Developing life-saving cures for primary immunodeficiency diseases.
Harnessing a Virus to Cure Patients Born With Genetic Immune Diseases
With the goal of curing primary immunodeficiency diseases, we are developing tools to transfer a working version of a mutant gene into a patient’s own bone marrow stem cells. Taking advantage of lentiviruses that other labs have engineered for safe use in humans, our scientists have inserted fragments of human DNA that will encode the corrected protein in the specific cell that needs it.
Primary immunodeficiency diseases (PIDDs) effect 1 in 500 people and are caused by inheriting a genetic defect (or "mutation") in one of our estimated 30,000 genes. The mutations result in mild to severe deficits in the immune system’s ability to fight bacterial, fungal, or viral pathogens. There are several hundred PIDDs currently described. Our immune cells turn over frequently and are constantly replaced by parental cells (called hematopoietic stem cells) that are located in our bone marrow. Compared to stem cells that replenish cells in other tissues, hematopoietic stem cells (HSCs) are relatively accessible, and many PIDDs can be treated by transplanting patients with HSCs from a healthy matched donor. Not all patients have a matched donor, however. For these cases, lentiviral gene therapy could provide a back-up option for a cure.
In lentiviral gene therapy, HSCs would be extracted from the patient, then taken to the lab, where they would be infected with the lentiviral gene therapy vector. Although the parts of the virus that allow it to replicate have been deleted, the virus is still able to integrate into the patient's genomic DNA. The result is the permanent addition of the corrective gene in the patients' HSCs. The HSCs would then be infused back into the patient; once in the patient, they will engraft into the bone marrow and begin to make immune cells that have the correct protein.
We are currently participating in a clinical trial of a gene therapy for X-linked severe combined immunodeficiency (X-SCID). We also plan to open similar trials for Wiskott-Aldrich syndrome (WAS; WAS gene mutation), X-linked agammaglobulinemia (XLA; BTK gene mutation) and X-linked hyper-IGM syndrome (X-HIGM; CD40L gene mutation) soon thereafter. Our researchers are building a pipeline of gene therapies that could eventually be used to treat hundreds of genetic immune disorders.
Precision Gene Editing to Correct Genetic Mutations
Our vision for the next generation of therapies for primary immunodeficiencies and other blood diseases is to insert corrective DNA directly into the mutant gene itself. This would allow us to use the cells' existing methods of regulating when and where the gene is turned on and off. This vision is rapidly becoming a reality, with the use of novel designer nucleases such as CRISPR/Cas9.
Most cells have "nucleases" – enzymes that metabolize DNA- that are used, for example, when fixing DNA breaks or as protection from foreign organisms. Scientists in the Center for Immunity and Immunotherapies were part of an NIH Roadmap initiative to develop nucleases that could be used to create a DNA break specifically within a defective gene of interest. If this break could be created in combination with delivering a piece of DNA that the cell could use as a "template" for repairing the DNA break, then the cell’s own DNA repair machinery (called homology-directed repair, or HDR) would incorporate the DNA template directly into the gene of interest, seamlessly repairing the break with the inserted DNA. The use of designer nucleases to create specific cut sites in genomic DNA, either with or without a donor template, is called gene editing.
Our scientists are rapidly advancing technologies that we will one day use to precisely edit defective genes in a patient’s own hematopoietic stem cells, in order to cure devastating immunodeficiency diseases such as immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX; FOXP3 gene mutation), X-linked hyper-IgM (X-HIGM; CD40L gene mutation), X-linked agammaglobulinemia (XLA; BTK gene mutation), Wiskott-Aldrich syndrome (WAS; WAS gene mutation), as well as hemoglobinopathies such as sickle cell disease and β-thalassemia (HBB gene mutations).