β-thalassemia is a genetic disease caused by diverse mutations of the β-globin gene that lead to profoundly reduced red blood cell (RBC) development. The unmet medical need in transfusion-dependent β-thalassemia is significant, with life expectancy of only ~30-50 years despite standard of care treatment of chronic blood transfusions and iron chelation therapy. Cardiomyopathy due to iron overload is the major cause of mortality, but iron-overload induced multiorgan dysfunction, blood-borne infections, and other disease complications impose a significant physical, psychosocial and economic impact on patients and families. An allogeneic bone marrow transplant (BMT) is curative. However, this therapy is limited due to the scarcity of HLA-matched related donors (<20%) combined with the significant risk of graft-versus-host disease (GvHD) after successful transplantation of allogeneic cells.
During infancy, gamma-globin-containing fetal hemoglobin protects β-thalassemia patients from developing disease symptoms until gamma globin is replaced by adult-type β-globin chains. The proposed therapeutic intervention combines the benefits of re-activating the gamma globin gene with the curative potential of BMT, but without the toxicities associated with acute and chronic immunosuppression and GvHD. We hypothesize that harvesting hematopoietic stem and progenitor cells (HSPCs) from a patient with β-thalassemia, using genome editing to permanently re-activate the gamma globin gene, and returning these edited HSPCs to the patient could provide transfusion independence or greatly reduce the need for chronic blood transfusions, thus decreasing the morbidity and mortality associated with iron overload. The use of a patient’s own cells avoids the need for acute and chronic immunosuppression, as there would be no risk of GvHD. Moreover, due to the self-renewing capacity of HSPCs, we anticipate a lifelong correction of this severe monogenic disease.
Our proposed treatment for transfusion dependent β-thalassemia will benefit patients in the state by offering them a significant improvement over current standard of care. β-thalassemia is a genetic disease caused by diverse mutations of the β-globin gene that lead to profoundly reduced red blood cell (RBC) development and survival resulting in the need for chronic lifelong blood transfusions, iron chelation therapy, and important pathological sequelae (e.g., endocrinopathies, cardiomyopathies, multiorgan dysfunction, bloodborne infections, and psychosocial/economic impact). Incidence is estimated at 1 in 100,000 in the US, but is more common in the state of California (incidence estimated at 1 in 55,000 births) due to immigration patterns within the State. While there are estimated to be about 1,000-2,000 β-thalassemia patients in the US, one of our proposed clinical trial sites has the largest thalassemia program in the Western United States, with a population approaching 300 patients. Thus, the state of California stands to benefit disproportionately compared to other states from our proposed treatment for transfusion dependent β-thalassemia.
An allogeneic bone marrow transplant (BMT) is curative for β-thalassemia, but limited by the scarcity of HLA-matched related donors (<20%) combined with the significant risk of graft-versus-host disease (GvHD) after successful transplantation of allogeneic cells. Our approach is to genetically engineer the patient’s own stem cells and thus (i) solve the logistical challenge of finding an appropriate donor, as the patient now becomes his/her own donor; and (ii) make use of autologous cells abrogating the risk of GvHD and need for acute and chronic immunosuppression.
Our approach offers a compelling pharmacoeconomic benefit to the State of California and its citizens. A lifetime of chronic blood transfusions and iron chelation therapy leads to a significant cost burden; despite this, the prognosis for a transfusion dependent β-thalassemia patient is still dire, with life expectancy of only ~30-50 years. Our proposed one-time treatment aims to reduce or eliminate the need for costly chronic blood transfusions and iron chelation therapy, while potentially improving the clinical benefit to patients, including the morbidity and mortality associated with transfusion-induced iron overload.
The goal of this proposal is to develop a therapy for beta-thalassemia, a genetic disease caused by mutations in the beta-globin gene, leading to impaired production of hemoglobin and a lifelong dependence on red blood cell (RBC) transfusions for survival. During infancy, gamma-globin containing fetal hemoglobin protects beta-thalassemia patients from developing disease symptoms. However, during normal development, the gamma-globin gene is inactivated and gamma-globin is replaced by the adult-type beta-globin chains that are defective in beta-thalassemia patients.
The proposed approach will use a novel gene-editing technology to permanently re-activate fetal gamma-globin expression in hematopoietic stem cells (HSC) isolated from patients in order to restore fetal hemoglobin production. The modified cells will then be returned to the patient via an autologous bone marrow transplant, with the goal of achieving normal hemoglobin levels and RBC production, thereby obviating or greatly reducing the need for chronic blood transfusions.
The proposed 4-year project plan includes preclinical work leading to the filing of an Investigational New Drug (IND) application as well as completion of a Phase 1 clinical trial in transfusion-dependent beta-thalassemia patients.
Significance and Impact
- The proposed therapy could have a great impact not only on beta-thalassemia, but also in related hemoglobinopathies.
- This proposal has great merit and the impact could be extraordinary.
- The proposed approach is competitive with other therapeutic strategies in development including viral mediated gene therapy, and there are significant advantages over current therapies should this approach prove efficacious.
- The Target Product Profile is well thought out and clear metrics have been proposed.
Scientific Rationale and Risk/Benefit
- The scientific rationale is extremely strong and the applicant has provided good preclinical evidence for the therapeutic approach.
- Reviewers expressed enthusiasm for the proposal with comments such as: “I am highly enthusiastic; this is a study that should be done; this is a trial we would want to do at our center.”
- Some questions relating to long-term stability and dose need to be answered to balance the risk/benefit ratio in favor of benefit.
- Two potential risks that are not addressed completely, are a potential effect on long term hematopoietic stem cell (HSC) activity and on the T-cell lineage and immune reconstitution; the applicants have not demonstrated that T-cell activity is not altered.
- Although the data on long-term reconstitution are encouraging and suggest stable modification, they are not definitive since serial transplantation has not been done and it is still an open question whether this will be a life-long treatment.
Design and Feasibility
- The development plan is well thought out and considers both the potential upside and downside.
- The project plan appears feasible and the applicant has articulated risk mitigation strategies at each step.
- The clinical plan is straightforward and feasible.
- Consistency of the manufacturing process is a concern; the manufacturing process may need refinement to obtain a consistent product with well defined specifications and predictable long term engraftment potential. The effect of genotype on stem cell mobilization and variability needs to be considered.
Principal Investigator (PI), Development Team and Leadership Plan
- There are no concerns about the team and collaborators - all are excellent.
- The budget is reasonable.
Collaborations, Assets. Resources and Environment
- The clinical sites, collaborators, assets and environment are excellent.
- Collaborations are with leading experts in the field.
- The applicant has identified appropriate, experienced contractors to manufacture reagents and cell products.
- Reviewers agreed that while this is an excellent proposal, there are some questions relating to risk versus benefit that should be addressed to strengthen the IND submission. Reviewers had the following recommendations:
- Long-term persistence of the gene modified HSC in vivo should be evaluated in serial transplantation experiments in an animal model to clearly demonstrate that long term reconstituting cells are not impaired by the manufacturing process; transplanted cells should be derived from the target patient population and transplant recipients should be followed for longer periods of time.
- Stem cell dose is critical. The applicant needs to evaluate the impact of the manufacturing process on the survival and potency of the HSC and demonstrate that what will be delivered to patients is an effective dose and that it can be reproducibly produced from genotypically diverse patients. Careful titration of the engraftment potential of shipped, frozen and thawed, control and gene modified HSC in an animal model would add confidence that dosing will be adequate.