Plerixafor and G-CSF combination mobilizes hematopoietic stem and progenitors cells with a distinct transcriptional profile and a reduced
            <i>in vivo</i>
            homing capacity compared to plerixafor alone

Lidonnici, Maria Rosa; Aprile, Annamaria; Frittoli, Marta Claudia; Mandelli, Giacomo; Paleari, Ylenia; Spinelli, Antonello E.; Gentner, Bernhard; Zambelli, Matilde; Parisi, Cristina; Bellio, Laura; Cassinerio, Elena; Zanaboni, Laura; Cappellini, Maria Domenica; Ciceri, Fabio; Marktel, Sarah; Ferrari, G.

doi:10.3324/haematol.2016.154740

Cited by 38 publications

(34 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…To estimate the frequency of SRC in UM171-expanded CD34 + CD38 − HSPCs, we performed limiting-dilution statistics on the “t0 equivalent” cell doses that were transplanted in four replicate experiments (Figure 4F). Estimated SRC frequency was 1 in 10,700 (95% confidence interval: 5,500–21,100), which compares with a recently reported SRC frequency of ∼1 in 141,203 in uncultured CD34 + cells from G-CSF-mPB (Lidonnici et al., 2016). Taken together, these data indicate that our protocol allows ex vivo expansion of genetically engineered mPB CD34 + CD38 − cells with SCID-repopulating potential and warrants further protocol optimization for clinical application.…”

Section: Resultsmentioning

confidence: 44%

Efficient Ex Vivo Engineering and Expansion of Highly Purified Human Hematopoietic Stem and Progenitor Cell Populations for Gene Therapy

et al. 2017

Self Cite

View full text Add to dashboard Cite

SummaryEx vivo gene therapy based on CD34+ hematopoietic stem cells (HSCs) has shown promising results in clinical trials, but genetic engineering to high levels and in large scale remains challenging. We devised a sorting strategy that captures more than 90% of HSC activity in less than 10% of mobilized peripheral blood (mPB) CD34+ cells, and modeled a transplantation protocol based on highly purified, genetically engineered HSCs co-infused with uncultured progenitor cells. Prostaglandin E2 stimulation allowed near-complete transduction of HSCs with lentiviral vectors during a culture time of less than 38 hr, mitigating the negative impact of standard culture on progenitor cell function. Exploiting the pyrimidoindole derivative UM171, we show that transduced mPB CD34+CD38− cells with repopulating potential could be expanded ex vivo. Implementing these findings in clinical gene therapy protocols will improve the efficacy, safety, and sustainability of gene therapy and generate new opportunities in the field of gene editing.

show abstract

Section: Resultsmentioning

confidence: 44%

Efficient Ex Vivo Engineering and Expansion of Highly Purified Human Hematopoietic Stem and Progenitor Cell Populations for Gene Therapy

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, most of these patients have been previously exposed to chemotherapy, radiation, or medications that affect bone marrow function; therefore, obtaining the necessary number of HSCs is a challenge in these patients. Although the optimal amount of CD34+ cells for autologous transplant is 5 × 10 6 /kg, a dose of at least 2 × 10 6 /kg CD34+ cells is required to ensure engraftment, lower doses may delay recovery of blood cells . Many risk factors have been associated with poor stem cell mobilization, including age, obesity, the underlying diagnosis (myeloma and lymphoma), previous radiotherapy or chemotherapy, disease status, among others .…”

Section: Discussionmentioning

confidence: 99%

“…In the field of autologous stem cell transplantation (ASCT) it is accepted that the ideal number of CD34+ HSCs necessary to ensure the recovery of hematopoietic function is approximately 5 × 10 6 per kg of body weight . Although the minimum number of cells required to guarantee engraftment is unknown, most authors agree that 2 × 10 6 /kg is sufficient, as lower doses may delay platelet and neutrophil engraftment . Lymphoma and myeloma are the most frequent contemporary indications of ASCT, with peripheral blood as the preferred source of HSCs for its faster hematopoietic and immune reconstitution, lower cost and greater donor comfort .…”

mentioning

confidence: 99%

“…Poor mobilization can be defined as the inability to collect the number of HSCs necessary to guarantee hematological recovery 15 days after transplantation (≤2 × 10 6 /kg BW). Different strategies have been used to reduce this probability, including different growth factors, such as filgrastim, lenograstim, or sargramostim; chemotherapy plus granulocyte colony‐stimulating factor (G‐CSF); chemotherapy plus pegfilgrastim; and, more recently, plerixafor as a single agent or combined with G‐CSF . Plerixafor is a molecule that binds reversibly to CXC motif, receptor 4 (CXCR4), an adhesion molecule expressed in hematopoietic cells that plays an important role in their retention in the bone marrow, antagonizing the union of stromal cell‐derived factor‐1 (SDF‐1).…”

mentioning

confidence: 99%

“…Plerixafor is a molecule that binds reversibly to CXC motif, receptor 4 (CXCR4), an adhesion molecule expressed in hematopoietic cells that plays an important role in their retention in the bone marrow, antagonizing the union of stromal cell‐derived factor‐1 (SDF‐1). This results in the mobilization of cells to the peripheral blood . Different studies have shown that plerixafor is well tolerated and highly effective in mobilizing HSCs, resulting in a higher proportion of CD34+ PBSC being collected, even in heavily pretreated patients .…”

mentioning

confidence: 99%

See 2 more Smart Citations

Reduced‐dose plerixafor as a mobilization strategy in autologous hematopoietic cell transplantation: a proof of concept study

et al. 2019

View full text Add to dashboard Cite

BACKGROUND Autologous stem cell transplantation (ASCT) is an effective treatment for patients with relapsing myeloma or lymphoma, diseases associated with unsuccessful peripheral blood stem cell (PBSC) collection. Plerixafor is a potent mobilizing agent, allowing more CD34+ cells to be obtained; however, the main obstacle for its use is its high cost. Our aim was to demonstrate that of the use of reduced doses of plerixafor (RD‐plerixafor) can be sufficient to collect at least 2 × 106/Kg CD34+ PBSC in patients with multiple myeloma (MM) or lymphoma undergoing ASCT. STUDY DESIGN AND METHODS Twenty patients were mobilized with filgrastim (10 μg/kg/4 days) plus a single dose of plerixafor 0.12 mg/kg in Day 4. Apheresis collection was performed on Day 5. One vial of plerixafor was used for two patients. http://clinicaltrials.gov NCT03244930. RESULTS Cell mobilization and collection was successful in 85% of patients (≥2 × 106 CD34+ cells per kilogram). The median collected CD34+ cell count was 4.62 × 106/kg (range, 1.27‐24.5). A 4.1‐fold‐increase in the median CD34+ PBSC pre‐count was observed (from 10.4/μl to 42.4/μl) after RD‐plerixafor administration. Seven patients had mild to moderate adverse events. CONCLUSION RD‐plerixafor is an effective, safe, and affordable strategy to ensure adequate PBSC mobilization in patients with MM or lymphoma who undergo ASCT.

show abstract

Pharmacological and molecular approaches for the treatment of β‐hemoglobin disorders

Lohani

Bhargava

Munshi

et al. 2017

Journal Cellular Physiology

View full text Add to dashboard Cite

β-hemoglobin disorders, such as β-thalassemia and sickle cell anemia are among the most prevalent inherited genetic disorders worldwide. These disorders are caused by mutations in the gene encoding hemoglobin-β (HBB), a vital protein found in red blood cells (RBCs) that carries oxygen from lungs to all parts of the human body. As a consequence, there has been an enduring interest in this field in formulating therapeutic strategies for the treatment of these diseases. Currently, there is no cure available for hemoglobin disorders, although, some patients have been treated with bone marrow transplantation, whose scope is limited because of the difficulty in finding a histocompatible donor and also due to transplant-associated clinical complications that can arise during the treatment. On account of these constraints, reactivation of fetal hemoglobin (HbF) synthesis holds immense promise and is a viable strategy to alleviate the symptoms of β-hemoglobin disorders. Development of new genomic tools has led to the identification of important natural genetic modifiers of hemoglobin switching which include BCL11A, KLF1, HBSIL-MYB, LRF, LSD1, LDB1, histone deacetylases 1 and 2 (HDAC1 and HDAC2). miRNAs are also promising therapeutic targets for development of more effective strategies for the induction of HbF production. Many new small molecule pharmacological inducers of HbF production are already under pre-clinical and clinical development. Furthermore, recent advancements in gene and cell therapy includes targeted genome editing and iPS cell technologies, both of which utilizes a patient's own cells, are emerging as extremely promising approaches for significantly reducing the burden of β-hemoglobin disorders.

show abstract

Plerixafor and G-CSF combination mobilizes hematopoietic stem and progenitors cells with a distinct transcriptional profile and a reduced in vivo homing capacity compared to plerixafor alone

Cited by 38 publications

References 15 publications

Efficient Ex Vivo Engineering and Expansion of Highly Purified Human Hematopoietic Stem and Progenitor Cell Populations for Gene Therapy

Efficient Ex Vivo Engineering and Expansion of Highly Purified Human Hematopoietic Stem and Progenitor Cell Populations for Gene Therapy

Reduced‐dose plerixafor as a mobilization strategy in autologous hematopoietic cell transplantation: a proof of concept study

Pharmacological and molecular approaches for the treatment of β‐hemoglobin disorders

Contact Info

Product

Resources

About