Funding opportunities

STEM CELL GENE THERAPY FOR SICKLE CELL DISEASE

Funding Type: 
Disease Team Planning
Grant Number: 
DT1-00701
Principle Investigator: 
Funds requested: 
$33 110
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
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. Recent data indicate that the median survival for {REDACTED} California patients is only 36 years, suggesting that serious problems regarding access to care exist 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 significant 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 a significant difference in short-term effects, the progressive deterioration in organ function results in increased mortality and decreased quality of life. Bone marrow transplant (BMT) from a healthy donor as a source of new blood-forming (“hematopoietic”) stem cells can benefit patients with SCD, by providing a source for life-long production of normal red blood cells. However, BMT 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, SCD continues to be a significant cause of morbidity and early mortality. The central hypothesis of this Disease Team Initiative is that using a patient’s own hematopoietic stem cells which are corrected in the hemoglobin gene using gene therapy has the potential to permanently cure this debilitating and common illness with significantly less toxicity than with a BMT from another person. Methods to add a normal copy of the hemoglobin gene to the stem cells from a patient’s own bone marrow stem cells have been developed. A clinical trial using stem cell gene therapy for patients with SCD will be developed and performed by this Team. Our group has world-leading experts in stem cell gene therapy and the care of children 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.
Statement of Benefit to California: 
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. Successful treatment of sickle cell disease using gene therapy and blood forming “hematopoietic” stem cells may provide a clinically beneficial way to treat sickle cell disease with greater safety than current options. The clinical trial to be performed will treat sickle cell patients from across the state.
Review Summary: 
Executive Summary The PI proposes to establish a multidisciplinary team to develop an autologous stem cell based gene therapy approach to correct sickle cell disease (SCD). SCD is a hereditary hemoglobin disorder that affects millions of people world wide and a disproportionate number of children in California because of its ethnic diversity. While current therapies for SCD using supportive measures can make a significant difference in short-term morbidity, the progressive deterioration in organ function results in mortality and significant decrease in quality of life. The curative treatment, allogeneic hematopoietic stem cell (HSC) transplantation, is available only to 20 percent of patients due to the lack of a suitably matched donor in the majority, and this therapy is associated with significant morbidity and mortality. The goal of this team is to develop stem cell gene therapy for SCA as a less toxic, yet curative approach. Reviewers agreed that the scientific rationale of the proposal was valid, and that the concept was sufficiently mature such that a clinical trial could be underway within 5 years. The strengths of the proposal were discussed. The approach of using autologous hematopoietic cell transplantation with introduction of a normal hemoglobin gene to replace the abnormal hemoglobin in SCD will normalize red cell physiology, without the immunological problems and organ toxicity of allogeneic HCS transplantation. Therefore, the concept is clinically significant, especially if challenges of gene vector expression can be overcome. The PI is a leader in the area of gene therapy using autologous HSC and has long standing track record of translating developments in the laboratory into clinic trials. The team members proposed by the PI have long-standing records of cooperation to optimize the care of sickle cell disease and other hematologic disorders. The research infrastructure is already in place to support of these studies, and the group has already established a core facility for GMP cell processing. Finally, the application reflects careful planning and detailed knowledge of the activities which will be needed to complete the proposed research successfully and clearly states the road to clinical application. A few concerns were raised by the panel. One reviewer was concerned that the potential pitfalls of this work were not specifically addressed in this application including graft failure, the need for chemotherapy to facilitate engraftment and the long term risks of durable engraftment with virally transfected cells. In addition, it was not clear from the proposal at what stage of development or readiness an optimized lentiviral vector is at the present time, and whether it would be ready for the proposed clinical trial. Furthermore, reviewers noted that the need for in vitro and in vivo studies of new vectors was not discussed in the application, but is an area in which the PI has considerable expertise. However, the reviewer acknowledged that this could reasonably be fleshed out during the planning process, along with the proposal of alternative strategies. In summary, the PI and the proposed team members have long-standing records of cooperation to optimize the care of sickle cell disease and other hematologic disorders that might benefit from hematopoietic stem cell transplantation, and the panel was supportive that a planning award could help this team considerably streamline the clinical development process to meet the expectation of a clinical trial within 5 years. Reviewer Synopsis The goal of this planning project is to develop a multidisciplinary team whose goal will be to perform a corrective gene therapy trial, using autologous cells, in patients with sickle cell anemia. Sickle Cell Anemia (SCA) affects more than 70,000 patients per year in the U.S. causing significant morbidity and mortality throughout life. While allogeneic hematopoietic stem cell transplantation (HSCT) after myeloablative chemotherapy, can correct the disease, the approach is hampered by problems achieving durable engraftment, with graft versus host disease and with regimen related toxicity and mortality. It also is less successful and more risky in older patients who already have experienced some of the more serious clinical sequelae of SCA (e.g. stroke, chest crises, etc). The goal of this team is to develop stem cell gene therapy for SCA as a less toxic, yet curative approach. Reviewer One Comments Concept: Sickle cell disease is a major public health problem affecting approximately 70,000 people in the U.S. The disease affects 1/500 African Americans and, in California, Hispanic Americans comprise up to 5 percent of SCD patients. Median survival in California is only 36 years. The curative treatment, allogeneic hematopoietic stem cell transplantation, is available only to 20 percent of patients due to the lack of a suitably matched donor in the majority, and this therapy is associated with significant morbidity and mortality. The approach of using autologous hematopoietic cell transplantation with introduction of a normal beta- or gamma- globin gene to replace the abnormal hemoglobin in SCD is therefore appealing. This is an approach that has been under development now for many years, resulting in improved methods of ensuring expression and of transducing stem cells. Moreover, the PI and his group have developed effective retroviral vectors that have been brought to the level of clinical trials in the treatment of congenital immune deficiencies and pediatric AIDS. However, correction of SCD with gene therapy has been a major challenge due to the need to control transgene expression in an erythroid-specific and differentiation-related manner that is sustained. While recent developments in this area are encouraging and the investigator has identified outside consultants in this field who will assist with development, it is somewhat concerning that these problems are not discussed in the application. Similarly, the need for in vitro and in vivo animal assessments of new vectors before clinical trials can be undertaken is not discussed. Thus, while the idea is mature, the readiness for clinical application is perhaps overstated. Nevertheless, it seems likely that with five years of funding, given the strong track record of this group in human stem cell transduction for clinical trials and the strong infrastructure that is already in place, a clinical trial will be underway within five years. The two-to-three year timeframe suggested in the application may be overly optimistic. Nevertheless, it seems likely that, with a CIRM Disease Team Award, the investigators could streamline the process of clinical development considerably. Principal Investigator: The PI is a world leader in the area of gene therapy using autologous hematopoietic stem cells and has a strong track record of translating developments in the laboratory into clinical trials. His group has developed this approach for treatment of adenosine deaminase deficient severe combined immune deficiency and pediatric HIV. In support of these studies, the group has established a clinical stem cell gene therapy core for GMP cell processing and GCP trial performance at CHLA. Dr. Kohn has been awarded a clinical trial planning grant from NIAID to support assembly of a team to conduct a trial of transduction of CD34 cells from patients with pediatric AIDS with a retroviral vector carrying a gene that inhibits HIV-1. Dr, Kohn has now led the submission of a clinical trial implementation cooperative agreement to follow up on this initial phase. Dr. Kohn leads the hematopoietic stem cell transplantation group at Children’s Hospital Los Angeles and the Co-investigator, Dr. Coates, leads the Clinical Hematology Center. These teams have long-standing records of cooperation to optimize the care of sickle cell disease and other hematologic disorders that might benefit from hematopoietic stem cell transplantation. Thus, the PI and Co-Investigator have outstanding expertise and leadership in the field. Planning Approach: The planning process will involve collaborative interactions among hematologists with expertise in sickle cell disease, bone marrow transplant physicians, gene therapy scientists, and clinical trial specialists with experience in the regulatory processes required for review and approval of clinical studies of stem cell therapy. Additional pediatric centers providing clinical care to SCD patients in California will be included in the team during the planning period. The Disease Team to be brought together by the planning grant includes the clinical team, hematopoietic stem cell transplant physicians, the gene therapy/stem cell processing/GMP group, the clinical grade vector production group, and a regulatory group. Several meetings will be held over a period of one to two months and a one day meeting will include the outside consultants. Subsequently, preclinical preparation will begin, to be followed by performance of the clinical trials. This plan seems well thought out, but a notable omission is the stage of preclinical development of an optimized vector and evaluation in animal models, an area in which the PI has considerable expertise. Reviewer Two Comments Concept: Concept/ Rationale. This application proposes to attempts to correct sickle cell disease (SCD) by stem cell gene therapy. The authors propose to use lentiviral vectors to insert the gene correction into HSC and then infuse corrected HSC back into patients. The approach would be useful since it would be an autologous transplant of HSC. The gene correction part remains speculative but hopeful. Maturity: Significant preclinical studies related to this application have been conducted by this lab. Seemingly appropriate vectors have been made in several labs and tested in preclinical studies. The PI directs the gene therapy program at Children’s hospital, LA (CHLA) and has conducted several similar type studies involving gene therapy followed by HSC transplantation for pediatric AIDS. These related research area would surely facilitate the proposed program. Significance. High if the expression of the gene vector can be maintained Principal Investigator: Outstanding. Dr. Kohn is director of the gene therapy program at CHLA. He has significant research support for related projects (no overlap). He has published work directly and indirectly relevant to this application. Planning Approach: The team has obviously prepared for applications like this before. The application clearly state the road to clinical application. This group has conducted clinical gene therapy studies before, which is a great plus for this application. The local team is experienced and knowledgeable, and the PI has assembled appropriate external consultants. The PI has identified key personnel areas in the application including groups focused on HSC transplant physicians, a regulatory group including data managers, and stem cell processing and GMP groups as part of the planning team. The team has prior experience with HSC transplant (without gene therapy) for SCD so translating the results of the project to the clinics would not be a significant issue. The application reflects careful planning and detailed knowledge of the activities which will be needed to complete the proposed research successfully. Reviewer Three Comments Concept: This team, lead by Dr. Kohn, has a long and outstanding track record applying gene therapy for the treatment of genetic and acquired immunodeficiency diseases. They definitely have performed the work that supports development of the current proposal. SCA is a critical and global health problem. Development of safe, non-toxic, curative therapy would have a major impact on the lives of hundreds of thousands of patients as well as on the field of healthcare overall. Potential pitfalls of this work, which were not specifically addressed in this application, include graft failure, the need for chemotherapy to facilitate engraftment and the long term risks of durable engraftment with viral transfected cells. These would need to be addressed in the full proposal submitted after completion of the planning phase. Principal Investigator: Dr. Kohn is highly qualified to carry out the proposed work. He has a long standing track record in the field and is one of the few investigators in the world who has successfully conducted human gene therapy studies in the clinic, in children and as a means to cure genetic diseases. Planning Approach: The team will utlilize the planning phase of this award in two phases. First, to finalize the clinical trial protocol, prepare regulatory documents and submission for regulatory review, production of clinical grade reagents, release assays, development of the clinical trial documents (consents, CRFs), and training of the clinical and laboratory investigators and second, to conduct the clinical trial which will include transplantation of gene-transfected autolgous cells. It is not exactly clear how far the development of the lenti-viral vector is for this clinical trial. It would be expected that this would be clarified during the planning phase and that an alternative construct would be considered if this was not possible in a timely fashion.
Conflicts: 

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