Disorders affecting the blood, including Sickle Cell Disease (SCD), are the most common genetic disorders in the world. SCD causes significant suffering and early death, despite major improvements in medical management and advances in understanding the complex disease-related biology. A bone marrow transplant (BMT) can greatly benefit patients with SCD, by providing a life-long source of normal red blood cells. However, BMT is limited by the availability of suitable donors and immune complications, especially for the more than 80% of patients who lack a matched sibling donor. An alternative treatment approach for SCD is to isolate some of the patient’s own bone marrow and then use gene therapy methods to correct the sickle gene defect in the blood stem cells before transplanting them back into the patient. The gene-corrected stem cells could make normal blood cells for the life of the patient, essentially eliminating the SCD. Such an approach would avoid the complications typically associated with transplants from non-matched donors. We will define the optimal techniques to correct the sickle gene mutation in the bone marrow stem cells to develop as a therapy for patients with SCD.
Development of methods for regenerative medicine using stem cells will have widespread applications to improve the health and to provide novel, effective therapies for millions of Californians and tens of millions of people worldwide. Many severe medical conditions can be cured or improved by transplantation of blood-forming hematopoietic stem cells (HSC), including genetic diseases of blood cells, such as sickle cell disease and inborn errors of metabolism, cancer and leukemia, and HIV/AIDS. Precise genetic engineering of stem cells to repair inherited mutation may be the best way to correct genetic defects affecting the mature cells they produce. This project will advance methods to precisely repair the genetic defect that underlies sickle cell disease in hematopoietic stem cells, which can then be transplanted to ameliorate the disease. These advances will have direct and immediate applications to enhance current medical therapies of sickle cell disease and will more broadly help to advance the capacities for regenerative medicine. All scientific findings and biomedical materials produced from our studies will be publicly available to non-profit and academic organizations in California, and any intellectual property developed by this Project will be developed under the guidelines of CIRM to benefit the people of the State of California.
Sickle Cell Disease (SCD) is a common genetic disorder affecting the blood. The objective of this Development Candidate Feasibility Award proposal is to test the feasibility of a potential therapy for SCD based on isolating a population of cells enriched in hematopoietic stem cell (HSCs) from the patient’s own bone marrow, using a gene editing technology to correct the sickle gene defect in those stem cells, and then transplanting the cells back into the patient. The gene-corrected HSCs have the potential to generate normal blood cells for the life of the patient, thereby reducing the severity of, or curing, the disease. Such an approach would avoid the complications typically associated with current therapies, which use transplants from non-matched donors. The proposed project plan includes optimizing techniques to correct the sickle gene mutation in the bone marrow stem cells, evaluating the hematopoietic potential of the corrected cells, and developing a process suitable for clinical application.
Objective and Milestones
- The stated target level of gene correction is marginal for the clinical objective of the project, although it is realistic given the efficiency of the gene editing strategy.
- The project milestones are appropriate, feasible and focused.
- Due to the risks of off-target gene modification and improper hematopoiesis, it is important to define a Go/No go milestone based on acceptable safety criteria.
- Criteria for reduced sickling need to be defined in the milestone(s).
Rationale and Significance
- SCD is an ideal disorder for targeted gene correction as it is a single mutation disorder. The rationale for use of autologous cells and targeted correction of the SCD mutation is a strength of this proposal
- If successful this would become a highly significant therapy for SCD and would have a transformative impact on the field.
- This is an exciting target and technology
Feasibility and Design
- The main question and concern is whether sufficient gene modification can be achieved in the HSCs to mediate a therapeutic effect. This project has a high risk for failure if sufficient numbers of gene modified cells cannot be attained to achieve the efficacy needed to cure the disease without significant off-target gene modification.
- Reviewers were of the opinion that to reduce symptoms of SCD, the levels of gene correction and engraftment of modified cells will need to be higher than has been observed for related disorders such as beta-thalassemia. Although the number of gene modified stem cells needed to reduce the symptoms of SCD is unknown, this proposal is operating on the low end of the hypothetical window.
- Reviewers recommended setting a clear early Go/No Go milestone based on achieving an acceptable level of gene-corrected stem cells with minimal off-target gene modification.
- There is concern that the gene-modified cells will be damaged and lose activity.
- The research plan is generally well designed and well described.
Qualification of the PI (Co-PI, Partner PI, if applicable) and Research Team
- The PI is an outstanding investigator and established leader in the field; he/she has made many contributions to the fields of cell and gene therapy and is exceedingly qualified to lead the research described.
- The corporate partner increases enthusiasm for this proposal.
- The budget is appropriate
Collaborations, Assets, Resources and Environment
- Collaborations are appropriate.
- The collaboration with the partner should provide crucial assets needed for successful translation of this project.
Responsiveness to the RFA
- The proposed research is highly responsive to the objectives of the RFA.