Executive Summary The proposal is focused on a therapy for heart failure involving injection of mesenchymal stem cells (MSCs) into heart muscle. The therapeutic MSCs will be isolated from the patients receiving the therapy, and the MSCs will be expanded in culture medium prepared with the patient’s own serum. These developments will provide an autologous cell source (no immunologic barrier), free of animal contamination. Key issues to be resolved in the planning process include details of the cell manufacturing process, institutional involvement, clinical trial design, and intellectual property and publishing rights. This proposal targets a disease of high incidence and substantial impact on both individual patients and national health care economics. The proposed therapeutic approach should allow an avoidance of issues of immune rejection and safety in that transplanted materials will be entirely autologous. The overall study design appears appropriate. However, the approach is not novel, as similar studies are ongoing in a number of medical centers, and the proposed research primarily represents an optimization of an established concept. Furthermore, no Phase III studies have been performed to date to confirm efficacy (especially long-term efficacy) of this approach. Reveiwers’ enthusiasm for the proposal was further diminished by the heterogeneity of results in many small scale studies, and in several larger controlled studies to date. The PI has founded three cardiovascular product companies and has experience in coordinating collaborations between academic institutions and industry. His/her limited experience in the basic science aspects of therapeutic development with two pertinent publications in PubMed was of concern to the reviewers. Reviewers viewed the planning approach as particularly weak, which raised the issue of responsiveness to the RFA. The planning approach was not described adequately, and many essential details were absent. Reviewer Synopsis As a new heart failure therapy, the investigators propose percutaneous transendocardial delivery of autologous serum processed autologous mesenchymal stem cells (AS-MSCs). Autologous culture medium to expand human mesenchymal cells eliminates safety issues associated with fetal calf serum. AS-MSCs may be expanded rapidly with stable gene expression in AS in the absence of growth factors. Subjects will have 150 ml of bone marrow aspirated. 100 ml will be used to expand the mesenchymal cell population in AS to develop a dosage of up to 100 million AS-MSCs, with a minimum of 20 million. Subjects ineligible for MSCs may receive 100 million frozen cells. This project requires tissue culture and processing, laboratory test controls to validate each dose, clinical protocol and IND preparation, hospital IRB approval, and then clinical trials in patients with coronary artery disease-induced heart failure. Reviewer One Comments Concept: This is an application from BioCardia for a planning grant to develop autologous serum processing of autologous MSCs for transendocardial delivery in heart disease. The case for autologous serum in bioprocessing is logical in principle, and possibly worthy of development, but insufficient information is provided for a knowledgeable evaluation. This limitation is true, even to the composition of the planning process team, whose members are not named. Principal Investigator: Peter Altman, the President of BioCardia, holds relevant scientific and business degrees from Berkeley. The company’s relevant activities are insufficiently described. Planning Approach: Given the complete lack of detail as to the identity of confirmed participating individuals, there is inadequate information to justify reviewers’ enthusiasm. Overall, the application is skeletal at best and little more than a promissory note. Reviewer Two Comments Concept: The investigators propose to clinically develop truly autologous mesenchymal stem cells (MSC) as a potential new treatment that may increase the functional ability of the myocardial wall and decrease ventricular remodeling in areas of infarction. A patient’s own serum will be used to avoid fetal calf serum and provide for autologous serum to grow mesenchymal cells taken from bone marrow. To obtain this serum, 250 ml of blood will be taken from each patient at each of two visits separated at least one week for a total blood volume of 500 ml. This blood will be stored as a source for autologous tissue culture medium. This eliminates safety issues associated with Fetal Calf Serum (FCS) which is typically used in these tissue culture experiments. Patients will have approximately 150 ml of bone marrow aspirated. 100 ml will be used to expand the mesenchymal cell population in the autologous serum to develop a dosage of up to 100 million MSCs, with a minimum of 20 million MSCs. Patients who are not eligible for MSCs due to difficulties in culturing a minimum of 20 million MSCs will receive frozen mononuclear cells at a dosage of 100 million cells. All patients will have aliquots of marrow and blood preserved at baseline and blood at each follow-up time for transcriptional and proteomic expression assays to answer the following question: “Will the patient respond to their own adult autologous cells?” The growth of the repository will enable more complicated questions to be addressed over time. While the overall approach is interesting it does not appear particularly mature. Questions regarding the success of growth and the quality of the cells and their properties remain to be answered. In ongoing clinical work 19 patients have been enrolled to date (with a perfect safety record) by the applicant involved in a team effort to evaluate the safety of adult cells in heart failure. Developing the therapeutic candidate in question requires principal investigator leads with expertise in heart failure, cell processing, cell delivery, cell tracking, and complex biotherapeutic regulatory submissions. Leads have all been identified at both private and public California institutions. To initiate such a program requires solution of the following issues including (1) cell manufacturing process and institutional involvement, (2) preclinical study designs and executions appropriate (with or without a comparable ESC collaboration to bench mark biodistribution and engraftment results), (3) clinical trial design, budget, and execution, and (4) IP and publishing rights of the various institutions and investigators. Principal Investigator: Dr. Altman has been founding CEO for 3 CV product companies. He has a record of collaboration with academic institutions and industry. Most of his expertise description is of his involvement in the strategy for company launches as well as in bringing various products to clinical use. Planning Approach: This is problematic. It is stated “The team to be assembled includes principal investigators with unique core competencies. They have been and will continue to be identified to their experience and commitment to this field of adult stem cell therapy as it relates to their core competencies. They will have experience, be dedicated to the advancement of science and patient care, and perform rigorous world class science.” It is stated that 5 primary lead investigators are critical to the success of the program: 1. Cell Processing and Clinical Cell Production Lead 2. Preclinical validation and testing lead 3. Clinical Leads: UC and Stanford Based Cardiologists 4. Molecular Diagnostics Sample Archiving Lead 5. Regulatory and QC Lead However, while it is stated that leaders have been identified, none are mentioned by name, so it is unclear what the team and its expertise will be. It is then stated that “Planning will involve getting each team lead to specify a plan which will be updated on a regular basis by the Program Manager who will be a facilitator (not an investigator) and present it to the other principal investigators for review as well as at least one peer review prior to completion. In this way the team will become cohesive and the review process will include critical input from those with relevant domain expertise.” This is not so much a plan as a plan to come up with a plan…more information is needed if an informed review is to be provided. Reviewer Three Comments Concept: Concept/ Rationale. The team proposes to isolate autologous bone marrow mononuclear cells or cultured MSC for transplantation into patients with heart failure. The cells will be autologous to avoid rejection. Patients own serum will be used to propagate the MSC to avoid problems with xenogeneic or allogeneic sources. Similar studies by many groups have established that the proposed therapy has a small positive effect on cardiac function. The PI suggests that lessons learned from the present application could be relevant to future work with ES or other cell types. This group (with collaborators) has transplanted 19 patients to date in a similar protocol. What seems to be the exact same protocol is already funded in a collaborative project with Biocardia and U. Miami. Overlap should be addressed in any application. Maturity: The concepts are mature and tested in many laboratories including the authors own group. The proposal is more directed to optimizing an already established concept rather than promoting a new concept. Significance. Correction of heart failure could provide significant health and financial benefits to the population. Principal Investigator: Good -Excellent. Dr. Altman received his Ph.D. in 2003 from UCSF and UC Berkeley in bioengineering and pharmaceutical chemistry. The PI is more of a businessman than a scientist, but has a track record of accomplishment especially in the start-up biotech area. The proposal states that over 2000 patients have been treated with products developed by Biocardia. There is not a long record of publications.