Sigh of relief as new study identifies possible drug treatments for telomere diseases – are we finally edging closing to unlocking the potential of telomerase?
A new study by researchers at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center could lead to a breakthrough in tackling so-called telomere diseases.
Longevity.Technology: Telomeres provide a natural countdown for our cells, ticking towards natural cell death with each replication. Unlocking the secrets of telomerase – the enzyme that maintains and rebuilds our telomeres and using it to extend and preserve life – has been a goal of science ever since its Nobel prize-winning discovery in 2009. However, its early promise was not borne out in therapies. Until now.
Telomere diseases cause cells to age prematurely because their telomere length can no longer be maintained. This can result in aplastic anemia, liver cirrhosis, and pulmonary fibrosis, among other diseases. If we can tackle these diseases, then there is hope for more general age-extension therapy from targeting telomeres.
Study senior investigator Suneet Agarwal said: “Once human telomerase was identified, there were lots of biotech startups, lots of investment, but it didn’t pan out. There are no drugs on the market, and companies have come and gone .”
The study used cells donated by patients with dyskeratosis congenita (DC), a rare genetic form of bone marrow failure caused by genetic mutations which cause aberrations in telomere length that leave the marrow unable to produce sufficient blood cells.
The current treatment for DC is a bone marrow transplant; this is a is high-risk procedure which is only able to help restore the blood system, whereas DC affects multiple organs.
The genetic mutations that cause DC disrupt telomerase formation or function by disrupting two molecules called TERT and TERC. TERT is an enzyme made in stem cells, and TERC is a so-called non-coding RNA that acts as a template to create telomeres’ repeating DNA sequences; TERT and TERC join together to form telomerase.
One of the key genes in the process is PARN, which is key in the processing and stabilising of TERC. When PARN is mutated, the result is less TERC, less telomerase and prematurely-shortened telomeres. Neha Nagpal, first author on the paper detailing the study, explained that the team focused on enzyme PAPD5, which opposes PARN and destabilises TERC: “We thought if we targeted PAPD5, we could protect TERC and restore the proper balance of telomerase.”
Following large-scale screening studies to identify PAPD5 inhibitors, the team tested inhibitors in stem cells drawn from DC sufferers and discovered boosted TERC levels and telomeres that had been restored to their normal length.
“…restoring telomeres in stem cells will increase tissue regenerative capacity in the blood, lungs, and other organs…”
In order to ascertain the treatment was safe, the research team induced DC-causing PARN mutations in human blood stem cells which they then transplanted into mice which were then treated with oral PAPD5 inhibitors. The results were the same – boosted TERC levels, restored telomere length and no adverse effects on the mice or their cell-forming abilities.
“This provided the hope that this could become a clinical treatment,” says Nagpal .
The team are now working on validating PAPD5 inhibition for other diseases that result from telomere maintenance deficiency and are developing two compounds, known as BCH001 and RG7834, which are still under wraps for now.
Argawal commented: “We envision these to be a new class of oral medicines that target stem cells throughout the body. We expect restoring telomeres in stem cells will increase tissue regenerative capacity in the blood, lungs, and other organs affected in DC and other diseases .”