New project to explore development of innovative gene therapy approach that could potentially lead to one-time cure for sickle cell disease
North Bethesda, Maryland, June 19, 2023—The Foundation for the National Institutes of Health and the National Heart, Lung, and Blood Institute (NHLBI) are launching a new project to develop a targeted gene editing method that could eventually lead to a safe and effective cure for sickle cell disease, especially for patients living in low-income countries with limited healthcare resources.
Sickle cell disease (SCD) is an inherited condition caused by a mutation in the gene associated with the production of hemoglobin, the protein inside red blood cells that carries oxygen to the body. The altered hemoglobin causes the red blood cells to develop an abnormal sickle shape that can block the flow of blood and lead to recurring pain, multi-organ damage, and early mortality. SCD affects an estimated 100,000 people living in the United States and millions more throughout the world, disproportionately affecting populations of African descent1.
Currently, hematopoietic stem cell (HSC) transplantation—in which patients receive blood stem cells from a donor to establish healthy blood production—offers a one-time cure of SCD. However, tissue compatibility between donor and patient remains a problem, and only about 10% of individuals with SCD can find a well-matched donor. To resolve this issue, researchers have developed a gene therapy approach in which HSCs are harvested from a patient’s own bone marrow, genetically modified to repair the defective gene outside the body (ex vivo), and then transplanted back into the patient’s blood. Although ex vivo gene editing is demonstrating early success in modifying SCD and its symptoms in clinical trials, the procedure requires a cell processing center and related resources to procure the cells needed, limiting the treatment’s accessibility to patients in high-income countries.
This new project will explore techniques for delivering gene editing tools to HSCs entirely inside the body, or in vivo. Researchers will first identify molecules that bind to a protein found on the surface of HSCs. The selected molecules will be added to lentiviral vectors (LVs) and engineered lipid nanoparticles (LNPs), two vehicles that can be used to deliver genetic material to the targeted HSCs without causing infections. If either or both methods perform well in a lab setting, the gene delivery systems will be further evaluated by systemic injection of HSC-targeted LVs and LNPs in a mouse model transplanted with human HSCs. A successful outcome could lead to a one-shot cure of SCD at the DNA level. A proven in vivo gene therapy method also has the potential to make SCD treatment more broadly available, even in a low-resource setting, and could be applicable to other diseases, such as HIV-1 infection.
“The development of in vivo HSC gene therapy has been an ultimate dream for a few decades. Efficacy with acceptable safety outcomes has been proven with ex vivo gene therapy in SCD, and now, in vivo HSC gene therapy has become the major goal,” said Naoya Uchida, one of the investigators for the project at NHLBI. “While it remains challenging, the path to the goal has become clear and promises to ultimately deliver a one-time cure that could reach areas of the world where the infrastructure for ex vivo gene therapy is less feasible and the disease is more common.”
This project builds on efforts launched in 2019 to develop affordable, gene-based cures for SCD and HIV-12. The FNIH will partner with NHLBI, with funding from the Bill & Melinda Gates Foundation, which is investing more than $800,000 over three years. The FNIH will be responsible for the financial and administrative management of the project. The project aims to foster fundamental creative discoveries, innovative research strategies, and applications that will ultimately protect and improve health in the U.S. and the world. Learn more here
About the Foundation for the National Institutes of Health
The Foundation for the National Institutes of Health (FNIH) connects the world’s leading public and private organizations to accelerate biomedical breakthroughs for patients, regardless of who they are, where they live, or what disease they have. Together with leading scientists and problem-solvers, and a successful track record of navigating complex problems, the FNIH accelerates new therapies, diagnostics, and potential cures; advances global health and equity in care; and celebrates and trains the next generation of scientists. Established by Congress in 1990 to support the mission of the NIH, the FNIH is a not-for-profit 501(c)(3) charitable organization. For more information about the FNIH, please visit fnih.org.