Targeted Gene Delivery for Sickle Cell Disease

Sickle cell disease (SCD), an inherited condition caused by a mutation in the gene associated with the production of hemoglobin inside red blood cells, causes the formation of abnormal sickle-shaped blood cells that can block circulation 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 descent.

Current Treatments

Currently, hematopoietic stem cell (HSC) transplantation allows for a one-time cure of SCD; however, tissue compatibility between patient and donor remains a problem, and a suitable donor can be found for only about 10% of patients. Another approach is gene therapy in which HSCs are harvested from a patient’s own bone marrow, genetically modified outside the body (ex vivo), and then transplanted back into the patient’s blood. Although ex vivo gene editing has shown success in modifying SCD and its symptoms in clinical trials, the procedure requires a cell processing center and related resources, limiting the treatment’s accessibility to patients in high-income countries.

A New Approach

This project proposes to develop a method for targeted, efficient genetic modification to HSCs that could be used to develop an in vivo (in the body) gene therapy cure for sickle-cell disease. An in vivo solution that requires only an injection would remove some of the barriers to accessing treatment for SCD patients in low- and middle-income countries, which often have limited funds and resources for healthcare.

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. 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.

The metric for success in this study is the detection of LV gene marking or LNP-mediated gene delivery in more than 20% of cells in the humanized mouse model. A successful outcome could lead to the development of widely applicable gene therapies for SCD; gene delivery to HSCs may also be valuable for future HIV functional cure approaches.

The project aims to foster fundamental creative discoveries, innovative research strategies, and applications that will ultimately protect and improve health in the U.S., sub-Saharan Africa, and the world. This project builds on existing efforts within the Cellular and Molecular Therapeutics Branch of the National Heart Lung and Blood Institute (NHLBI) Intramural Research Program.