Funding opportunities

Autologous Delivery of Pim-1 Enhanced Cardiac Stem Cells: A Novel Clinical Therapy for Cardiac Muscle Regeneration Post MI

Funding Type: 
Disease Team Research I
Grant Number: 
Funds requested: 
$15 239 823
Funding Recommendations: 
Not recommended
Grant approved: 
Public Abstract: 
There have been consistent advancements in the prevention and treatment of cardiovascular disease. Despite these advancements and partly due to the increasing age of the human population, heart attacks continue to be a human plague currently affecting 5 million people. Heart attack is the most common cause of hospital admission leading to 300,000 deaths each year in the US. The average 5-year survival for these patients is only 50%. The most aggressive treatment for these patients is heart transplantation but this is limited to only 2,000 patients each year because of a serious lack of suitable donors. Therefore, there is an urgent need for new ways to treat patients suffering from heart failure. In the last 10 years, much work has been done on the use of stem cell therapy for organ failure. Recent reports indicate some successes using stem cell therapies to treat heart attack but only limited, short-term benefit has been seen. {REDACTED} has discovered a new type of stem cell therapy for heart attack. This technique uses stem cells taken from the patient’s own heart. The cells, called adult human cardiac progenitor cells (hCPCs), are modified to produce a protein (Pim-1) known to protect the heart and also found to protect hCPCs after they are returned to the patient’s heart. Animal data shows that Pim-1 modified hCPCs are able to generate new heart tissue that persists for at least 6 months and causes major improvements in the heart’s ability to work. In this proposal, the {REDACTED} will partner with {REDACTED} and his colleagues at {REDACTED}, who are recognized experts in tracking fate of stem cells. They will validate survival of Pim-1 modified hCPCS in small and large animal models using state-of-the-art molecular imaging technologies. The third member of the disease team is {REDACTED}. {REDACTED} exists specifically to advance the Pim-1 technology to the point of evaluation by the Food and Drug Administration (FDA) for potential use in human patients. We anticipate that the work conducted in this proposal will result in an application to FDA for the first human clinical trial using the patient’s own hCPCs, modified to produce Pim-1, as a therapy for heart attack and prevention of subsequent heart failure through the generation of new heart muscle. Funding of this proposal will: 1) Develop procedures for Pim-1 modification in hCPCs, 2) Develop quality-assured procedures and perform clinical quality manufacturing of Pim-1 modified hCPCs, 3) Demonstrate safety and efficacy of these modified hCPCs under quality-assured pre-clinical conditions in large animal models, 4) Design the human clinical trial protocol and related documentation that will be proposed to FDA, 5) Compile all documents required for the submission of the Investigational New Drug Application (IND) to FDA, and 6) Submit the IND to FDA by the end of year 4 of this proposal.
Statement of Benefit to California: 
In 2004, the total healthcare cost in the US was 1.9 trillion dollars and cardiovascular disease ranked as the most costly disease category, accounting for 8.3% of these overall costs. Cardiovascular disease and, in particular, myocardial infarction resulting in congestive heart failure, continues to be the number one cause of death in the US, killing some 300,000 Americans each year. Congestive heart failure is also the leading cause of hospital admissions. There are nearly 5 million Americans who are suffering from this illness, with 550,000 new cases reported annually. Despite recent advances in drug therapies for acute myocardial infarction, the average five-year survival for patients suffering this condition remains only at roughly 50% level. While cardiac transplantation is a well-established treatment for end-stage congestive heart failure, this treatment is limited to only 2,000 patients per year due to a severe and chronic shortage of acceptable donor hearts. As the most populous state, California bears the greatest public health impact of myocardial infarction and congestive heart failure as well, a burden that is only getting heavier as the population ages. Thus, there is a clear need for development of novel therapies for these disease conditions, the development of which will benefit California tremendously, from its population to the state’s public health system and its foundation in biomedical research. One such cutting edge treatment uses the Pim-1 modified cardiac progenitor cell (CPC) technology developed by investigators at {REDACTED}, which has already shown significant promise in relevant animal models of ischemic heart disease. In addition to the cost saving benefits that will be realized by the California healthcare system as a result of the development of this technology, there will also be significant economic development benefits realized by the State. Although biotechnology is a robust business sector in California, this sector is currently suffering from the economic downturn as venture funding dries up and jobs are being lost. Funding of this proposal will directly support existing jobs within California’s biotechnology industry at the firms designated for the development work. All the funds specifically targeting scientific procedures will be reinvested in California, fueling economic growth and recovery in addition to furthering a likely revolutionary treatment of heart failure. This funding will also serve to create new jobs at {REDACTED} and other companies associated with the Pim-1 modified hCPC technology. Synergy can result as other cell therapies using related technologies and targeting other disease areas are likely to develop as a consequence of this funding. These funds will also directly support education and jobs at {REDACTED} coping with painful budget reductions resulting in loss of critical talent and research momentum.
Review Summary: 
The applicant describes activities leading to an Investigational New Drug (IND) application for a cell product intended to repair cardiac tissue injured during myocardial infarct (MI). The proposed product is composed of an autologous cardiac progenitor cell (CPC) population derived from a biopsy of the patient’s heart. The CPCs are expanded in culture, transfected with a lentiviral construct that will drive expression of the human Pim-1 regulatory gene and are then injected into the myocardium of the patient using a catheter. The investigator proposes that forced Pim-1 expression will enhance survival of transplanted cells and significantly improve myogenesis and regeneration when compared to other cell-based approaches that are currently being explored. To test this hypothesis, they plan to study myocardial structure and performance after transplantation of modified human CPCs into relevant preclinical models of myocardial infarction and to follow the fate of transplanted cells using in vivo imaging with the ultimate goal of validating and optimizing CPC-mediated cardiac repair. Plans are proposed for development and manufacturing of the cell product in preparation for the IND application. Reviewers acknowledged that this application addresses an important unmet clinical need in cardiac repair and promises, based on convincing preliminary data using mouse cardiac cell populations, to provide better outcomes than other approaches currently under investigation. However, due to major concerns regarding the maturity of the project – the human cell product has not yet been defined – and serious gaps in the pre-clinical development plan, reviewers did not recommend this application for funding. MI resulting in congestive heart failure is still a leading cause of death in the US. There is considerable clinical research activity in the field of cardiac repair, undoubtedly because the medical need is great and because there is a sense that cell therapies hold promise. Reviewers found the scientific rationale for the proposed therapeutic approach to be interesting, as it builds on several Phase I and Phase II clinical trials during which a variety of cell types have been administered to patients following MI. These trials have already demonstrated that stem cells can be delivered safely to the hearts of MI patients and that some patients do appear to benefit from such treatments. Problems with cell persistence have emerged from these trials and are addressed in this application. However, the novel aspects proposed here (i.e. the use of biopsies from infarcted hearts for autologous cell preparations and the genetic modification of those cells) add layers of logistic and clinical complexity related to the manufacture of the therapeutic product as compared to other approaches being tested. If the applicant’s rationale for the therapy is correct, and these cells prove significantly more effective than other approaches, the product will likely be adopted even if it is more complex to manufacture. However, this complexity will discourage adoption if only small differences in efficacy are observed. If successful, the results of the proposed work could transform treatment for heart failure as it promises potential improvement in cardiac structure and function that are superior to outcomes of current treatments. Overall, reviewers felt that the pre-clinical development plan is logical and may be achievable as presented, but they identified several deficiencies and gaps that would need to be addressed prior to seeking an IND. The preliminary data presented in the application were judged to be supportive of the idea that forced Pim-1 expression improves survival of transplanted CPCs and increases their effect on myocardial performance in infarcted mice. However, since they were performed entirely using mouse CPCs, not human, reviewers felt that the technology for manufacturing, characterizing, and transfecting human CPCs is not mature. Although CPCs isolated from mouse hearts based on the expression of a specific surface marker appear to have some interesting properties, cells isolated on the same basis from human biopsies are much less well defined, and their identity is controversial. Further, it is not clear what time period will be required to manufacture human CPCs or how many can be manufactured, nor is it clear how easily they will be transduced with the viral construct as primary human cells are often much more difficult in this regard than similar mouse cells. It is also still unknown whether the effect of Pim-1 overexpression observed in mouse cells will hold in human cells. The applicant acknowledges that the exact composition of each human CPC population may vary depending on differences between patients and on cell culture effects but does not clarify how a consensus phenotypic profile will be defined. Reviewers expressed concern that gene transduction efficiency and the cell product’s efficacy and safety might all be influenced by the anticipated variability in cellular phenotype and urged that product composition needs to be defined before other pre-clinical studies, such as studies into the interaction between the cells and the delivery catheter, can be performed. In order to overcome variability amongst different cell preparations, the applicant discusses using various markers to facilitate selection of efficacious human CPC populations but does not specify if antibodies will ultimately be used to enrich a specific subpopulation from the biopsy. If so, the plan lacks the development of such antibodies and corresponding sorting technologies suitable for human use. Similarly, the proposed viral construct has not yet been assembled, and critical regulatory hurdles related to viral construct use were not adequately addressed. Overall, reviewers identified a lack of a comprehensive regulatory strategy and described milestones as vague with no hard endpoints. Reviewers were further uncertain whether human heart biopsies could be obtained for development purposes when patients will receive no potential clinical benefit. Occasionally, the applicant refers to CPC cell lines for development work, but does not describe how they relate to the primary cultures envisioned for use as the therapeutic product. The applicant acknowledges that patients with diseased hearts may not contain as many CPCs as normal individuals and proposes to explore this issue during the early stage of the grant period. Thus, the feasibility of recovering the therapeutic cells from the target population is apparently unknown at present. Given these issues, reviewers doubted that filing a successful IND in 4 years would be possible. Reviewers identified a number of additional major hurdles that need to be overcome before this proposal would near IND submission. The safety issue regarding the integration site of the transgene is addressed in the proposal, but the potential tumor risk associated with the ectopic expression of a known oncogene, Pim-1, is not; this was cause of major concern amongst reviewers. They further criticized that the potential arrhythmogenicity of the transplanted cells was not addressed. Reviewers pointed out that the proposed preclinical animal model, which involves permanent vessel ligation, mimics the acute but not the chronic phase of MI and hence does not address the greatest clinical need. Similarly, reviewers felt that increased myocardial volume is of greatest clinical interest, whereas preliminary data pointed to increased vascularity, a common response to injection of many cell types in this animal model, as the main outcome following mouse Pim-1-CPC transplantation. The proposed large animal model studies were judged to be well controlled as they include comparisons to other transplanted cell types, but specific go / no-go expectations for improved efficacy of human Pim-1-CPC over other cell types were not stated. To better assess the effects of immune suppressants, a necessary component in xenotransplant paradigms, reviewers suggested the inclusion of a non-immune suppressed group in the vehicle only controls. The proposed imaging studies may provide interesting confirmatory evidence for mechanism of action, may be useful in developing release criteria related to biodistribution and are well supported by preliminary data. However, reviewers stated that these studies are actually not essential to regulatory filings, which instead depend on strong safety and efficacy data. If biodistribution data are sought, reviewers suggested that very sensitive PCR assays, rather than in vivo imaging, might be required to reach sufficient sensitivity. Given the goal of an IND filing, reviewers suggested that imaging studies could be deemphasized in favor of more extensive efficacy work involving product characterization and definition. Reviewers felt that an excellent team has been assembled for this project, consisting of academic and commercial entities. The principal investigator (PI) developed relevant technology and has assembled co-investigators with additional expertise and resources, including several investigators who have participated in past major MI cell therapy trials. Many members of the core team have worked together productively in the past, and appropriate, well respected contract organizations and consultant groups were recruited to handle regulatory and Good Manufacturing Practice tasks. All relevant expertise is on board. The budget is reasonable for the studies outlined, with the exception of the budget for the imaging group, which was considered somewhat high. Facilities, infrastructure, and resources for the project are excellent, and letters of support assure access to these facilities and other institutional support for the project. In conclusion, although reviewers praised the qualifications of the assembled team, they did not recommend this application for funding due to major concerns regarding the maturity of the project and serious gaps in the pre-clinical development plan.
  • Charles S. Cox
  • Darin Weber

© 2013 California Institute for Regenerative Medicine