scholarly journals A Novel Therapy for Sickle Cell Disease (SCD): Co-Transplantation of Nicord® [Ex Vivo Expanded Umbilical Cord Blood (UCB) Progenitor Cells with Nicotinamide] and an Unmanipulated Unrelated UCB Graft Leads to Successful Engraftment and Cure of Severe SCD

2018 ◽  
Vol 24 (3) ◽  
pp. S191-S192 ◽  
Author(s):  
Suhag Parikh ◽  
Joel A. Brochstein ◽  
Stephen Wease ◽  
Paul L. Martin ◽  
Mitchell E. Horwitz ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Cord Blood ◽  
Progenitor Cells ◽  
Umbilical Cord ◽  
Sickle Cell ◽  
Umbilical Cord Blood ◽  
Ex Vivo ◽  
Cell Disease ◽  
Novel Therapy

scholarly journals Umbilical Cord Blood Transplantation for Children with Thalassemia and Sickle Cell Disease

2011 ◽  
Vol 17 (9) ◽  
pp. 1375-1382 ◽  
Author(s):  
Annalisa Ruggeri ◽  
Mary Eapen ◽  
Andromachi Scaravadou ◽  
Mitchell S. Cairo ◽  
Monica Bhatia ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Sickle Cell ◽  
Umbilical Cord Blood ◽  
Cord Blood Transplantation ◽  
Umbilical Cord Blood Transplantation ◽  
Cell Disease ◽  
Blood Transplantation

Study of In Vitro Proliferation Potential of CD133 Positive Cells Derived from Umbilical Cord Blood.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4039-4039
Author(s):  
Ri Zhang ◽  
Wenjin Gao ◽  
Yuanyuan Sun ◽  
Jingcheng Miao ◽  
Xueguang Zhang
Keyword(s):  
Cord Blood ◽  
Progenitor Cells ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Ex Vivo ◽  
Ex Vivo Expansion ◽  
Hematopoietic Stem ◽  
Low Concentration ◽  
Tgf Β1

Abstract Transforming growth factor-beta 1 (TGF-β1) is known to maintain primitive human hematopoietic stem/progenitor cells with polyfunctional role in a quiescent state and CD133 is a new stem cell antigen that may provide an alternative to CD34 for the selection and expansion of hematopoietic cells for transplantation. To investigate the specific effect of TGF-β1 on proliferation and differentiation of CD133 positive cells derived from umbilical cord blood (UCB) during short-term culture in vitro, CD133 positive cells from 20 fresh UCB samples were selected using Miltenyi Biotec’s CliniMACS separation device and were cultured in IMDM medium with 20% FCS in the presence of a cytokine combination of SCF, IL-6, thrombopoietin, IL-3 and Flt3-ligand for up to 2 weeks and TGF-β1 with low concentration was also added to the mediumon day 4. The proliferative response was assessed at day 7, day 10 and day 14 by evaluating the following parameters: nucleated cells (NC), clonogenic progenitors (CFU-GEMM,CFU-GM and BFU-E), and immunophenotypes (CD133 and CD34). The results showed that efficacious expansion of various hematopoietic stem/progenitor cells was constantly observed during the culture. The fold expansion of NC on day7, day10 and day14 expansion were 33.59,224.26 and 613.48, respectively. The fold expansion of CFU-GEMM, CFU-GM and BFU-E on day 10 were 24.89, 41.62 and 49.28, respectively, obviously higher than that without ex vivo expansion (P<0.05). The expansions of CD133+, CD133+CD34+ and CD34+ subpopulation on day 14 were up to 25.83-fold, 16.16-fold and 60.54-fold, respectively. Furthermore the expansion systems with TGF-β1 showed more CD133+ cells than control at every time points. Our datas suggested that the CD133+ cells from human UCB have great expansion potential for ex-vivo expansion. The low concentration of TGF-β1 may delay over-differentiation of hematopoietic stem/progenitor cells.

scholarly journals Enhanced self-renewal of human long-term hematopoietic stem cells by a sulfamoyl benzoate derivative targeting p18INK4C

2021 ◽  
Vol 5 (17) ◽  
pp. 3362-3372
Author(s):  
Yinghui Li ◽  
Wenshan Zhang ◽  
Yu Zhang ◽  
Yahui Ding ◽  
Ming Yang ◽  
...  
Keyword(s):  
Cord Blood ◽  
Progenitor Cells ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Kinase Inhibitor ◽  
Ex Vivo ◽  
The Self ◽  
Self Renewal ◽  
Hematopoietic Stem

Abstract The use of umbilical cord blood transplant has been substantially limited by the finite number of hematopoietic stem and progenitor cells in a single umbilical cord blood unit. Small molecules that not only quantitatively but also qualitatively stimulate enhancement of hematopoietic stem cell (HSC) self-renewal ex vivo should facilitate the clinical use of HSC transplantation and gene therapy. Recent evidence has suggested that the cyclin-dependent kinase inhibitor, p18INK4C (p18), is a critical regulator of mice HSC self-renewal. The role of p18 in human HSCs and the effect of p18 inhibitor on human HSC expansion ex vivo need further studies. Here we report that knockdown of p18 allowed for an increase in long-term colony-forming cells in vitro. We then identified an optimized small molecule inhibitor of p18, 005A, to induce ex vivo expansion of HSCs that was capable of reconstituting human hematopoiesis for at least 4 months in immunocompromised mice, and hence, similarly reconstituted secondary recipients for at least 4 more months, indicating that cells exposed to 005A were still competent in secondary recipients. Mechanistic studies showed that 005A might delay cell division and activate both the Notch signaling pathway and expression of transcription factor HoxB4, leading to enhancement of the self-renewal of long-term engrafting HSCs and the pool of progenitor cells. Taken together, these observations support a role for p18 in human HSC maintenance and that the p18 inhibitor 005A can enhance the self-renewal of long-term HSCs.

scholarly journals Allogeneic stem cell transplantation with omidubicel in sickle cell disease

2021 ◽  
Vol 5 (3) ◽  
pp. 843-852
Author(s):  
Suhag Parikh ◽  
Joel A. Brochstein ◽  
Einat Galamidi ◽  
Aurélie Schwarzbach ◽  
Joanne Kurtzberg
Keyword(s):  
Stem Cell ◽  
Sickle Cell Disease ◽  
Stem Cell Transplantation ◽  
Cord Blood ◽  
Cell Transplantation ◽  
Sickle Cell ◽  
Ex Vivo ◽  
Cell Disease ◽  
Hematopoietic Stem ◽  
Cell Dose

Abstract Many patients with sickle cell disease (SCD) do not have HLA-matched related donors for hematopoietic stem cell transplantation (HSCT). Unrelated cord blood (UCB) is an alternative graft option but is historically associated with high graft failure rates, with inadequate cell dose a major limitation. Omidubicel is a nicotinamide-based, ex vivo–expanded UCB product associated with rapid engraftment in adults with hematologic malignancies. We hypothesized that increasing the UCB cell dose with this strategy would lead to improved engraftment in pediatric patients undergoing myeloablative HSCT for SCD. We report the outcomes of a phase 1/2 study in 13 patients with severe SCD who received omidubicel in combination with an unmanipulated UCB graft and 3 who received a single omidubicel graft. Grafts were minimally matched with patients at 4 of 6 HLA alleles. Median age at transplant was 13 years. A median CD34+ expansion of ∼80-fold was observed in omidubicel and led to rapid neutrophil engraftment (median, 7 days). Long-term engraftment was derived from the unmanipulated graft in most of the double cord blood recipients. Two of the 3 single omidubicel recipients also had sustained engraftment. Incidence of acute graft-versus-host disease (GVHD) was high, but resolved in all surviving patients. Event-free survival in the double cord group was 85% (median follow-up 4 years). All 3 patients in the single cord group were alive at 1 year after transplantation. Ex vivo expansion of UCB with omidubicel supports engraftment in patients with SCD. This approach to decreasing the incidence of GVHD should be optimized for general use in patients with SCD. This study was registered at www.clinicaltrials.gov as #NCT01590628.

Preliminary Results of a Pilot Trial of Unrelated Umbilical Cord Blood Transplantation (UCBT) Augmented with Cytokine-Primed Aldehyde Dehydrogenase-Bright (ALDHbr) Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3641-3641 ◽  
Author(s):  
Joanne Kurtzberg ◽  
Andrew Balber ◽  
Adam Mendizabal ◽  
Melissa Reese ◽  
Ann Kaestner ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cord Blood ◽  
Progenitor Cells ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Ex Vivo ◽  
Study Endpoint ◽  
Primary Study ◽  
Cell Dose ◽  
Large Expansion

Abstract Umbilical cord blood (UCB) transplantation results in delayed myeloid and platelet engraftment, likely due to lower cell dosing with cord blood. One strategy to overcome this problem is to augment the graft with ex vivo expanded cells. Previous studies have shown large expansion of progenitor cells in vitro, but when infused, these cells had little to no effects on hematopoietic reconstitution in the recipient. We hypothesized that these cells may have terminally differentiated in culture, loosing the potential for further expansion in vivo. The ALDHbr fraction of non-erythroid, non-monocytic cells is enriched for stem and progenitor cells. We performed preclinical studies showing that ALDHbr cells cultured ex vivo in SCF, FLT-3 and IL-7 expanded several fold with survival of both differentiated and immature cells. We designed a clinical trial to test whether infusion of primed (but not expanded) ALDHbr cells would be safe and would impact engraftment and survival after unrelated donor UCB transplantation (UCBT). ALDHbr cells were isolated from the 20% fraction of cryopreserved cord blood units (CBU) 6 days before thei nfusion of donor cells. The cells were cultured in SCF/FLT3/IL7 for 5 days. Release criteria included TNC with viability, negative bacterial/fungal cuture taken 2 days before planned infusion and negative gram stain. After written informed consent, patients were assigned to receive sorted cells (n=3) or sorted and primed cells (n=8) augmenting a standard UCBT which was administered with the 80% fraction of the CBU. The study cells were given 4 hours after the standard infusion on day 0. The primary study endpoint was safety and secondary endpoints: engraftment, Graft versus Host Disease (GvHD) and overall survival. Thus far, 11 patients (55% male, 82% Caucasian, median age 1.26 years) with pediatric malignant (n=5) or non-malignant (n=6) diagnoses have been infused. The median precryopreservation cell dose of the CBU was 13.89×10e7/kg and median cell dose infused 9.53×10e7/kg (range 4.13–18.6). The cell yield post sort ranged from 50,000–100,000 ALDHbr cells. After priming, the TNC content remained stable. Cells were infused without clinical reactions. The cummulative incidence (CI) of neutrophil engraftment by day +42 was 90.9% (95% CI 78–100) and no patient experienced graft failure. The CI of platelet engraftment (50K by 100 days) was 79.5% (95% CI 63.6–95.5). The median day to neutrophil (ANC 500/uL) and platelet engraftment (50K) were 17 (range 12–33) and 50 (range 38–90). Median CD4 counts at 100 and 180 days were 123, and 257/uL, higher than those seen with standard transplants. Overall survival at latest followup (1–9 months) was 90.9% (95% CI 73.9–100%). One death occurred in a newborn with a metabolic disease from congenital pulmonary hypertension, unrelated to the study. Although the study population is small, these results compare favorably to a similar population of patients in the COBLT study where the CI of ANC engraftment by day 42 was 78% (p=0.001), platelet engraftment was 50% and overall survival was 57%(p=.2). We conclude that isolation and priming of ALDHbr cells is feasible, infusion is safe and effects on engraftment and survival appear promising.

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