About the Consortium

Purpose

The goal of the NHLBI Progenitor Cell Translational Consortium (PCTC) is to translate advances in progenitor cell biology towards application to heart, lung, and blood diseases. The initiative will focus on the use of progenitor cell-based disease models to understand disease mechanisms and to develop novel therapies, and the application of progenitor cell-based therapies for the treatment of heart, lung, and blood diseases.

Research Objectives and Scope

Stem cell research promises major new insights and therapeutic approaches for human disease of the heart, lungs, and blood, but critical barriers to effective translation exist, many of which entail shared challenges among these distinct organ systems. The NHLBI has provided significant support for the development of the progenitor cell biology field through the NHLBI Progenitor Cell Biology Consortium (PCBC) and the Lung Repair and Regeneration Consortium (LRRC). The PCTC will leverage the advances in progenitor cell biology made by the PCBC and LRRC and the broader scientific community. Scientists have made significant progress in applying bioengineering to heart, lung and blood diseases, developing organs-on-a-chip and developing decellularized scaffolds for tissue replacement. The use of patient-specific induced pluripotent stem cells (iPSCs), bioengineering and genome editing offers unique opportunities for developing personalized disease models and tissues for regenerative medicine. Coupling multiple organ chips together may offer unique opportunities in drug discovery. Advances in 3D printing also offer exciting new opportunities for regenerative medicine, including incorporation of vascular scaffolds into bioengineered tissues and organs.

In translating advances in progenitor cell biology to treat specific cardiovascular, pulmonary, or hematologic diseases, the selected disease area may involve more than one organ system, e.g., pulmonary arterial hypertension, and other areas of expertise e.g., large animals, bioengineering, genome editing, transplant immunology, systems biology, bioreactors for scale-up of cell production, product development, etc.

Focus areas include the continued development of patient-specific disease models using progenitor cells and genome editing; the use of progenitor cells (including gene modified progenitors) and their differentiated progeny for cell therapy and tissue engineering; the development of strategies to promote the reparative potentials of endogenous progenitor cells; and expansion of efforts to employ direct reprogramming of cells in vivo to treat disease. When needed to inform translational potential and strategies, studies may further elucidate disease mechanisms, e.g., obtaining a better understanding of the principles governing how terminally differentiated cells re-enter the cell cycle to proliferate. Modeling and therapeutic development for rare diseases are encouraged.

For different diseases the starting point on the translational continuum varies, and this influences how far towards clinical implementation investigators can anticipate to progress during a seven year period. Projects may vary substantially in their objectives and scope of research.

Collaborations: The consortium will leverage shared expertise in tools and technologies, as well as intellectual insights. The requirement for collaboration will be an integral part of the PCTC. The program may leverage regulatory support from the new Production Assistance for Cellular Therapies (PACT) program so that investigators are well informed about the specific long term needs for their project to be translatable, e.g., advice on standard operating procedures, Good Laboratory Practices, and interactions with the FDA to develop IND and IDE applications; investigators will be expected to obtain regulatory advice early in the project, consult frequently with their advisors to ensure that unforeseen regulatory barriers do not arise, and report on them to NHLBI.

Specific Areas of Research Interest

Research examples appropriate for the PCTC include, but are not limited to, those listed below:

• Transplantation of genome-edited iPSC-derived hematopoietic progenitor cells for treatment of sickle cell disease and other monogenic hematologic diseases
• Genome editing of cystic fibrosis lung stem/progenitor cells to ameliorate lung disease and promote regeneration
• Derivation of mature, functional cardiomyocytes from progenitor cells and transplantation of tissue-engineered cardiac patches into large animal models of heart failure
• Engineering durable effective organ replacement therapies for patients with advanced lung disease
• Direct differentiation of cardiac fibroblasts into cardiomyocytes in situ to improve function in pre-clinical models of heart failure
• Determining mechanisms of phenotypic reprograming induced by severe viral infection and development of progenitor-based therapies for lung injury repair
• Development of strategies to promote reparative activities of progenitor cells in acute lung injury and in pulmonary fibrosis
• Derivation of patient-specific mature endothelial and smooth muscle cells and transplantation to revascularize ischemic myocardium or limbs
• High level transgene expression in iPSC-derived megakaryocytes for correction of Glanzmann’s thrombasthenia and Wiskott-Aldrich syndrome
• Developing methods and strategies for studying the biology of specific progenitor cells, strategies to genome-edit the target cells, and establishing novel approaches for cell delivery, replacement or engraftment in rare, congenital lung diseases
• Applying regenerative strategies to reverse the degenerative process in chronic lung diseases including COPD
• Generation of functional neutrophils and macrophages from iPSCs for chronic granulomatous diseases

Consortium Structure

The PCTC will be a highly interactive and synergistic Consortium of investigators who will share ideas, data and resources to advance translation of progenitor cell biology. In addition to interactions within a Research Hub, extensive collaboration among Research Hubs is expected and may include collaborations between investigators at multiple institutions. The Consortium consists of Research Hubs, and an Administrative Coordinating Center (ACC) that will be responsible for enabling collaboration across the consortium through logistical support and a variety of tasks. The ACC will also administer funds to support pilot studies, ancillary and collaborative research studies, and skills development activities. The NHLBI will work in partnership with the Research Hubs and ACC under cooperative agreements.