药代动力学
间充质干细胞
分布(数学)
干细胞
组织分布
医学
药理学
病理
生物
内科学
细胞生物学
数学
数学分析
作者
Sagar Munjal,Hannah M. Miller,Erik J. Woods,Brian H. Johnstone
标识
DOI:10.1016/j.jtct.2023.12.333
摘要
The objective of this nonclinical study was to establish the biodistribution in animals of repeated high doses of a mesenchymal stem cell therapy to support a first-in-human study in steroid-refractory acute GVHD (SR-aGVHD) patients. Allogeneic hematopoietic cell transplantation (HCT) is a life-saving procedure for treating hematological malignancies, bone marrow failure and inherited blood disorders. Despite the high remission rate attained with the procedure, serious long-term complications frequently occur. Up to 80% of patients develop often life-threatening acute graft versus host disease (aGVHD), which is treated with high doses of immune suppressing steroids. However, up to 35-50% of HCT patients will develop steroid-refractory (SR)-aGVHD. The prognosis for these patients is extremely poor with only a 20% survival rate. We are developing a novel bone marrow-mesenchymal stem cell (BM-MSC) therapy (OSSM-007), derived from deceased organ donor vertebral body bone marrow, to address SR-aGVHD. Using a combination of priming with the potent inflammatory factor interferon gamma (IFNγ) and by stabilizing cell structures to withstand injury incurred by cryopreservation, we have generated a potent MSC product that is nearing clinical testing. We conducted a biodistribution study in mice to (1) determine the total body exposure and persistence of OSSM-007 with intravenous administration at a dose of 2 million cells/mouse and (2) to determine the effects of IFNg priming by comparing to unprimed MSC (OSSM-001). The presence of human cells was detected by quantitative polymerase chain reaction. The results are presented in the table below. Detection of human DNA was generally the highest at the administration site (tail), one day following dosing (Day 2) as opposed to 2 days following dosing (Day 6) and rapidly decreased to become undetectable on Day 94, suggesting that the vBM MSC were cleared within three months. Based on the incidence of positive animals, intravenous administration of OSSM-001 and OSSM-007 lead to the greatest detection and to the biodistribution of the cells in the lungs. Furthermore, incubation with IFNg (OSSM-007) did not appear to have a noticeable impact on the biodistribution or persistence of BM-MSC administered intravenously. Combined with contemporaneous tumorigenicity and toxicity study, these results indicate that systemic exposure of multiple OSSM-007 doses that are equivalent to 4.8 billion/60 kg patient is transient and safe.
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