Sickle cell disease (SCD)results from an inherited mutation in the hemoglobin gene that causes red blood cells to "sickle" under conditions of low oxygen. It occurs with a frequency of 1/500 African-Americans, and is also common in Hispanic-Americans, who comprise up to 5% of SCD patients in California. The median survival based on 1991 national data was 42 years for males and 48 years for females. More recent data indicate that the median survival for Southern California patients with SCD is only 36 years, suggesting that serious problems exist regarding access to optimal medical care in this community. By twenty years of age, about 15% of children with SCD suffer major strokes and by 40 years of age, almost half of the patients have had central nervous system damage leading to significant cognitive dysfunction. These patients suffer recurrent damage to lungs and kidneys as well as severe chronic pain that impacts on quality of life. While current medical therapies for SCD can make an important difference in short-term effects, the progressive deterioration in organ function results in compromised quality of life and early deaths in ethnic populations who are generally adversely affected by health care disparity. Transplantation of bone marrow from a healthy donor as a source of new adult blood-forming ("hematopoietic") stem cells can benefit patients with SCD, by providing a source for life-long production of normal red blood cells. However, bone marrow transplant is limited by the availability of well-matched donors and the problems that arise from immune reactions between the cells of the donor and the patient. Thus, despite major improvements in clinical care of SCD patients, SCD continues to be a major cause of illness and early death.
The stem cell therapy approach to be developed by this Disease Team will be used to treat patients with SCD by transplanting them with their own bone marrow adult hematopoietic stem cells that are genetically corrected by adding a novel therapeutic hemoglobin gene that blocks sickling of the red blood cells. This approach has the potential to permanently cure this debilitating and common illness with significantly less toxicity than with a bone marrow transplant from another person. A clinical trial using stem cell gene therapy for patients with SCD will be performed by this multi-disciplinary Disease Team, combining world-leading experts in stem cell gene therapy, clinical bone marrow transplantation and the care of patients with sickle cell disease. Successful use of stem cell gene therapy for sickle cell disease has the potential to provide a more effective and safe treatment for this disease to a larger proportion of affected patients.
Development of methods for regenerative medicine using genetically-corrected human stem cells will result in novel, effective therapies that improve the health for millions of Californians and tens of millions of people world-wide. Sickle cell disease is an inherited disease of the red blood cells that results from a specific hemoglobin gene mutation. Sickle cell disease disproportionately afflicts poor minority patients in the State of California, causing severe morbidity, early mortality and high medical costs. We will perform a clinical trial to evaluate a novel treatment for patients with sickle cell disease, using their own adult blood-forming stem cells, after correcting the hemoglobin gene defect. Successful treatment of sickle cell disease using adult blood forming “hematopoietic” stem cells corrected with gene therapy may provide a clinically beneficial way to treat sickle cell disease with greater safety and wider availability than current options. The clinical trial to be performed will treat sickle cell disease patients from across the state of California through the network of institutions incorporated into this Disease Team. 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 State of California.
This application proposes a continuation of an ongoing CIRM Disease Team program focused on filing an Investigational New Drug (IND) application for a gene-modified stem cell therapy for sickle cell disease (SCD). The goal of the current proposal is to complete a Phase 1 clinical trial. SCD is a genetic disease caused by a mutation in the hemoglobin gene that causes red blood cells to assume an abnormal sickle shape under conditions of low oxygen. These sickle cells are prone to clog small capillary blood vessels, which can cause strokes, damage to the lungs and kidneys, and chronic pain. Allogeneic hematopoietic stem cell (HSC) transplant can be an effective, life-long treatment for SCD but its practice is limited by the availability of well-matched donors and immunological complications of graft rejection and graft-versus-host disease. This application proposes to avoid immune-related issues by transplanting autologous HSCs, genetically modified to express an anti-sickling form of hemoglobin in red blood cells. The applicants propose to test the safety and efficacy of this gene-modified HSC treatment in a small Phase 1 clinical trial.
Significance and Impact
- SCD is a significant unmet medical need. While allogeneic HSC transplantation can be curative, well-matched donors are not available for most patients and even well-matched transplants carry immune-related risks.
- If successful, the impact of this proposal could be considerable as the approach is potentially curative and would allow treatment of patients not eligible for allogeneic HSC transplant.
- There are several other groups pursuing cell/gene therapy strategies to treat SCD but all are at a similarly early stage of clinical development.
- The Target Product Profile is not well-developed and should include more detail about desired clinical endpoints.
Scientific Rationale and Risk/Benefit
- The scientific rationale for autologous, gene-modified HSC transplant for SCD is strong.
- The potential benefit may be limited by technical challenges inherent in the approach. The applicant faces challenges in harvesting, genetically modifying and engrafting sufficient numbers of HSCs to affect disease course. Reviewers noted that the capability of the applicants’ gene therapy vector to infect cells is at the low end of what may be clinically relevant.
- There is substantial patient risk associated with the approach but reviewers generally found it acceptable for the proposed Phase 1 population, which is a subset of SCD patients who do not respond to available treatment options.
Therapeutic Development Readiness
- Reviewers raised concerns about whether the applicant is ready to file an IND application and begin a Phase 1 clinical trial in the timeframe proposed. Many preclinical proof-of-concept studies have been completed, however some key preclinical studies will not be completed by the proposed filing date of Q4 2013, but should be completed by Q1 2014; hence the strong recommendation to file in Q1 2014, when the studies will be completed and analyzed.
Design and Feasibility
- Reviewers expressed significant concerns regarding the feasibility of product manufacturing. It is possible that bone marrow from some patients may not yield sufficient numbers of HSCs or achieve a sufficient level of gene modification to enable clinical benefit.
- Reviewers raised concerns that the proposed Phase 1 clinical trial is not large enough to provide a reasonable chance to reveal safety issues or demonstrate preliminary proof-of-concept to support a decision to move into Phase 2.
Principal Investigator (PI), Development Team and Leadership Plan
- The PI is a world expert in gene therapy and has experience with clinical trials testing gene-modified HSCs.
- Reviewers raised significant concerns about the regulatory strategy and recommended that the applicants enlist regulatory affairs support to help address FDA issues raised during the pre-IND meeting and direct the IND filing. The major issue was one of timing, and reviewers strongly suggested the applicant file in Q1 of 2014 after the studies have been completed, rather than in Q4 of 2013.
- The assembled team is generally well-qualified, including the Co-PI serving as clinical lead, the clinical expert in SCD and the lead biostatistician.
- Some concern was raised over the size of the budget, although per patient costs were described as reasonable.
Collaborations, Assets, Resources and Environment
- The sites proposed for viral vector production and cell transduction are experienced.
- A collaboration has been established for a potential Phase 2 trial.