Disease Team Therapy Planning I
Heart attack leads to death of a portion of the heart wall. Dead cells cannot contribute in the pump function of the heart, which leads to exhaustion of the remaining healthy parts of the heart muscle upon time and results in heart failure. Patients with heart failure eventually need heart transplantation to survive. There are two ways to help patients with a very weak heart: prevent them from getting a heart attack or make sure that the dysfunctional part of the heart wall starts contributing in the heart function by making new cells that replace dead cells Over the years, a lot of time, research, effort, education and money have been spent on preventing patients from getting a heart attack. However, despite reduction of risk factors, heart disease is the number one cause of death in the United States. The second option is to replace dead cells with newly formed cells that are contributing to the pump function of the heart thereby preventing exhaustion of the remaining healthy part. In every organ, there is a continuous manufacture of newly formed cells. The source for this new cell formation is their stem cell population. Stem cells are very primitive “naïve” cells that can stay “young” and uncommitted and replicate themselves more than mature cells. The heart has a source of stem cells too, the so-called Cardiac Progenitor Cells (CPCs). This resident source of “naïve” cells is meant for replacement of cells with natural aging, which is a gradual process and requires a modest manufacture for cell replacement. In contrary, cell loss upon a heart attack is massive and requires a robust cell replacement machinery. Although the CPCs try to replace some of the dead cells after a heart attack, they become overwhelmed by the amount of work that they have to perform and run out in their replicating capacity. In order to make new cells in the heart after a heart attack, we want to isolate these “weak” stem cells from the heart and use “doping” to increase their capacity to divide and survive. How to “dope” stem cells? Proteins dictate a cell whether to live, die, divide, commit to a certain cell type or stay uncommitted. Modifying and manipulating certain specific proteins in a cell can influence cellular processes. Our group has identified the protein Pim-1 in the heart, where it plays an important role in cell division, survival and commitment towards heart cells. Modifying stem cells with higher level of Pim-1 is an ideal “doping” for our heart stem cells. We obtain human stem cells from heart failure patients and modify them to have higher Pim-1 levels. These cells are then injected into the heart to form new muscle and improve cardiac function. Early results in animal models show that Pim-1 cells make a significant difference in heart function and new cell formation compared to unmodified cells. The purpose of this proposal is to take this approach from the laboratory to where it is needed, a patient’s bedside.
Statement of Benefit to California:
Heart disease is the leading cause of death in California (By Laura E. Lund, M.A.1 and Nan Pheatt, M.P.H. Center for Health Statistics). In addition, heart disease is a major cause of chronic illness in California. This strains California’s health care system and its economy, as well as the emotional and financial resources of families. It is clear that action is needed now to halt the consequences of heart disease. Clinical application of engineered stem cells opens a new field in the industry, thereby creating new employment opportunities. In an academic setting, this field of research can be a source of knowledge and educating young scientists in the field. In addition, stem cell therapy and its clinical application is not only essential in the heart but also in other organs. Cell based therapy can be useful in a variety of patient populations suffering from chronic illness due to e.g diabetes, spinal cord injury and Parkinsons. Improvement of their quality of life and survival will lead to contribution to the society and economy of the state of California. Should this technology become implemented in clinical trial, hospitals in our state will be engaged to enroll their patient population, thereby offering cutting edge cellular cardiomyoplasty to Californians that will be the best therapeutic option in the country. California will become known nationally as the destination for treatment of advanced heart failure, thereby raising both research and clinical profiles of cardiac care and attracting new researchers and clinician to work in our State. The successful implementation of this therapeutic approach will also stimulate research at State colleges and universities, translating into more federal funding for regenerative medicine research in our State and a logical transition from CIRM to subsequent support by federal government and the biotech / pharmaceutical industry. The eventual impact is to bring the best treatment for heart failure to our State, together with the best scientists and clinicians working together to rapidly translate their work into deliverable patient care that will accelerate and become self-sustaining by infusion of capital from multiple sources, creating a revenue stream that will reward CIRM investment and perpetuate the initial advances underwritten by this proposal.
EXECUTIVE SUMMARY Project Synopsis This application describes preclinical development of a regenerative cardiac therapy to achieve an IND filing. The treatment is intended for use in recent heart attack patients suffering persistent, significantly compromised cardiac function who are also candidates for coronary artery bypass graft surgery (CABG). The proposed therapeutic is autologous cardiac progenitor cells (CPC) obtained during CABG then genetically modified ex vivo to express a gene that promotes their survival and proliferation. These cells will be directly injected back into the patient’s heart muscle. During first 3.5 years of the award, the investigators plan to optimize their gene expression vector, select, expand and characterize the cell preparation, develop and qualify assays, perform shipping studies, develop a GMP manufacturing process, and perform efficacy and GLP safety studies in a relevant preclinical model. The applicants plan to develop their first in man protocol, compile their data and submit an IND in the fourth year. Consultations with the FDA are also planned. Significance and Impact - Given that patients with severely compromised left ventricular function have limited treatment options, the proposed therapy could have significant impact if successfully developed. - The impact of this candidate therapy will depend upon the clinical benefit observed as well as the relative efficacy of this product to other simpler autologous therapies already in clinical development for this indication. - The selected delivery device would at least initially limit the availability of the treatment to major medical centers. Project Rationale and Feasibility - Reviewers agreed the Target Product Profile (TPP) is immature for the developmental stage of this RFA and found the program better suited to an early translational RFA. For example, the identity and composition of the cell product are ill defined, as are therapeutic gene delivery requirements. Reviewers identified this as a critical flaw for a development stage program. - The description of the production process is vague and caused concern that the applicants may have limited translational research experience. For example, the methods planned to isolate, expand, and transduce human CPC are absent, and the described gene delivery vector encodes a potentially immunogenic marker protein. - The lack of yields and lot success rates of the process hindered the reviewers’ evaluation of the project’s feasibility. - Reviewers did not find the applicant’s preclinical data with human CPC sufficiently compelling to justify a full-scale development program. Data in the relevant preclinical model are still in process, and the post-injury cell administration timing in the immune-compromised model is incompatible with the clinical scenario. - Logistical difficulties of processing, releasing and delivering cells to patients on time are not addressed. - Descriptions of IND enabling studies are vague, and potential ectopic tissue formation merits further discussion. PI and Planning Leader - The team consists of a respected PI with extensive publications in basic, mechanistic cardiac research and a planning leader with cardiovascular drug development experience. - The small planning team neither describes cell therapy translation experience nor efforts to recruit consultants with this experience, reducing the likelihood of successfully translating this gene modified cell product.