From surveillance to gene editing: Charting a new future for bone marrow failure care

In children, a low blood cell count can be caused by infections, autoimmune diseases or certain medications. However, in rare cases, sometimes as rare as one in a million, a low blood cell count is a sign of something very serious: The body cannot make enough blood cells. When this occurs, collectively these conditions are called bone marrow failure disorders. These disorders have distinct causes and clinical features, but they all share a capacity to advance into leukemia.

At St. Jude, scientists and clinicians are working to understand these rare disorders at their genetic roots. By combining expert surveillance, advanced sequencing and emerging genetic technologies, they are searching for ways to treat these rare but intense pediatric illnesses.

“Bone marrow failure syndromes are pre-leukemic conditions that greatly affect the quality of life,” said Marcin Wlodarski, MD, PhD, Department of Hematology, director of the Bone Marrow Failure and Myelodysplastic Syndrome Clinic (BMF/MDS Clinic). “There have been no new therapies for these diseases for at least 40 years, but we are working on new cures, such as gene editing, which are now on the horizon.”

When blood stem cells cannot meet demand

In bone marrow failure syndromes, a patient’s blood stem cells are unable to function properly. Responsible for making all other blood cells for the body, they fail to keep up with demand. As the body struggles to maintain enough blood cells, these stem cells acquire mutations that enable them to become fitter and reproduce faster. At first, that adaptation may help compensate for the shortage, which is necessary for these children to have enough blood cells. However, it can transform blood stem cells and lead to the pre-leukemic condition myelodysplastic syndrome (MDS). Certain secondary mutations can then drive progression to acute myeloid leukemia.

That risk makes surveillance central to care. If clinicians can detect concerning changes before leukemia develops, they may be able to intervene early. If problematic blood stem cells can be replaced with healthy, functional cells by transplantation before progression to leukemia, the source of the bone marrow failure should be gone, allowing the blood system to recover.

“Bone marrow transplant is the only existing curative treatment for bone marrow failures,” said Alyssa Kennedy, MD, PhD, Departments of Hematology and Pathology, who studies bone marrow failures and cares for patients in the BMF/MDS Clinic, “but there are major side effects of the procedure, so we only want to do it if necessary. If we go too early, we subject patients to unnecessary side effects; if we go too late, after progression to leukemia, outcomes are worse.”

Treating bone marrow failure symptoms

Before a transplant becomes necessary, care focuses largely on managing the consequences of low blood cell counts. Treatments focus on how bone marrow failure disorders consist of a lack of one or more of the major blood cells: red blood cells, white blood cells (including immune cells) or platelets. For example, the number one cause of mortality for bone marrow failure disorders is immunodeficiency. Without enough immune cells, patients can develop infections that their body is unable to control. Preventive measures can reduce that risk and help protect patients while they are being monitored.

Low platelet counts create a different challenge as it leads to excessive bleeding and impaired wound healing. Platelet infusions can help. Similarly, patients with too few red blood cells may experience fatigue and tissue damage because their organs are not receiving enough oxygen. Blood transfusions can temporarily ease those symptoms, but repeated transfusions lead to iron overload. That toxic accumulation of iron from these treatments limits their long-term utility.

Therefore, clinicians have tried to target stem cells directly. Giving growth factors or hormones can help blood stem cells grow and create more blood cells, addressing the core of these diseases. However, these approaches have many systemic side effects, also limiting their use.

“Unfortunately, we have already arrived at the horizon of our current capabilities,” Wlodarski explained. “The biggest promise is in new gene editing and gene therapy technologies that may be able to cure blood stem cells before the progression to the worst stages of the disease.”

Gene editing promises new cures for bone marrow failures

So far, researchers have uncovered over 160 genes that, when mutated, lead to bone marrow failure disorders. That genetic complexity presents a challenge, but it also creates a therapeutic opportunity. If the disease begins in blood stem cells, then repairing mutations in those cells could, in theory, restore healthy blood production.

Kennedy has focused on finding such a cure for Shwachman-Diamond syndrome (SDS). SDS is marked by bone marrow failure and pancreatic dysfunction, caused by mutations in blood stem cells. Kennedy’s lab is working to understand these underlying disease-causing mutations to determine whether there are possible gene editing solutions. If they can successfully alter blood stem cells’ DNA to a healthy state, corrected cells should have a competitive growth advantage over their uncorrected counterparts. This amplification effect is important, as many gene editors’ efficiency is low, but the growth advantage will likely overcome that issue in SDS.

“In a way, it’s the perfect disease to go after as a proof of principle that we can edit blood stem cells to cure these patients,” Kennedy said.

While SDS may serve as a proof of concept, understanding how to correct the gene or genes relevant to this one disease may not transfer to bone marrow failures caused by other mutations. Therefore, St. Jude launched the Partnership to Advance the Development of Individualized Genomic Medicines (PARADIGM) and Delivering Rare-disease In Vivo Editors (DRIVE), a program dedicated to creating a platform for bespoke gene therapies for rare bone marrow failure disorders.

Creating the future of bone marrow failure care

For those patients who find themselves among the one in a million who face these rare disorders, the BMF/MDS Clinic is one of the few specialty clinics that has a staff experienced in treating and managing these diseases. Combining that clinical excellence with investigations into the genetic and molecular bases of these disorders, St. Jude scientists are finding the targets that could lead to new, improved treatments or cures for these children. Together, they are building a new future of bone marrow failure care.

“Approaches like gene editing and gene therapy are still in their infancy and will not be available for some time, but a decade from now, the entire landscape of bone marrow failure disorders could be changed,” Wlodarski said. “Until then, we will continue to give patients the best care we can, surveilling them for progression and treating them using the latest and best evidence, so that they can have the best quality of life possible.”