Scientists at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center have published a study “Small-Molecule PAPD5 Inhibitors Restore Telomerase Activity in Patient Stem Cells” in Cell Stem Cell that may offer a breakthrough in treating dyskeratosis congenita (DC) and other so-called telomere diseases, in which cells age prematurely. Using cells donated by patients with the disease, the researchers identified several small molecules that appear to reverse this cellular aging process.
Suneet Agarwal, MD, PhD, the study’s senior investigator, hopes at least one of these compounds will advance toward clinical trials. If so, it could be the first treatment for DC that could reverse all of the disease’s varying effects on the body. The current treatment, bone marrow transplant, is high-risk, and only helps restore the blood system, whereas DC affects multiple organs.
“Genetic lesions that reduce telomerase activity inhibit stem cell replication and cause a range of incurable diseases, including dyskeratosis congenita (DC) and pulmonary fibrosis (PF). Modalities to restore telomerase in stem cells throughout the body remain unclear. Here, we describe small-molecule PAPD5 inhibitors that demonstrate telomere restoration in vitro, in stem cell models, and in vivo. PAPD5 is a non-canonical polymerase that oligoadenylates and destabilizes telomerase RNA component (TERC),” write the investigators.
“We identified BCH001, a specific PAPD5 inhibitor that restored telomerase activity and telomere length in DC patient induced pluripotent stem cells. When human blood stem cells engineered to carry DC-causing PARN mutations were xenotransplanted into immunodeficient mice, oral treatment with a repurposed PAPD5 inhibitor, the dihydroquinolizinone RG7834, rescued TERC 3′ end maturation and telomere length. These findings pave the way for developing systemic telomere therapeutics to counteract stem cell exhaustion in DC, PF, and possibly other aging-related diseases.”
The compounds identified in the study restore telomeres, protective caps on the tips of our chromosomes that regulate how our cells age. Telomeres consist of repeating sequences of DNA that get shorter each time a cell divides.
The body’s stem cells, which retain their youthful qualities, normally make telomerase that builds telomeres back up again. But when telomeres can’t be maintained, tissues age before their time. A spectrum of diseases can result—not just DC, but also aplastic anemia, liver cirrhosis, and pulmonary fibrosis.
The discovery of telomerase 35 years ago, earning a Nobel Prize in 2009, galvanized the scientific world. Subsequent studies suggested the enzyme could be a key to reversing aging, as well as treating cancer, in which malignant cells become “immortal” and divide indefinitely.
For years, researchers have tried to find a simple and safe way to manipulate telomerase, preserve telomeres, and create cures for telomere diseases.
“Once human telomerase was identified, there were lots of biotech startups, lots of investment,” says Agarwal, who has researched the biology of telomerase for the past decade. “But it didn’t pan out. There are no drugs on the market, and companies have come and gone.”
DC can be caused by mutations in any of multiple genes. Most of these mutations disrupt telomerase formation or function—in particular, by disrupting two molecules called TERT and TERC that join together to form telomerase. TERT is an enzyme made in stem cells, and TERC is a non-coding RNA that acts as a template to create telomeres’ repeating DNA sequences. Both TERT and TERC are affected by a web of other genes that tune telomerase’s action.
One of these genes is PARN. In 2015, Agarwal and colleagues showed in Nature Genetics that PARN is important for processing and stabilizing TERC. Mutations in PARN mean less TERC, less telomerase, and prematurely shortened telomeres.
The new study, led by postdoctoral fellow Neha Nagpal, PhD, delved further, focusing on an enzyme that opposes PARN and destabilizes TERC, called PAPD5.
“We thought if we targeted PAPD5, we could protect TERC and restore the proper balance of telomerase,” says Nagpal, first author on the paper.
Nagpal and her colleagues first conducted large-scale screening studies to identify PAPD5 inhibitors, testing more than 100,000 known chemicals. They got 480 initial hits, which they ultimately narrowed to a small handful.
They then tested the inhibitors in stem cells made from the Martins’ cells and those of other patients with DC. The compounds boosted TERC levels in the cells and restored telomeres to their normal length.
But the real challenge was to see if the treatment would be safe and specific, affecting only the stem cells bearing TERT. To test this, the team introduced DC-causing PARN mutations into human blood stem cells, transplanted those cells into mice, then treated the mice with oral PAPD5 inhibitors. The compounds boosted TERC and restored telomere length in the transplanted stem cells, with no adverse effect on the mice or on the ability to form different kinds of blood cells.
“This provided the hope that this could become a clinical treatment,” says Nagpal.
In the future, Agarwal, Nagpal, and colleagues hope to validate PAPD5 inhibition for other diseases involving faulty maintenance of telomeres—and perhaps even aging itself. They are most excited about two compounds, known as BCH001 and RG7834 that are under further development.
“We envision these to be a new class of oral medicines that target stem cells throughout the body,” Agarwal says. “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.”