Senolytic drugs reverse premature blood stem cell ageing in sickle cell disease

Researchers have found that blood stem cells in children and young adults with sickle cell disease carry hallmarks of premature ageing, a discovery that may explain the condition’s raised risk of stem cell failure and blood cancers

Sickle cell disease causes blood stem cells to age prematurely, according to a study from St Jude Children’s Research Hospital, Memphis, Tennessee, USA. It also found that a class of drugs already in use to treat other conditions may be able to reverse the effect. Patients with sickle cell disease experience higher rates of blood stem cell dysfunction and blood cancers than their peers, though the reason for this has not been clear. 

Researchers at St Jude have found that blood stem cells from young patients with sickle cell disease carry features of ageing, likely raising the risk of further complications. Giving the test subjects senolytics – a class of drugs that target processes related to ageing – improved disease symptoms in laboratory models with implications for curative gene therapies.

“We saw that blood stem cells from even young patients with sickle cell disease have many markers of senescence or aging,” said Dr. Shannon McKinney‑Freeman, senior co‑corresponding author and a member of the St Jude Department of Haematology.

“They become incapable of doing their job of making all other blood cells, including oxygen‑carrying red blood cells. But when we gave anti‑aging drugs we eliminated these damaged cells and recovered the lost blood‑forming potential in the bone marrow,” she said.

Sickle cell disease is the most common genetic blood disorder in the world, affecting up to twenty million. In people with the disease, blood stem cells carry a mutation in the gene for haemoglobin, causing the red blood cells they produce to become sickle‑shaped and to fail to deliver oxygen effectively. This has many effects, including chronic stress on blood stem cells as they work to produce large numbers of red blood cells to compensate for their inefficiency at delivering oxygen around the body. The researchers set out to understand how that chronic stress affected these cells and uncovered a substantial effect in samples taken from patients.

“When we looked at blood stem cells from children and young patients with sickle cell disease – six to 23 years old – we saw their blood stem cells looked much older,” said Dr. Aditya Barve, first author of the study and a member of the St Jude Department of Haematology. The researchers then implanted the patients’ stem cells in mice and treated them with anti‑ageing therapy. The treatment significantly decreased markers of senescence and the scientists observed increased blood formation that matched that of a control group of mice without sickle cell disease that underwent the same process.

To extend the finding, the researchers repeated the process using two US Food and Drug Administration (FDA) approved senolytic drugs, dasatinib and quercetin, given in combination, and observed the same positive benefits. As the drugs are already approved by the FDA for another purpose, the approach could move more quickly into clinical testing, including to enhance ongoing curative gene therapy trials.

Curative gene therapy efforts for sickle cell disease have recently been complicated by variable outcomes. Gene therapy requires the collection of large numbers of a patient’s blood stem cells, alteration of their DNA to overcome the sickle cell mutation, and transplantation back into the patient to restore normal red blood cell production.

While gene therapy has the potential to cure a patient, it has experienced setbacks, including an inability to collect enough viable cells to begin treatment. And in the longer term some patients have developed blood cancers. The ageing findings offer an explanation for the disease’s increased incidence and suggest a route to improve both stem cell collection and long‑term results.

“When we alter cells with gene therapy, we are trying to cure patients for the rest of their lives through what is essentially a bone marrow transplant using their own blood stem cells,” said Dr. Akshay Sharma, co‑corresponding author and a member of the St Jude Department of Bone Marrow Transplantation and Cellular Therapy.

“Before gene therapy existed, we performed transplants for patients with sickle cell disease using blood stem cells from a donor, trying to find a young and healthy donor, because stem cells that are decades older than the patient may not remain ‘fit’ for the patient’s lifetime.

“Our findings show that we also need to consider methods to eliminate the older senescent cells and enrich for young, functional stem cells from a patient before collecting them for gene therapy,” he added.

Current approaches to collecting the cells needed for gene therapy do not take senescent cells into account. The research provides a starting point for further work into how this might be addressed, whether through senolytic therapy or another mechanism, potentially improving stem cell collection and the quality of starting material, and in turn the outcomes of gene therapy.

“Both anti‑aging drugs and gene therapies are still relatively new. By combining our knowledge of these novel approaches with fundamental research into how sickle cell disease manifests in blood stem cells, we’ve opened a completely new field to explore for improving the lives of the many people impacted by this disorder,” McKinney‑Freeman concluded.

For further reading please visit: 10.1126/scitranslmed.adv0628