R43 SBIR: Development of an iPSC-derived human vascular system for drug development. ABSTRACT Human inducible pluripotent stem cells (iPSCs) can be differentiated into vascular endothelial (iEC) and smooth muscle (iSMC) cells and hold immense potential for developing drugs in genetically defined subpopulations and for patients with vascular rare diseases, such as Marfan's syndrome, from which iPSCs can be acquired. However, it has not been clearly demonstrated that iECs and iSMCs are phenotypically similar to differentiated human primary adult vascular cells, including disease risk factor and drug responsiveness. This cannot be understated as recent studies with iPSC-derived hepatocytes have shown that these cells provide limited utility to the FDA and pharmaceutical industry for drug discovery as they retain many "fetal"-like characteristics, failin to express primary hepatocyte levels of many cytochrome p450 enzymes, including the CYP3A family, which is responsible for metabolizing over 60% of drugs in humans. HemoShear, LLC is a biotechnology research company that utilizes patented methodologies (US 7,811,782) to restore in vivo biology to human primary cells in co-culture in vitro. In this system, vascular cels are rescued from a non-physiological "state" as indicated by restoration of region-specific in vivo morphology, expression of mature differentiation markers and function. Importantly, cells respond to drugs and disease, thrombotic and inflammatory risk factors that approximate in vivo human exposure levels, which are often 1 to 2 orders of magnitude different from standard 2D static systems. The purpose of this SBIR is to determine whether iECs and iSMCs in the HemoShear Vascular system achieve in vivo-like responsiveness similar to human primary vascular cells for utility in safety and drug discovery development, creating the framework for a much needed platform for drug development in genetically defined vascular diseases.

Public Health Relevance

R43 SBIR: Development of an iPSC-derived human vascular system for drug development. NARATIVE Human inducible pluripotent stem cells (iPSCs) can be differentiated into vascular endothelial (iEC) and smooth muscle (iSMC) cells and hold immense potential for developing drugs in genetically defined subpopulations and for patients with vascular rare diseases, such as Marfan's syndrome, from which iPSCs can be acquired. However, it has not been clearly demonstrated that iECs and iSMCs are phenotypically similar to differentiated human primary adult vascular cells, including disease risk factor and drug responsiveness. Thus, the pharmaceutical industry and regulatory agencies view the use of iPSC-derived cells as promising but currently limited. HemoShear is a biotechnology research company that utilizes patented methodologies to restore in vivo responsiveness to human primary cells in vitro. The purpose of this SBIR is to determine whether iECs and iSMCs in the HemoShear Vascular system achieve in vivo-like responsiveness similar to human primary vascular cells for utility in safety and drug discovery development, creating the framework for a much needed platform for drug development in genetically defined vascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Center for Advancing Translational Sciences (NCATS)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
1R43TR001206-01
Application #
8780984
Study Section
Special Emphasis Panel (ZRG1-CVRS-C (10))
Program Officer
Brooks, Pj
Project Start
2014-09-20
Project End
2015-03-19
Budget Start
2014-09-20
Budget End
2015-03-19
Support Year
1
Fiscal Year
2014
Total Cost
$249,013
Indirect Cost
Name
Hemoshear, LLC
Department
Type
DUNS #
809452217
City
Charlottesville
State
VA
Country
United States
Zip Code
22902