As cells divide over time, the telomeres — long, protective DNA sequences at the ends of chromosomes — gradually shorten. When they become too short, cells stop dividing in an effort to protect against DNA damage, causing tissues to age. However, in people born with abnormally short telomeres, known as telomere biology disorders (TBDs), cells stop dividing too early, leading to a range of medical complications including bone marrow failure, pulmonary fibrosis, and an increased risk of cancer.
In a recent study, researchers at Elixirgen Therapeutics — a clinical-stage biotech company co-founded by biologist Aki Ko — tested a new gene therapy for TBDs in individuals with bone marrow failure (1). The therapy, called EXG-34217, uses a virus to deliver ZSCAN4 — a gene encoding a protein that extends telomeres — into the patient’s own stem cells. In two individuals, the therapy successfully lengthened telomeres and improved immune cell counts without causing major adverse side effects, pointing to EXG-34217 as a promising new therapy for TBD-related bone marrow failure.
Since co-founding Elixirgen Therapeutics in 2017, Aki Ko has served as the biotech company's Chief Executive Officer.
Credit: Elixirgen Therapeutics
“[TBDs] are caused by mutations in genes that encode a number of proteins that regulate telomeres,” said Chantal Autexier, a cell biologist at McGill University who was not involved in the study. Such mutations usually affect genes that produce or stabilize telomerase, an enzyme that helps maintain telomere length by adding repeat DNA sequences to the ends of chromosomes after each cell division. Although TBDs can impact any tissue with high cell turnover, “often, the cause of early death is bone marrow failure,” noted Autexier.
With this in mind, Ko and his team sought to develop new therapies to extend telomeres in individuals with TBD-related bone marrow failure. The team began by isolating hematopoietic stem cells (HSCs) from people with TBDs. HSCs reside in the bone marrow and give rise to all blood cell types, including those of the immune system. Building on earlier studies showing that ZSCAN4 protein expression could lengthen telomeres in preclinical TBD models, the team treated the isolated HSCs ex vivo with a viral gene therapy vector engineered to deliver the human ZSCAN4 gene (2). ZSCAN4 elongates telomeres through telomere recombination, a telomerase-independent process that extends shortened telomeres using intact ones as templates. This treatment produced a modified stem cell product — EXG-34217 — which was then prepared for reinfusion into the patients.
Before infusing the treated cells, the team examined them to see if the therapy was working. “We found already that at the ex vivo stage, before they’re being returned to the patient, the hematopoietic stem cells already had extended telomeres,” said Ko. “That's a good sign; ZSCAN4 extended the telomeres in that state.”
However, Ko and his team needed to determine whether EXG-34217 effectively extended telomeres in vivo after reinfusion. “Do these hematopoietic stem cells with longer telomeres then create different blood cells that also have longer telomeres?” he asked. To answer this, the team followed up with the treated patients at five and 24 months post-treatment to assess whether telomere elongation persisted in the blood cells that developed from reinfused HSCs.
They found that both patients who received the therapy showed increased neutrophil counts in their blood, indicating stronger bone marrow function and immune recovery. In one patient, the therapy also extended telomere length in lymphocytes, one of the major cell types into which HSCs differentiate in the body.
One of the key principles for our company is patient-centric design of the therapies from the ground up.
– Aki Ko, Elixirgen Therapeutics
Additionally, neither patient experienced any significant adverse effects from the therapy. “This was very important for us,” said Ko. “One of the key principles for our company is patient-centric design of the therapies from the ground up. And so, we have done a lot … to make this particularly gentle as a treatment for the patients.”
Autexier concurred that EXG-34217’s safety profile set it apart from the only currently available treatment for TBD-related bone marrow failure: HSC transplantation. Because patients with TBDs are highly sensitive to DNA damage, the conditioning regimens needed for a transplant — such as chemotherapy or radiation — can speed up disease progression. “This provides an alternative … or at least maybe a little bit of an improvement over the current therapy,” she said.
Nonetheless, Autexier noted that one key limitation of the study was that “they only had two patients.” She added, “It would be nice to have more patients and more characterization of the cells in which they measure the telomere length.”
Despite these limitations, Ko remains optimistic that ongoing research into ZSCAN4-induced telomere elongation could present a promising new avenue for treating TBD-related bone marrow failure. “We will continue to enroll and treat patients and see some additional data,” he said. “Hopefully we can bring this towards approval soon.”
References
- Myers, K.C. et al. Clinical use of ZSCAN4 for telomere elongation in hematopoietic stem cells. N Engl J Med Evid 4, EVIDoa2400252 (2025).
- Zalzman, M. et al. Zscan4 regulates telomere elongation and genomic stability in ES cells. Nature 464, 858–863 (2010).
