A Phase 1 Trial of a Single ProHema® CB Product as Part of Single Cord Blood Unit Transplant After Busulfan/Cyclophosphamide/ATG Conditioning for Pediatric Patients With Inherited Metabolic Disorders

The purpose of this study is to describe the safety profile of ProHema-CB as part of a single cord blood unit transplant after a myeloablative conditioning regimen in pediatric patients with inherited metabolic disorders. The safety profile will primarily be assessed by neutrophil engraftment.

Start Date01 Jun 2015

Sponsor / Collaborator

Fate Therapeutics, Inc.

NCT01627314 / TerminatedPhase 2

A Phase 2 Controlled Trial of a Single ProHema®-CB Unit (Ex Vivo Modulated Human Cord Blood) As Part of a Double Umbilical Cord Blood Transplant Following Myeloablative or Reduced Intensity Conditioning For Patients Age 15-65 Years With Hematologic Malignancies.

This study is an open-label randomized, prospectively and historically controlled trial of the safety and efficacy of a single ProHema-CB unit used as part of a double CB transplant following myeloablative or reduced intensity conditioning for subjects age 15-65 years with hematologic malignancies. A maximum of 60 eligible subjects will be enrolled and treated in the trial at approximately 10 centers within the U.S.

Start Date01 Jul 2012

Sponsor / Collaborator

Fate Therapeutics, Inc.

NCT01527838 / CompletedPhase 1

A Phase I Trial of a Single FT1050 (16,16-Dimethyl Prostaglandin E2) Ex Vivo-Modulated Umbilical Cord Blood (CB) Unit Following a Reduced Intensity Conditioning Regimen For Adults With Hematologic Malignancies

This trial is a prospective, open-label, single-arm trial of the safety of a single FT1050-treated CB unit for hematopoietic reconstitution after a reduced-intensity conditioning regimen for hematologic malignancies. A maximum of 40 eligible adult subjects will be enrolled and treated in the trial at approximately 2-4 centers within the U.S.

Start Date01 Jan 2012

Sponsor / Collaborator

Fate Therapeutics, Inc.

100 Clinical Results associated with FT-1050 treated UCB

100 Translational Medicine associated with FT-1050 treated UCB

100 Patents (Medical) associated with FT-1050 treated UCB

169

Literatures (Medical) associated with FT-1050 treated UCB

28 Nov 2023·Radiation Research

Pharmacokinetics and Biodistribution of 16,16 dimethyl Prostaglandin E2 in Non-Irradiated and Irradiated Mice and Non-Irradiated Non-Human Primates

Article

Author: Triesler, Sarah ; Singh, Pratibha ; Sampson, Carol H ; Jackson, Isabel L ; Plett, P Artur ; Gibbs, Allison ; Langevin, Brooke ; Pelus, Louis M ; Masters, Andi ; Zodda, Andrew ; Gopalakrishnan, Mathangi ; Orschell, Christie M ; Faria, Eduardo De

Exposure to high-dose ionizing radiation can lead to life-threatening injuries and mortality. Bone marrow is the most sensitive organ to radiation damage, resulting in the hematopoietic acute radiation syndrome (H-ARS) with the potential sequelae of infection, hemorrhage, anemia, and death if untreated. The development of medical countermeasures (MCMs) to protect or mitigate radiation injury is a medical necessity. In our well-established murine model of H-ARS we have demonstrated that the prostaglandin E2 (PGE2) analog 16,16 dimethyl-PGE2 (dmPGE2) has survival efficacy as both a radioprotectant and radiomitigator. The purpose of this study was to investigate the pharmacokinetics (PK) and biodistribution of dmPGE2 when used as a radioprotector in irradiated and non-irradiated inbred C57BL/6J mice, PK in irradiated and non-irradiated Jackson Diversity Outbred (JDO) mice, and the PK profile of dmPGE2 in non-irradiated non-human primates (NHPs). The C57BL/6J and JDO mice each received a single subcutaneous (SC) dose of 35 ug of dmPGE2 and were randomized to either receive radiation 30 min later or remain non-irradiated. Plasma and tissue PK profiles were established. The NHP were dosed with 0.1 mg/kg by SC administration and the PK profile in plasma was established. The concentration time profiles were analyzed by standard non-compartmental analysis and the metrics of AUC0–Inf, AUC60–480 (AUC from 60–480 min), Cmax, and t1/2 were evaluated. AUC60–480 represents the postirradiation time frame and was used to assess radiation effect. Overall, AUC0–Inf, Cmax, and t1/2 were numerically similar between strains (C57BL/6J and JDO) when combined, regardless of exposure status (AUC0–Inf: 112.50 ng·h/ml and 114.48 ng·h/ml, Cmax: 44.53 ng/ml and 63.96 ng/ml; t1/2: 1.8 h and 1.1 h, respectively). PK metrics were numerically lower in irradiated C57BL/6J mice than in non-irradiated mice [irradiation ratio: irradiated values/non-irradiated values = 0.71 for AUC60–480 (i.e., 29% lower), and 0.6 for t1/2]. In JDO mice, the radiation ratio was 0.53 for AUC60–480 (i.e., 47% lower), and 1.7 h for t1/2. The AUC0–Inf, Cmax, and t1/2 of the NHPs were 29.20 ng·h/ml, 7.68 ng/ml, and 3.26 h, respectively. Despite the numerical differences seen between irradiated and non-irradiated groups in PK parameters, the effect of radiation on PK can be considered minimal based on current data. The biodistribution in C57BL/6J mice showed that dmPGE2 per gram of tissue was highest in the lungs, regardless of exposure status. The radiation ratio for the different tissue AUC60–480 in C57BL/6J mice ranged between 0.5–1.1 (50% lower to 10% higher). Spleen, liver and bone marrow showed close to twice lower exposures after irradiation, whereas heart had a 10% higher exposure. Based on the clearance values from mice and NHP, the estimated allometric scaling coefficient was 0.81 (95% CI: 0.75, 0.86). While slightly higher than the current literature estimates of 0.75, this scaling coefficient can be considered a reasonable estimate and can be used to scale dmPGE2 dosing from animals to humans for future trials.

04 Apr 2023·Radiation Research

Further Characterization of Multi-Organ DEARE and Protection by 16,16 Dimethyl Prostaglandin E2 in a Mouse Model of the Hematopoietic Acute Radiation Syndrome

Article

Author: Wu, Tong ; Fisher, Alexa ; Zhou, Daohong ; Liu, Liqiong ; Miller, Steven J ; Pelus, Louis M ; Bhatwadekar, Ashay D ; Chua, Hui Lin ; Sampson, Carol H ; Li, Hongge ; McKinzie, David L ; Orschell, Christie M ; Plett, P Artur ; Luo, Qianyi ; Meyer, Timothy B ; Chittajallu, Supriya ; Feng, Hailin ; Fischer, Kathryn D ; Zhang, Xin ; Ortiz, Miguel

Survivors of acute radiation exposure suffer from the delayed effects of acute radiation exposure (DEARE), a chronic condition affecting multiple organs, including lung, kidney, heart, gastrointestinal tract, eyes, and brain, and often causing cancer. While effective medical countermeasures (MCM) for the hematopoietic-acute radiation syndrome (H-ARS) have been identified and approved by the FDA, development of MCM for DEARE has not yet been successful. We previously documented residual bone marrow damage (RBMD) and progressive renal and cardiovascular DEARE in murine survivors of H-ARS, and significant survival efficacy of 16,16-dimethyl prostaglandin E2 (dmPGE2) given as a radioprotectant or radiomitigator for H-ARS. We now describe additional DEARE (physiological and neural function, progressive fur graying, ocular inflammation, and malignancy) developing after sub-threshold doses in our H-ARS model, and detailed analysis of the effects of dmPGE2 administered before (PGE-pre) or after (PGE-post) lethal total-body irradiation (TBI) on these DEARE. Administration of PGE-pre normalized the twofold reduction of white blood cells (WBC) and lymphocytes seen in vehicle-treated survivors (Veh), and increased the number of bone marrow (BM) cells, splenocytes, thymocytes, and phenotypically defined hematopoietic progenitor cells (HPC) and hematopoietic stem cells (HSC) to levels equivalent to those in non-irradiated age-matched controls. PGE-pre significantly protected HPC colony formation ex vivo by >twofold, long term-HSC in vivo engraftment potential up to ninefold, and significantly blunted TBI-induced myeloid skewing. Secondary transplantation documented continued production of LT-HSC with normal lineage differentiation. PGE-pre reduced development of DEARE cardiovascular pathologies and renal damage; prevented coronary artery rarefication, blunted progressive loss of coronary artery endothelia, reduced inflammation and coronary early senescence, and blunted radiation-induced increase in blood urea nitrogen (BUN). Ocular monocytes were significantly lower in PGE-pre mice, as was TBI-induced fur graying. Increased body weight and decreased frailty in male mice, and reduced incidence of thymic lymphoma were documented in PGE-pre mice. In assays measuring behavioral and cognitive functions, PGE-pre reduced anxiety in females, significantly blunted shock flinch response, and increased exploratory behavior in males. No effect of TBI was observed on memory in any group. PGE-post, despite significantly increasing 30-day survival in H-ARS and WBC and hematopoietic recovery, was not effective in reducing TBI-induced RBMD or any other DEARE. In summary, dmPGE2 administered as an H-ARS MCM before lethal TBI significantly increased 30-day survival and ameliorated RBMD and multi-organ and cognitive/behavioral DEARE to at least 12 months after TBI, whereas given after TBI, dmPGE2 enhances survival from H-ARS but has little impact on RBMD or other DEARE.

01 Apr 2022·Stem Cell Reviews and ReportsQ3 · MEDICINE

Upregulation of SIRT1 Contributes to dmPGE2-dependent Radioprotection of Hematopoietic Stem Cells

Q3 · MEDICINE

Article

Author: Singh, Pratibha ; Mohammad, Khalid S ; Capitano, Maegan L ; Li, Hongge ; Liu, Liqiong ; Yao, Chonghua ; Orschell, Christie M ; Plett, P Artur ; Patterson, Andrea M ; Sampson, Carol H ; Pelus, Louis M

Exposure to potentially lethal high-dose ionizing radiation results in bone marrow suppression, known as the hematopoietic acute radiation syndrome (H-ARS), which can lead to pancytopenia and possible death from hemorrhage or infection. Medical countermeasures to protect from or mitigate the effects of radiation exposure are an ongoing medical need. We recently reported that 16,16 dimethyl prostaglandin E₂ (dmPGE₂) given prior to lethal irradiation protects hematopoietic stem (HSCs) and progenitor (HPCs) cells and accelerates hematopoietic recovery by attenuating mitochondrial compromise, DNA damage, apoptosis, and senescence. However, molecular mechanisms responsible for the radioprotective effects of dmPGE₂ on HSCs are not well understood. In this report, we identify a crucial role for the NAD⁺-dependent histone deacetylase Sirtuin 1 (Sirt1) downstream of PKA and CREB in dmPGE₂-dependent radioprotection of hematopoietic cells. We found that dmPGE₂ increases Sirt1 expression and activity in hematopoietic cells including HSCs and pharmacologic and genetic suppression of Sirt1 attenuates the radioprotective effects of dmPGE₂ on HSC and HPC function and its ability to reduce DNA damage, apoptosis, and senescence and stimulate autophagy in HSCs. DmPGE₂-mediated enhancement of Sirt1 activity in irradiated mice is accompanied by epigenetic downregulation of p53 activation and inhibition of H3K9 and H4K16 acetylation at the promoters of the genes involved in DNA repair, apoptosis, and autophagy, including p53, Ku70, Ku80, LC3b, ATG7, and NF-κB. These studies expand our understanding of intracellular events that are induced by IR but prevented/attenuated by dmPGE₂ and suggest that modulation of Sirt1 activity may facilitate hematopoietic recovery following hematopoietic stress. Graphical Abstract.

100 Deals associated with FT-1050 treated UCB

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Indication	Highest Phase	Country/Location	Organization	Date
Hematologic Neoplasms	Phase 2	US	Fate Therapeutics, Inc.	01 Jul 2012
Acute Lymphoblastic Leukemia	Phase 2	US	Fate Therapeutics, Inc.	01 Jan 2012
Chronic Lymphocytic Leukemia	Phase 2	US	Fate Therapeutics, Inc.	01 Jan 2012
Hodgkin's Lymphoma	Phase 2	US	Fate Therapeutics, Inc.	01 Jan 2012
Non-Hodgkin Lymphoma	Phase 2	US	Fate Therapeutics, Inc.	01 Jan 2012
Hematopoietic stem cell transplantation	Phase 2	US	Fate Therapeutics, Inc.	01 Jan 2011

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02354443 (PROVIDE, CTgov)	Phase 1	Genetic Diseases, Inborn \| Metabolic Diseases	1	ProHema-CB Transplant	aygbqdxgpj(lklenfdauc) = gsjfmayikk htrlpfupjl (govgvvcmmi, humcbcnqvq - vvmyrohtmo) View more	-	10 Oct 2018

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