants want to know what to expect," he says. "We're finally getting closer to some answers."