U01HL163983

Novel therapeutic gene editing to induce fetal hemoglobin for sickle cell disease - project summary

Despite advances in the medical care of sickle cell disease (SCD), most patients continue to experience debilitating pain, poor quality of life, progressive organ deterioration, and premature death. We are developing a novel, potentially curative therapy for SCD based on genome editing of autologous hematopoietic stem cells (HSCs) to induce the production of fetal hemoglobin (HBF, 22) in red blood cells (RBCs).

Natural genetic variants can generate high levels of HBF that alleviate or eliminate the pathophysiology of SCD. Our published studies show that one of these variants can be recreated by CAS9-mediated disruption of a -globin gene promoter motif recognized by BCL11A, a transcriptional repressor protein that drives the normal perinatal switch from -globin to -globin expression.

New preliminary data show that transfection of normal or SCD patient donor CD34+ cells with ribonucleoprotein (RNP) complex consisting of CAS9 and guide RNA (gRNA) targeting the BCL11A binding motif, followed by xenotransplantation into immunodeficient mice, consistently achieved =70% on-target editing in bone marrow-repopulating HSCs, with no off-target mutations detected by rigorous genome-wide activity analysis at a sensitivity of 0.1%.

The modified HSCs generated RBCs in vivo with >30% pancellular HBF and 18-31% sickling in 2% O2, compared to <5% HBF and 62-71% sickling in unmodified control RBCs (p<0.0001).

We will now translate our findings "from bench to bedside" by designing and carrying out a first-in-human clinical study, termed St. Jude Autologous Genome Edited Stem Cells (SAGES1), examining the safety and efficacy of autologous -globin promoter-edited CD34+ cells (drug product SJ-1001) according to 3 aims.

Aim 1 will define the mechanism of action, potency, and safety profile of SJ-1001 through FDA-enabling and exploratory research studies.

Aim 2 will establish CGMP clinical scale manufacturing of SJ-1001 by optimizing process development, generating drug product release assays for the clinical trial, and transferring these protocols to the St. Jude Current Good Manufacturing Practice (CGMP) facility.

Aim 3 will establish and manage the SAGES1 clinical trial to evaluate one-time SJ-1001 infusion as a cure for SCD. This will include the development of an enhanced multidisciplinary informed consent process, safety and efficacy assessments, and post-therapy mechanistic studies.

Our work has the potential to relieve suffering and extend the lifespan of thousands of patients with severe SCD.

St. Jude Children's Research Hospital

THE DIVISION OF BLOOD DISEASES AND RESOURCES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE PATHOPHYSIOLOGY, DIAGNOSIS, TREATMENT, AND PREVENTION OF NON-MALIGNANT BLOOD DISEASES, INCLUDING ANEMIAS, SICKLE CELL DISEASE, THALASSEMIA, LEUKOCYTE BIOLOGY, PRE-MALIGNANT PROCESSES SUCH AS MYELODYSPLASIA AND MYELOPROLIFERATIVE DISORDERS, HEMOPHILIA AND OTHER ABNORMALITIES OF HEMOSTASIS AND THROMBOSIS, AND IMMUNE DYSFUNCTION. FUNDING ENCOMPASSES A BROAD SPECTRUM OF HEMATOLOGIC INQUIRY, RANGING FROM STEM CELL BIOLOGY TO MEDICAL MANAGEMENT OF BLOOD DISEASES AND TO ASSURING THE ADEQUACY AND SAFETY OF THE NATION'S BLOOD SUPPLY. PROGRAMS ALSO SUPPORT THE DEVELOPMENT OF NOVEL CELL-BASED THERAPIES TO BRING THE EXPERTISE OF TRANSFUSION MEDICINE AND STEM CELL TECHNOLOGY TO THE REPAIR AND REGENERATION OF HUMAN TISSUES AND ORGANS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Memphis, Tennessee 38105 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Required) (PA-20-183)

Amendment Since initial award the End Date has been extended from 08/31/27 to 08/31/28 and the total obligations have increased 198% from $1,183,000 to $3,525,340.