Engineered telomerase RNA and polygenic scores reveal new insights into telomere biology

Similar to the way in which traffic jams at the ends of a lace prevent him from fraying, telomeres – repetitive DNA sequences and a protein structure – protect the point from chromosomes from damage.

Whenever our cells are divided, the telomeres lose a little of this DNA. Finally, telomeres become so short that they can no longer continue to divide and chromosomes lose their protection. When there is a significant drop in the number of cells that can be divided, tissues and organs lose their ability to undergo the renewal processes that support a healthy function. Telomeres are naturally shortening as we age, but in people with Telomeres Biology Disorders (TBD) such as Critératose Critonita, this process is accelerated.

The essential role that telomeres play in aging and age -related diseases have long made a target of research. Recent works at Boston Children continue to expand our understanding of telomeres and set the foundations for new approaches to TBD.

An approach to one and a lengthening of telomeres

For more than a decade, Suneet Agarwal, MD, PH.D., Leader co-program of the hematopoietic cell transplant program (STEM) of Boston Children’s, sought a way to lengthen telomeres and bring the cellular aging process. A large part of the work of its laboratory focused on telomerase, an enzyme that strengthens shortcut telomeres: could we manipulate telomerase to support the maintenance of telomeres, potentially opening the door to new TBD treatments? The question sparked Agarwal and his colleague Neha Nagpal, Ph.D., to investigate more.

The progress of chemical engineering has led to improved synthetic RNA with therapeutic uses. However, some RNA classes pose engineering challenges due to their size and function. The component of the telomerase RNA (TERC) is a long non -coding RNA which has proven to extend the length of the telomeres in human stem cells.

To identify the complex structure of TRC RNA and other challenges, Nagpal and Agarwal have developed an enzymatic method that can stabilize RNA of any size. They have also shown that this modified form of Terc (ETERC) can work in human cells and seems to have a lasting targeted effect.

After introducing Eterc into different types of cells, the team found that one exposure seemed to increase the length of the telomeres in human stem cells, which lasted around 69 days – the equivalent of years of human life. In addition, Etter has left intact normal cellular mechanisms. An article on this work appears in Biomedical engineering of nature.

“What is good on this subject is that we can give the telomeres a temporary boost which does not disturb other natural cellular processes,” explains Agarwal. “It has a specific effect in the cells, then it disappeared.”

According to: Find a way to deliver ETERM to cells beyond the laboratory. Agarwal suspects which will imply a combination of approaches, such as nanotechnology and agents of small molecules. It is optimistic that such an innovation is possible.

“At Boston Children’s”, he says, “we will develop and test each of these strategies until we have effective treatments for TBDs”.

Decrocketing the genetics of telomeres disease

Other Boston Children’s teams focus on studying the genetic foundations of TBD. Studies have previously identified variants in genes that regulate the length, maintenance, structure and function of telomeres. However, these genetic variants can have large -scale effects in terms of severity of TBD symptoms, the age of the appearance of symptoms and affected organs.

For example, some people carrying variants in genes associated with TBD develop a serious failure of the bone marrow of childhood, while others develop pulmonary fibrosis or hepatic disease in adulthood. Still others may never develop symptoms.

“People with variants in genes associated with TBD want to know if they are developing a serious illness,” said Vijay Sankaran, MD, PH.D., doctor-scientist in 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 these differences could be the result of TBD genetic-causal variants combining with common genetic variations associated with the length of telomeres in the general population. Using samples from the British British Biobank, they have developed polygenic scores to provide an estimate of this combined effect, then applied this estimate to various cohorts of patients.

In work published in the Journal of Clinical InvestigationThey found that rare and high impact genes and current genetic variants and with small effects seem to have an independent impact on the development of TBD and gravity.

For example, people with severe early TBD tend to have polygenic scores linked to shorter telomeres. This suggests that many common genetic variants which slightly affect the length of telomeres – not a single rare genetic variation – influence that, or to what extent someone develops a TBD. This can also explain why relatives with the same differences in rare variation experience the development of TBD.

Although it is too early to say if the results could be used clinically, the Sankaran hopes that they will open the way for 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 are finally getting closer to certain answers.”