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Principal Investigator: David Scott Johnson
Organization: GIGAMUNE, INC.
Fiscal Year: 2024
Award: $300,000
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
Project Title: In vivo Sickle Cell Disease Gene Therapy Using a Novel Virus Like Particle
Organization: GigaMune, Inc.
PI: David S. Johnson, Ph.D.
β-hemoglobinopathies are the most common monogenic disorders worldwide. These autosomal recessive
disorders affect the normal production of adult hemoglobin due to mutations in the β-globin gene. The two most
common diseases are: i) β-thalassemia, which is characterized by low or absent β-globin production, and ii)
sickle cell disease (SCD), in which a mutant form of β-globin is produced that results in red blood cells (RBCs)
shaped like “sickles” rather than the normal disc shape.
Gene therapies could provide life-long cures for these patients. The FDA recently approved Zynteglo, an ex vivo
manufactured cell-based gene therapy, for the treatment of β-thalassemia and is reviewing two ex vivo gene
therapies (lovo-cel and exa-cel) for β-hemoglobinopathies. Ex vivo gene therapies for β-thalassemia and SCD
remove hematopoietic stem cells (HSCs) from patients, edit the HSCs using lentiviral transgene delivery or
Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas gene editing, and infuse the cells
back into patients, with the goal of long-term production of healthy erythrocytes.
In vivo gene therapies are more accessible because they can be administered at most hospitals, and they do
not require myeloablation with busulfan. Lipid nanoparticles (LNPs) and adeno-associated virus (AAV) could be
used in vivo to deliver gene therapies such as CRISPR/Cas machinery for knockout of the B-cell lymphoma 11A
(BCL11A) enhancer, but they are not cell-type specific. Conventional lentivirus is generally not immunogenic on
first dose and delivers larger payloads than LNPs and AAVs. However, conventional lentivirus lacks cell type
specificity.
We have recently used bioinformatics and high-throughput screening to innovate novel lentiviral particles for
engineering genes into T cells, achieving >95% target cell transduction efficiency and >95% cell type specificity.
The Specific Aim of this Phase I SBIR project is to test a novel lentiviral technology for editing HSCs for the
treatment of β-hemoglobinopathies. In Phase I, we will use in vitro assays to assess the efficiency and specificity
of HSC-tropic LV which deliver CRISPR/Cas9 machinery for knockout of the BCL11A enhancer versus HSC-
tropic LV for transgenic expression of anti-sickling βAS3-globin.
Terms: <21+ years old><Adeno-Associated Viruses><Adenoviridae><Adenoviruses><Adult><Adult Human><Affect><American><Antibodies><B lymphoma><B-Cell Lymphomas><B-globin><B-thalassemia><Back><Binding><Bio-Informatics><Bioinformatics><Biotech><Biotechnology><Blood Precursor Cell><Blood erythrocyte><Bone Marrow Blood-Deriving Cell><Bone Marrow Blood-Forming Cell><Bone Marrow Cells><Bone Marrow Purging><Bussulfam><Busulfan><Busulfanum><C-KIT Gene><CD117><CD117 Antigens><CD34><CD34 gene><CRISPR><CRISPR based therapeutics><CRISPR based treatment><CRISPR therapeutics><CRISPR treatment><CRISPR-Cas based therapeutics><CRISPR-based disease therapeutics><CRISPR-based therapy><CRISPR/Cas system><CRISPR/Cas therapeutics><CRISPR/Cas9 therapeutics><CRISPR/Cas9 therapy><CRISPR/Cas9 treatment><CRISPR/Cas9-based therapy><Cannot achieve a pregnancy><Capsid><Cardiomyopathies><Cas9 based therapeutics><Cell Body><Cell Line><Cell Shape><Cell Therapy><CellLine><Cells><Circulation><Clustered Regularly Interspaced Short Palindromic Repeats><Clustered Regularly Interspaced Short Palindromic Repeats based therapeutics><Clustered Regularly Interspaced Short Palindromic Repeats therapeutics><DNA Therapy><Dependoparvovirus><Dependovirus><Difficulty conceiving><Disease><Disorder><Doctor of Philosophy><Dorsum><Dose><Economics><Engineered Gene><Engineering><Enhancers><Envelope Protein><Erythrocytes><Erythrocytic><Fe overload><Fetal Hb><Fetal Hemoglobin><Gene Cluster><Gene Transfer Clinical><Genes><Genetic Alteration><Genetic Change><Genetic Diseases><Genetic Intervention><Genetic defect><Genome><Globin><Goals><Grant><HPCA1><Hb SS disease><HbF><HbSS disease><Hematopoietic Progenitor Cells><Hematopoietic stem cells><Hemoglobin><Hemoglobin F><Hemoglobin S Disease><Hemoglobin sickle cell disease><Hemoglobin sickle cell disorder><Hemoglobinopathies><High Throughput Assay><Hospitals><Human><Infertility><Investigators><Iron Overload><Ischemia><Jobs><Knock-in><Knock-out><Knockout><Lentivirinae><Lentivirus><Life Expectancy><MGF Stem Cell Factor><Marrow erythrocyte><Mast Cell Growth Factor><Mast Cell Growth Factor Receptor><Mediating><Membrane><Mendelian disease><Mendelian disorder><Mendelian genetic disorder><Methods><Modern Man><Molecular Interaction><Mutation><Myocardial Diseases><Myocardial Disorder><Myocardiopathies><Nature><Occupations><Paper><Patients><Ph.D.><PhD><Pharmacology><Phase><Pre-Clinical Model><Preclinical Models><Production><Professional Positions><Proteins><Proto-Oncogene Protein c-kit><Publishing><Red Blood Cells><Red Cell><Research Personnel><Researchers><Ribonucleoproteins><SBIR><SCF Receptor><SCF Receptor Gene><SCFR><Sales><Shapes><Sickle Cell><Sickle Cell Anemia><Small Business Innovation Research><Small Business Innovation Research Grant><Specificity><Steel Factor><Stem Cell Factor><Stem Cell Factor Receptor><Stem Cell Factor Receptor Gene><Strains Cell Lines><Structure><Sulfabutin><T-Cells><T-Lymphocyte><Technology><Testing><Training><Transgenes><Uncertainty><Virus-like particle><Work><adeno associated virus group><adulthood><autosome><base editor><beta Globin><beta Thalassemia><blood cell progenitor><blood corpuscles><blood progenitor><blood stem cell><blood-forming stem cell><c kit><c-kit Ligand><c-kit Protein><c-kit Receptor><cell mediated therapies><cell transduction><cell type><cell-based therapeutic><cell-based therapy><cellular therapeutic><cellular therapy><cellular transduction><cultured cell line><design><designing><doubt><economic><env Antigens><env Gene Products><env Polyproteins><env Protein><fertility cessation><fertility loss><fetal form of hemoglobin><fetal globin><gene editing method><gene editing methodology><gene editing strategy><gene editing techniques><gene repair therapy><gene therapy><gene-based therapy><gene-editing approach><genetic condition><genetic disorder><genetic therapy><genome mutation><genomic therapy><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic progenitor><hemopoietic stem cell><high throughput screening><human progenitor><human stem cells><in vitro Assay><in vivo><in vivo Model><infertile><injury to organs><innovate><innovation><innovative><kit Ligand><kit Proto-Oncogene Protein><knockin><lipid based nanoparticle><lipid nanoparticle><manufacture><membrane structure><monogenic disease><monogenic disorder><mouse model><murine model><mutant><myeloablation><myocardium disease><myocardium disorder><novel><novel virus><organ injury><p-Globin><p-Thalassemia><p145(c-kit)><p145c-kit><particle><promoter><promotor><protein expression><safe patient><seropositive><sickle RBC><sickle cell disease><sickle cell disorder><sickle disease><sickle erythrocyte><sickle red blood cell><sicklemia><sickling><single-gene disease><single-gene disorder><thymus derived lymphocyte><transduced cells><transduction efficiency><transgene><transgene delivery><transgene expression><treatment center><vaso-occlusive crisis><vasoocclusive crisis><virus-like nanoparticles><viruslike particle><β-globin><β-thalassemia>