Sickle cell disease (SCD), which results from an inherited mutation in the hemoglobin gene that causes red blood cells to "sickle" under conditions of low oxygen, 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 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 developed to be performed by this Team. This multi-disciplinary Disease Team combines 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 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 develop 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 developed 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.
The goal of this proposal is develop a new cell therapeutic, based on correction of a genetic defect in the patient’s own blood cells, that is less toxic and more widely available than current options for treating sickle cell disease (SCD), a common and debilitating illness. To bring this candidate to the clinic, the applicants have proposed a series of Aims and milestones that are designed to enable both an Investigational New Drug (IND) filing as well as finalization of a clinical plan. In the first year, the applicants plan to identify and obtain bone marrow samples from SCD patients that will be used as a source of hematopoietic stem cells for preclinical studies. In addition, the vector that will be used to modify these cells will be optimized and further defined in terms of its activity and stability. The results of these studies will be presented to the Food and Drug Administration (FDA) in a pre-IND conference in order to refine the subsequent development strategies. In the second year, the applicants propose to manufacture the cell therapeutic under Good Laboratory Practices (GLP) and obtain the toxicology and efficacy data that are required for clinical translation. In the third year, the applicants propose to finalize the cell transduction process, define laboratory and clinical endpoints, describe the product release criteria for manufacturing as well as qualify the assays that will be used to evaluate the therapeutic. Upon completion of those studies, the applicants will apply for an IND. The remainder of the project would include finalizing the clinical protocols, establishment of trial and data safety monitoring plans, addressing the response of the regulatory review, and securing reagents that will be used in patient trials. If the IND is obtained on schedule, the applicants suggest that they would be 100% ready to enroll participants by the end of year 4.
Overall, the reviewers concluded that the proposed cell therapy for SCD represents a scientifically valid and clinically advantageous approach that could overcome the major limitations of existing treatments, thereby improving the lives of patients while also decreasing the costs to society. Based on a solid premise, a feasible and mature plan, and an outstanding and proven research team, the reviewers were confident that the objectives could be met and an IND could be obtained within the time frame of this award.
The reviewers were uniformly impressed with the scientific rationale of the proposed therapeutic, describing the approach as straightforward and logical. The transplantation of genetically engineered hematopoietic stem cells into SCD patients makes good sense, as transplants from healthy donors have been used for decades as a source of cells of hematopoietic lineage for patients with a wide variety of disorders and in some contexts, can be curative for SCD. Furthermore, the reviewers appreciated the relevance of the proposed genetic correction, which they judged to be based on a clear scientific precedent. Importantly, they noted that the use of a transgene that exerts dominant anti-sickling properties was highly cogent, as it will be necessary to overcome the defective activity of the patient’s remaining, uncorrected gene product. Moreover, this gene addition strategy may overcome the limitations of several sickle cell gene replacement approaches that are currently under development, as the efficiency of these alternatives is not yet sufficient for clinical application.
From a clinical perspective, the reviewers highlighted several compelling advantages over current treatment options. First, the use of a patient’s own cells as the basis of therapy could overcome two of the most serious complications of an allogeneic transplant, that of immune rejection of the curative tissues as well as the risk of graft versus host disease. Furthermore, such cells could circumvent the need to find an appropriately matched marrow donor, an extremely difficult task given the disproportionate representation of ethnic minorities that suffer from SCD. Finally, the use of bone marrow as a source of hematopoietic stem cells, rather than obtaining them from cytokine-mobilized peripheral blood, would carry less risk of exacerbating vaso-occlusive disease in the targeted, vulnerable population. Taken together, this combination of sound rationale and practical approach convinced the reviewers that if successful, the proposed therapy would have a significant impact on the field, both improving the lives of patients as well as mitigating the societal and economic costs of the disease.
The reviewers were extremely enthusiastic about the feasibility of the proposal, noting that the applicants provided a logical series of quantifiable milestones with appropriate endpoints and criteria for success. They found the preliminary data to be strongly supportive of the overall approach, both documenting the previous successes of this team in developing related therapeutic methodologies as well as citing proof of efficacy in a murine model of SCD. While confident that the overall goals would be met, some reviewers questioned the extent to which the chosen preclinical model would reflect the human condition, given the differences in scale, lifespan, the xenogeneic immune environment, and an inability to model the potential effects of SCD pathology on the human transduction and engraftment procedures. Nonetheless, the reviewers concurred that the PI and team has the appropriate expertise and track record to meet these all of these challenges and more, some of which are likely to be answered only in the context of a clinical trial.
In terms of achievability, the reviewers were satisfied that the applicants had identified what are likely to be the most serious challenges to developing the proposed therapy and had included methods to address them. For example, the applicants had anticipated the need for robust cryopreservation methods as well as strategies to overcome potential silencing of the transgene. Additional strengths included the detailed plans for characterizing and optimizing the vector activity and cell transduction processes, the judicious choice of vector for gene transduction, and a well-considered plan for cytoreduction. These tasks were thought to comprise a tight timeline, but the reviewers believed that the team was well positioned to meet these goals based on their previous successes with similar approaches. To enhance this probability, the reviewers offered some suggestions to address a few minor weaknesses that were discussed. First, some felt that the proposed rheological studies may not be germane to the requirements for an IND and if eliminated, could lead to an opportunity to reduce the budget and refocus the timeline. Others recommended the inclusion of unmodified and unselected marrow when developing the clinical protocol for transplantation in order to more effectively guarantee hematopoietic recovery and ameliorate the risk of viral infections. Finally, they stressed the need to submit this protocol early to the NIH Recombinant Advisory Committee so that public review would not unnecessarily delay the IND filing. Overall, this comprehensive and thoughtful plan convinced the reviewers that the proposed milestones and timelines were compatible with achieving an IND within the duration of this award, if not sooner.
The reviewers expressed great confidence in the capabilities of the principal investigator (PI), whom they described as a highly regarded international leader in the genetic modification of hematopoietic stem cells. The PI has a longstanding and successful track record in the field including prior experience obtaining INDs in relevant areas. In fact, one reviewer described the PI as the best-positioned researcher in the state to bring the proposed project to fruition. Complementing this leadership are two co-principal investigators, each of whom is considered to be an outstanding clinician and respected translational scientist that brings relevant expertise to the project. The reviewers had high praise for the overall structure of the leadership plan, with each co-PI coordinating the activities of their respective institutions and providing an effective and efficient synergy to the overall direction of the project. They did emphasize, however, that it is imperative to appoint the project manager as soon as possible in order to most effectively realize the potential of this arrangement. Finally, the inclusion of a patient advocate at the earlier stages of the project spoke to the practical foresight and judgment of this team.
The reviewers agreed that the collaborations, resources and environment of the Disease Team added considerable strength and credibility to the project. The personnel were described as a highly collaborative group with a proven track record in productivity and scientific excellence. Letters of support were strong, and the supporting vector team and hematopoietic and process/manufacturing components were all considered to be excellent. In general, reviewers found no fault with the team structure and appreciated the care with which the complementing skill sets were selected and juxtaposed. Additional strengths that were discussed included the existing infrastructure based on prior work, excellent documentation to reaffirm the commitment of the participating institutions, and the unique and relevant access to patients and samples that would be available to the team.
In summary, the proposed cell therapy for SCD represents a scientifically valid and clinically advantageous approach that could overcome the major limitations of existing treatments. Based on a solid premise, a feasible and mature plan, and an outstanding and proven research team, the reviewers were confident that the objectives could be met and an IND could be obtained.