Disease Team Research I
The adult human heart contains small numbers of cardiac stem cells that are able to partially repair the heart following a heart attack or throughout the course of progressive heart failure. We have developed a method to isolate these cells and grow them to large numbers in the lab. Isolation begins with a minimally-invasive biopsy taken from a patient’s heart. Our method can be used to then generate clusters of cells (termed “cardiospheres [CSps]”) or individual cells (termed “cardiosphere-derived cells [CDCs]”), each with their own advantages and disadvantages. When delivered to animals after a heart attack or in the midst of heart failure, these cells can better repair the heart, form new heart muscle and new blood vessels. CDCs are currently being given to patients after a recent heart attack, using a catheter to deliver the single cells into a blood vessel supplying the heart, as part of an ongoing clinical trial. The proposed research aims to test both CSps and CDCs in large animals in the midst of heart failure, using a catheter to deliver the cells directly into the heart muscle, in preparation for another clinical trial. Preliminary data shows that CSps may be a more potent cell therapeutic when compared to their single cell counterparts. Direct injection into the muscle not only allows for safe delivery of the cell clusters, but also increases the effective dose of the cells. Patients with heart failure also stand to benefit more from such a cell-based therapeutic when compared to those victims of a recent heart attack. As such, this research will involve not only animal studies, but also cell manufacturing studies, and the preparation and filing of an IND in order to begin a clinical trial. The first study will test both cell products along with the direct-injection catheter in a large scale animal model in order to determine the optimum cell dose. The second study will determine the optimum number of injections to perform during the procedure. These results will be available by the end of the first year, and will allow for a final pivotal study to be conducted during the course of the second year. This pivotal study will examine both the safety and efficacy of cell delivery in the large scale animal model, utilizing a group of control animals, and will serve as key preclinical data when filing an IND. During the course of the first two years, cell manufacturing studies will be conducted in parallel. These studies will enable us to develop procedures to reproducibly generate, store, ship, and deliver the cell therapeutic in the manner that will be adopted during the clinical trial. During the third year, the preclinical and manufacturing data will be combined with a clinical protocol formulated during the course of the pivotal animal study, to constitute the bulk of an IND. Following pre-IND discussions and IND review, we will begin conducting a clinical trial in patients with heart failure in the hope of halting disease progression for these individuals.
Statement of Benefit to California:
Few families in California are not impacted by heart disease. Cardiovascular disease remains the leading cause of death and disability in Americans- on average, cardiovascular disease kills one American every 37 seconds. The death toll from cardiovascular disease is greater than that for cancer, chronic respiratory diseases, accidents, and diabetes combined. Death rates have improved, but new treatments are urgently needed. Aside from the human costs, cardiovascular disease exacts a tremendous fiscal toll: the American Heart Association estimates that the total costs of cardiovascular disease in the United States approached one-half trillion dollars in 2008. All taxpayers must bear the economic burden of resulting death and disability. Clearly, virtually all Californians stand to benefit, directly or indirectly, from the development of more effective treatments of cardiovascular disease. Heart disease is a particularly good target not just because of the magnitude of the public health problem, but also because heart muscle does not ordinarily regenerate once it has been destroyed by heart attacks and other types of damage. We seek to tap into the innate repair mechanisms of the heart by harvesting adult cardiac stem cells. The present work seeks to provide the scientific basis for regulatory filings that would allow us to reintroduce cardiac stem cells into patients with advanced heart failure. The treatment would be “autologous”, in that cells from any given patient would be used to treat that same patient. Thus, the cells are a perfect genetic match, obviating the risk of rejection. If our studies are successful, we may offer a cost-effective way to reduce the tremendous damage to Californians inflicted by major types of cardiovascular disease. This in turn may also reduce the economic burden presently borne by taxpayers who support the health care systems in California. In addition to the public health benefits, spinoff technology developed by this disease team will benefit existing California-based biotechnology companies, leading to fuller employment and an enhanced tax base.
The goal of this proposal is to develop an autologous cardiac stem cell (CSC) preparation for the treatment of patients with ischemic heart failure. For nearly a decade, various cell therapies have been studied in patients, mainly using bone marrow-derived cells or skeletal myoblasts. The safety profile has been favorable for bone-marrow-derived cells and less so for skeletal myoblasts. However efficacy has been, at best, modest. Efforts continue to explore optimal cell types, delivery methods, survival and proliferation, as well as electromechanical integration and long-term stability and safety. To achieve this goal, the applicant focuses this proposal on determining the best cell type to be delivered, the effective dose and the route of injection in a relevant model. CSCs are resident heart progenitors that have been reported to differentiate into all cardiac lineages including cardiomyocytes, endothelial cells and smooth muscle cells. The applicant plans to isolate and expand biopsy-derived CSCs ex vivo, and inject the cells into injured hearts to effect cardiac regeneration. Two cardiac biopsy-derived cell types, “cardiospheres” (CSps) and “cardiosphere-derived cells” (CDCs), will be compared for their ability to repair infarcted hearts in a relevant preclinical model of ischemic heart disease. The first series of studies will optimize delivery and dosing as well as assess safety/efficacy of the two cell preparations. Once the best cell type, dose, and route of administration are established an Investigational New Drug Application (IND) enabling preclinical study will be performed in a relevant model. The project will culminate in submission of an IND within two and one-half years of the project start, to support a clinical trial of autologous CSCs in patients with severe heart failure. Reviewers agreed that an established body of research and clinical data supports the applicant’s approach (to improve the outcomes of cell transplantation in cardiac failure), and that the significance of the proposed work is high. They noted that the proposed work builds upon the approach employed by the applicant in a recently initiated phase I trial of CDC in heart disease. Because CSCs are resident in the heart and are pre-programmed to reconstitute all cardiac lineages, CSCs represent a logical therapeutic candidate. Reviewers noted that this autologous regenerative approach, if successful, could have tremendous impact. The panel universally agreed that heart disease has a major impact on quality of life as well as a large economic impact. This proposal targets patients with severely compromised cardiac function for which long-term treatment options are limited. For this patient population, even slowing the progression of heart disease would be of great benefit. In general, the group judged the preliminary data to be strong. Data from five clinical production runs were included demonstrating that scale up of sufficient numbers is possible to support the proposed studies. Publications by both the applicant and others demonstrate that transplanted CSp and CDC can improve cardiac function in murine models of myocardial infarction (MI). Preliminary data provided in this application demonstrate that intramyocardial (im) CDC delivery produces superior results to intracoronary (ic) injection in a large animal model, and therefore the applicants will target delivery to specific sites in the injured heart with a mapping catheter. Human CSps, which can only be delivered via intramuscular (im) injection owing to their large size, appear to be more efficacious than CDC in a murine MI model. One reviewer commented that further data in the large animal model demonstrating superior efficacy of CSps is necessary to fully justify the proposed development work. The detailed experimental plan assured reviewers that this is a well thought out program. Milestones were judged to be both feasible and reasonable, with an IND filing targeted for the middle of year 3. The established clinically relevant model and group’s track record in this system were also viewed as strengths of the plan. Reviewers appreciated plans to implant defibrillation devices to address potential arrhythmias. Some minor concerns were raised regarding safety assessments. Reviewers would have appreciated details of tests in place to assess karyotypic changes of expanded cells and a discussion of the potential risks acquired from exposure to bovine serum. The panel suggested the applicant address what becomes of cells that do not survive at the injection site by testing for both wash out and early cell death, and requested further assessment of progenitor cell fate. They noted that improved preclinical efficacy with im vs ic injection was not unique to biopsy-derived cardiac progenitors. Therefore, in order to establish superiority of the proposed therapy, the investigators were advised to perform a preclinical comparison of biopsy-derived cells to more accessible autologous cells. Lastly, since multiple direct cardiac injections could increase tissue damage, reviewers suggested investigators include testing of fewer injection sites during preclinical development. Reviewers agreed that this team is exquisitely qualified to perform the proposed work, and a pre-existing infrastructure is in place to support an IND filing. The PI has already initiated a related phase I trial, has an internationally established track record using cardiac progenitors in preclinical models, has experience with Good Manufacturing Practice (GMP) production of cardiac biopsy-derived cells, and commits 35% time to the program. The PI’s significant overseas commitments raised a minor concern. Other critical expertise is provided by the co-investigator, who has successful IND experience, and by the project manager, who has experience running small companies. Some key positions remain to be hired, including the external advisory board and the FDA consultant. The histolopathologist should provide a letter of support. The budget and personnel requested were felt to be modest, but appropriate given the efficiencies provided by the pre-existing infrastructure and host institution support. Resources and environment are exceptionally good and appropriate for these studies. All the necessary facilities and equipment, including Good Laboratory Practice (GLP) facility, are on site. Overall, reviewers were impressed by this applicant’s well thought out and focused research and development plan. They noted promising preliminary in vivo data. The outstanding assembled research team, along with the existing infrastructure to support an IND filing gave reviewers confidence that this team could achieve an IND filing for the treatment of heart failure within the proposed timeline.
- John Wagner