Grant Award Details
- Conduct a pre-IND meeting and prepare protocol for CRISPR/Cas9 gene edited autologous HSC therapy to cure sickle cell disease
- Part B: post award activities to prepare for IND filing
Grant Application Details
- Curing Sickle cell Disease with CRISPR-Cas9 genome editing
The principal objective of this program is to bring a Cas9-based gene editing cure for sickle cell disease to the pre-IND stage of development.
Area of Impact
The principal barriers to transplant for SCD are lack of a donor and the toxicity of transplant, which can be overcome by the Cas9-based approach
Mechanism of Action
Ex vivo editing of autologous stem cells would be followed by re-implantation of edited cells, bypassing donor requirements and eliminating risks of graft-versus-host disease and rejection. Because sickle RBCs have a markedly reduced lifespan, low level sickle gene correction would be predicted to generate a clinical benefit by virtue of enrichment of the longer-lived corrected RBCs in circulation. After conventional transplant, clinical benefit with as few as 2-5% donor HSCs has been observed.
Unmet Medical Need
Fewer than 1% of individuals with sickle cell disease pursue an allogeneic bone marrow transplant cure today, principally because most affected persons lack a suitable donor. This proposal could make a cure universally available because it corrects the sickle mutation in a persons' own stem cells.
conduct a pre-IND meeting and prepare a protocol
Major Proposed Activities
- Test Optimal Editing Reagents in stem cells from subjects with sickle cell disease and show correction in >2% sickle stem cells
- Translate optimal method for gene editing with GMP-comparable reagents and processes for cell processing and cryopreservation.
- Ramp-up testing of reagents to manufacture a demonstration clinical-scale lot of the gene-corrected CD34+ cell product that meets all release criteria
Sickle cell disease (SCD) affects over 6000 primarily African-Americans in California. A survival of <40 years of age was observed in a large cohort of California patients. The estimated lifetime cost of care is $9 million per person. This project aims to improve SCD therapy by preparing for a clinical trial that might cure SCD after giving back sickle gene-corrected hematopoietic stem cells to a person with SCD. If successful, this would be a universal life-saving and cost-saving therapy.
- Expert Opin Biol Ther (2018) Promise of gene therapy to treat sickle cell disease. (PubMed: 30324810)
- Stem Cells (2018) Improving Gene Editing Outcomes in Human Hematopoietic Stem and Progenitor Cells by Temporal Control of DNA Repair. (PubMed: 30372555)