A compound that improved DNA repair in cells from patients with progeria and Down syndrome extended median lifespan by 8,6% in mice with progeria, a disease that causes accelerated aging
A compound that improved DNA repair in cells from patients with progeria and Down syndrome extended median lifespan by 8,6% in mice with progeria, a disease that causes accelerated aging
On November 1, Nature Communications published a study by Elsa Logarinho’s group at the University of Porto. The compound UMK57 increases the activity of KIF2C, a protein that dismantles microtubules, the filaments that form part of the cell’s internal skeleton. It reduced the number of unrepaired DNA breaks in patients’ skin cells. In mice with progeria, median lifespan was 17,1 weeks with treatment, compared with 15,7 weeks without treatment.
When both strands of DNA break, the cell needs to bring the broken ends together. In 2024, a University of Toronto group described how this happens: microtubules push the nuclear envelope inward to form a tubular fold, which captures the break and allows its ends to meet. These folds require microtubule turnover: some filaments grow while others are dismantled, with KIF2C responsible for dismantling them. In 2020, another group showed that without KIF2C, repair becomes less effective, breaks accumulate, and their movement within the nucleus is impaired.
Logarinho’s group found in 2020 that skin cells from older people contain less KIF2C than those from younger people, and that UMK57 reduces chromosome segregation errors and slows cellular senescence. The authors have now tested whether the compound also promotes DNA repair independently of cell division, using cells from patients with two conditions associated with excess DNA damage and accelerated aging. These are Hutchinson-Gilford progeria, in which a mutation in the LMNA gene distorts the shape of the nucleus, and Down syndrome, which involves an extra copy of chromosome 21. Cells from patients with either condition contain less KIF2C than cells from healthy children and have more stable microtubules.
In progeria cells, UMK57 restored normal microtubule turnover, and in cells from both conditions, it reduced the number of unrepaired breaks. After exposure to etoposide, a drug that causes DNA breaks, the proportion of cells with nuclear envelope folds increased in healthy cells but remained unchanged in patient cells. With UMK57, this proportion also increased in patient cells, and the number of breaks fell. In another experiment, an hour of etoposide treatment caused breaks in most cells of all types. Over the next day, patient cells repaired these breaks less effectively, but with UMK57, their repair approached that of healthy cells. The numbers of misshapen nuclei and senescent cells also fell.
The researchers used two control experiments to test whether the effect depended on KIF2C. UMK95 differs from UMK57 by a single chemical group and does not accelerate microtubule disassembly in vitro; it had no effect in progeria cells. When KIF2C was almost completely depleted, UMK57 lost its effect because little KIF2C remained for it to activate. With partial depletion, the effect persisted. Errors during cell division also cause DNA breaks, so the researchers arrested healthy cells in G1, preventing division, and exposed them to etoposide. UMK57 reduced the number of breaks in these cells as well.
Mice with progeria were treated from 5 to 13 weeks of age. The compound has poor solubility, and liver enzymes broke it down within minutes in vitro, so it was delivered continuously through a subcutaneous pump. In the survival experiment, mice were euthanized after losing 25% of their body weight or becoming severely ill. Median lifespan was 17,1 weeks in the 16 treated mice, compared with 15,7 weeks in the 14 controls. Treated mice began losing weight later, and their spinal curvature was reduced by almost 40%. Wasting also developed in the treated mice toward the end of life.
The authors write that few interventions currently enhance DNA repair because it requires several pathways to work together, “which cannot simply be enhanced by increasing the activity of just one or a few genes.” UMK57 acts at the step where the broken ends are brought together: it increases KIF2C activity and, in turn, microtubule turnover. The authors next plan to test the compound in mice with Down syndrome, refine it, and assess its safety. Logarinho is listed as an inventor on a patent covering the use of UMK57.