UCLA researchers from the Department of Microbiology, Immunology and Molecular Genetics and Pediatrics have developed a potent bi-functional lentiviral expression vector to treat sickle cell disease and beta-thalassemia.
BACKGROUND: Beta-hemoglobinopathies, such as sickle cell disease and beta-thalassemia, are genetic disorders characterized by dysfunctional hemoglobin production due to a beta-globin gene mutation. These disorders can manifest in severe pain crises, stroke, and organ damage or life-long dependence on red blood cell transfusions. Most current therapies are limited and non-curative, with autologous hematopoietic stem cell transfer and gene therapy becoming a novel treatment option that can provide long-term clinical benefits. One such gene therapy option is the use of beta-globin lentiviral vectors which when introduced to patients, enable the production of healthy beta-globin proteins. However, a major limitation in these therapies is low titer due to vector size, which can lead to reduced transduction efficiency and increased clinical expense. Thus, devising a method to improve transduction efficiency and clinical targets of these vectors may provide valuable treatments to improve patient outcomes and minimize clinical costs of treating these debilitating diseases.
INNOVATION: Dr. Kohn and colleagues in the Department of Microbiology, Immunology, & Molecular Genetics at UCLA have developed a novel bi-functional lentiviral vector that can target beta-hemoglobinopathies and may be significantly more potent and effective than existing vectors. Researchers utilized the novel Mini-G lentiviral vector backbone with a reduced size to allow for a higher titer of production, yielding more patient doses of vector and increasing hematopoietic stem cell transduction efficiency. Additionally, inclusion of a reverse-orientation, modified anti-sickling beta-globin gene (BAS3-globin), and two regulatory microRNA elements that upregulates fetal globin expression by silencing transcription factors BCL11A and ZNF410 in this vector allows it to target sickle cell disease through two mechanisms: the production of an anti-sickling Beta-globin and the upregulation of fetal hemoglobin. Further, because of the ability of this vector to upregulate fetal hemoglobin, it may also be effective in patients with beta-thalassemia. Thus, this novel lentiviral vector may pose a more potent, accessible, and cost-effective treatment for patients with beta-hemoglobinopathies.
POTENTIAL APPLICATIONS:
- Treatment of beta-hemoglobinopathies.
ADVANTAGES:
- Uses the Mini-G vector to minimize vector size, allowing for high titer of production and stem cell transduction efficiency
- Utilization of two anti-sickling methods, including upregulation of fetal hemoglobin, allows this therapy to also be potentially useful for beta-thalassemia.
DEVELOPMENT-TO-DATE: UCLA researchers have developed a novel lentiviral vector for treatment of beta-hemoglobinopathies that combines two anti-sickling mechanisms to maximize treatment efficiency.
Related Papers (from the inventors only):
Hart, K. L. et al. A novel high-titer, bifunctional lentiviral vector for autologous hematopoietic stem cell gene therapy of sickle cell disease. Molecular Therapy - Methods & Clinical Development 32, 101254 (2024). https://pubmed.ncbi.nlm.nih.gov/38745893
KEYWORDS: Gene therapy, beta-hemoglobinopathies, lentiviral vector, shRNA, sickle cell disease, autologous stem cell therapy, clinical expense