Targeted Bone Regeneration via Activation of Resident Stem Cells

National Center For Advancing Translational Sciences

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Abstract

The team previously completed manufacturing of Good Manufacturing Practice (GMP)-compliant drug product (hBMP6 plasmid) to be used in subsequent IND-enabling and clinical studies, with drug product stability studies ongoing. PCR- and antibody-based bioanalytical assays have been developed, while a method using mass spectrometry is still being optimized. Measuring hBMP6 content in the GLP toxicology samples using a PCR assay were completed. The method development and sample analysis of the anti-drug-antibody (ADA) assay were completed as well. The collaborators previously demonstrated efficacy in minipigs. The FDA requested additional efficacy studies in a second species with longer leg bones. Data from subsequent efficacy studies that we conducted in sheep were not conclusive, so the team conducted additional studies in sheep and added a second species (goat) to address the potential for spontaneous osteogenesis obscuring the efficacy of the hBMP-6 treatment. The in vitro component of the study examined the spontaneous osteogenesis in hBMP6-transfected bone marrow-derived mesenchymal stem cells from pigs, sheep, and goats. The in vivo component evaluated the spontaneous bone regeneration after introducing a >1 cm surgical segmental bone defect in sheep and goats. The results from both studies suggested that neither sheep nor goats are ideal animal models to assess the critical-sized (>1 cm) defects due to underlying spontaneous osteogenesis. The IND application will include the available efficacy data from the earlier minipig studies plus the other comprehensive IND-enabling data generated by NCATS.