CureSC: Moving Promising Genetic Therapies Safely into Clinical Trials

The NHLBI Cure Sickle Cell Initiative (CureSC) focuses on curative gene therapies while further examining the total effects of sickle cell disease (SCD) on a person’s life — from their mental health to their work and finances.

  • CureSC is funding two clinical trials in conjunction with the California Institute of Regenerative Medicine (CIRM). It is also funding data collection to allow for a comparative, contemporaneous cohort of patients who have not received curative therapies. This will provide comparator data to the investigators as well as to the FDA to demonstrate the effects of these genetically based curative therapies.
  • NHLBI is conducting clinical trials for potential curative therapies. NHLBI researchers are now using the ReFRAME drug repurposing library, which looks at drugs that are already FDA-approved and have the potential to treat SCD pain in a cost-effective way.

Understanding VEXAS

VEXAS syndrome is a disease that causes inflammatory and hematologic (blood) manifestations. The syndrome, first described by NIH researchers in 2020, is caused by somatic mutations in the UBA1 gene of blood cells and acquired later in life.

  • NHLBI researchers found that patients with VEXAS syndrome are at high risk of thrombosis, mainly venous, which can be recurrent despite use of blood thinners.
  • A small study showed that an increase in white blood cell count may be the first sign of VEXAS in some patients. Researchers suggested UBA1 mutation testing, particularly in older men with other blood count abnormalities.
  • Researchers are conducting a clinical trial to understand whether stem cell transplants may be a curative therapy for VEXAS.

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Advancing Research in Bone Marrow Transfers and Aplastic Anemia

Results from a recent NHLBI-supported study showed that adult blood cells are derived not just from blood stem cells (hematopoietic stem cells) as previously believed but also from long-lived embryonic blood progenitors. These findings could spark new strategies for developing treatments for blood disorders and cancers, as well as improve outcomes of bone marrow transplants.

  • In early 2023, NHLBI is starting a new clinical trial that will study a potential new curative therapy for aplastic anemia, a rare autoimmune condition resulting in anemia.
  • The therapy, ruxolitinib, is currently FDA-approved for myeloproliferative neoplasms and graft-versus-host disease. In a recent animal trial, ruxolitinib treatment resulted in prolonged overall survival and alleviated T-cell–mediated immune destruction.

Therapeutic Approaches to SCD

Sickle cell disease (SCD) and beta-thalassemia are caused by certain mutations in a gene that creates hemoglobin. The gene, called beta-globin, is turned on in red blood cells (RBCs) around the time of birth as the fetal version, called gamma-globin, is turned off. However, under the stress condition of hypoxia (low oxygen), gamma-globin genes are turned on in adults, and adult expression of gamma-globin can alleviate symptoms in people with SCD and beta-thalassemia.

  • A recent NHLBI-supported study identified a new molecular pathway, which is sensitive to oxygen levels, that turns on the gamma-globin gene in adult RBCs. Hypoxia stabilizes hypoxia-inducible factor 1 (HIF1), which turns on the gamma-globin gene in adult RBCs.
  • Using young red blood cells from individuals with SCD and testing in vitro, researchers found that prolyl- hydroxylase inhibitors (PHIs) can stabilize HIF1, leading to increased fetal hemoglobin and significantly less sickling of cells. This important finding could lead to new therapeutic approaches for reversing disease progression in people with these conditions.

Developing and improving treatments for the severe pain episodes that people with SCD endure has been front and center for NHLBI.

  • This year, a proof-of-concept clinical study by NHLBI scientists showed that the pyruvate kinase activator mitapivat (AG-348) improved molecular hallmarks of SCD, increased blood oxygen levels, and reduced sickling in patients with sickle cell anemia.
  • Another SCD study identified 20 compounds in existing FDA-approved drugs that may be repurposed to treat SCD pain.
  • Should some of these therapies become available, millions of people around the world could have improved access to safe, affordable treatments.