Early Translational III
Angiogenesis or the generation of new blood vessels is a critical part of the normal healing process. Newly created vessels ensure the delivery of oxygen, nutrients, and specific repair signals to injured tissues. Indeed, even though additional repair mechanisms are required, such as replenishment of tissue-specific cell types, angiogenesis contributes to the healing of a number of different processes such as nerve regeneration, skin, muscle and bone repair among others. Insufficient angiogenesis is a hallmark of chronic wounds and often present in the elderly, people with high cholesterol, diabetes, and heavy drinkers and smokers. More than $4 billion has been invested in research and development and over 600 clinical trials targeting a variety of disorders including diabetes-related complications, peripheral arterial disease, stroke and wound healing as a few examples, are currently under way. Most of the studies have focused on the development of molecules facilitating self-repair by increasing endogenous angiogenesis. Stem cell technologies open the possibility for the generation and engineering of blood vessels in vitro suitable for transplantation in specific local areas. Thus, even though stem cells technologies can allow for the large-scale generation of vessels suitable for the healing of a wide variety of disorders, safety concerns hamper their translation into the clinic.
Statement of Benefit to California:
Rarely does a new technology come along that has the potential to make such a major impact on human health like stem cell reprogramming does. The successful development of stem cell therapies for disorders in which the generation of new vessels is necessary for healing will have an obvious and direct effect on the patients and families affected. Furthermore, regenerative medicine techniques are not limited to the generation of new vasculature and bear the potential to treat a vast array of diseases including Parkinson’s, Alzheimer’s, diabetes and blood disorders. All of these disorders place a tremendous burden on the State in terms of health care cost. The idea of connecting basic discoveries in stem cell research to clinical applications is new and unique to the California initiative. As such, California is the primary beneficiary of this technological investment. We envision 2 major positive effects for Californians: (1) California patients will be privileged once stem cell therapies are developed and ready to be implemented. This will create a positive wave in the general perception and awareness as to the position of California and its medical institutions worldwide. (2) California will witness the growth of its technological/industrial infrastructure to develop new forms of treatments on the wave of new basic discoveries. This combination is powerful and dividends will be generated in due time in the form of revenue from health care delivery and intellectual property.
This Development Candidate Feasibility (DCF) proposal aims to test vascular progenitor cells (VPCs) capable of differentiating into both endothelial and smooth muscle cells as a therapy for ischemic conditions such as limb ischemia and heart attack. The applicant has developed a method to generate vascular progenitors by direct conversion from human fibroblasts and proposes to optimize this method by testing alternative input cells, conversion factors and gene delivery methods. Optimized direct conversion VPCs will be assessed for genomic and epigenomic integrity. Next, the group will compare the performance of vascular progenitors differentiated by direct conversion to those differentiated from induced pluripotent stem cells in a series of in vitro and in vivo assays of endothelial cell and angiogenic function as well as in ischemic heart and limb models. Finally, the group will assess both types of VPCs for their tumorigenic potential. Objective and Milestones - Reviewers were highly enthusiastic about this proposal. The Target Product Profile is both scientifically and clinically reasonable. The panel found the objectives and milestones focused, complete, logical and achievable in three years. - The panel appreciated the direct conversion approach as it does not require traversing a pluripotent state and could therefore improve safety of the ultimate therapeutic candidate. However, they noted that this potential safety benefit remains to be demonstrated. Rationale and Significance - If successfully developed, the proposed therapeutic could have a significant impact upon the large unmet medical need presented by a variety of ischemic diseases including myocardial infarction and critical limb ischemia. Research Project Feasibility and Design - Strong preliminary data generated by the team, including well-established assays and protocols for generating and characterizing VPCs, increase the program’s likelihood of success. - Reviewers appreciated the clear, well-considered experimental plan and the applicant’s focus on clinical translation. - Current direct conversion methods could present an obstacle to clinical translation as they modify the cell’s DNA. It is not yet known whether direct conversion can be achieved using non-integrating methods or a streamlined reprogramming factor set. However, this did not dampen reviewer enthusiasm for the application. Qualification of the PI (Co-PI and Partner PI, if applicable) and Research Team - Reviewers highlighted the PI and his/her unique record of achievements as strengths of the proposal. - Levels of commitment, staffing and the budget are appropriate to achieve the program’s goals. Collaborations, Assets, Resources and Environment - This program will take place at the PI’s institution where resources required for successful execution of the project are available. Responsiveness to the RFA - This proposal is responsive to the RFA.