Hematopoietic reconstitution dynamics of mobilized- and bone marrow-derived human hematopoietic stem cells after gene therapy

Mobilized peripheral blood is increasingly used instead of bone marrow as a source of autologous hematopoietic stem/progenitor cells for ex vivo gene therapy. Here, we present an unplanned exploratory analysis evaluating the hematopoietic reconstitution kinetics, engraftment and clonality in 13 pediatric Wiskott-Aldrich syndrome patients treated with autologous lentiviral-vector transduced hematopoietic stem/progenitor cells derived from mobilized peripheral blood (n = 7), bone marrow (n = 5) or the combination of the two sources (n = 1). 8 out of 13 gene therapy patients were enrolled in an open-label, non-randomized, phase 1/2 clinical study (NCT01515462) and the remaining 5 patients were treated under expanded access programs. Although mobilized peripheral blood- and bone marrow- hematopoietic stem/progenitor cells display similar capability of being gene-corrected, maintaining the engineered grafts up to 3 years after gene therapy, mobilized peripheral blood-gene therapy group shows faster neutrophil and platelet recovery, higher number of engrafted clones and increased gene correction in the myeloid lineage which correlate with higher amount of primitive and myeloid progenitors contained in hematopoietic stem/progenitor cells derived from mobilized peripheral blood. In vitro differentiation and transplantation studies in mice confirm that primitive hematopoietic stem/progenitor cells from both sources have comparable engraftment and multilineage differentiation potential. Altogether, our analyses reveal that the differential behavior after gene therapy of hematopoietic stem/progenitor cells derived from either bone marrow or mobilized peripheral blood is mainly due to the distinct cell composition rather than functional differences of the infused cell products, providing new frames of references for clinical interpretation of hematopoietic stem/progenitor cell transplantation outcome.</p

A ligação entre o balanced scorecard e o scenario planning em contexto empresarial

Mestrado em Controlo de Gestão e dos NegóciosCom a chegada do século XXI, estão a ocorrer no mundo diversas transformações económicas, tecnológicas e sociais, o que contribui para um aumento das incertezas. A elaboração da estratégia assume-se cada vez mais, como um fator critico de sucesso, nesse sentido o Balanced Scorecard surge como uma ferramenta de extrema importância, contudo estima-se que 70 por cento dos Balanced Scorecard implementados falharam (McCunn, 1998), seja por dificuldades na implementação por parte das organizações, seja por limitação do próprio método. Por forma a se tentar colmatar estas falhas, o presente trabalho tem por objetivo efetuar a ligação entre o Balanced Scorecard e o Scenario Planning, por forma a verificar se estas duas ferramentas se complementam e assim se consegue minimizar as limitações identificadas na implementação do Balanced Scorecard, como tal, foi efetuado um estudo de caso com a empresa Suma, onde se elaborou cenários prospetivos para o horizonte temporal 2019-2030, bem como se definiu com base nesses cenários, estratégias, objetivos e metas para o Balanced Scorecard.With the arrival of the 21st century, economic, technological and social transformations are taking place in the world, which contributes to an increase of uncertainties. The elaboration of the strategy is increasingly becoming a critical success factor. Scorecard emerges as an extremely important tool, however it is estimated that 70 percent of the Balanced Scorecard implemented has failed (McCunn, 1998), either due to difficulties in implementation by organizations, or by limitation of the method itself, the present work aims to make the connection between the Balanced Scorecard and Scenario Planning, in order to verify if these two tools complement each other and thus it is possible to minimize the limitations identified in the implementation of the Balanced Scorecard, as such, a case study was conducted with Suma company, which prepared prospective scenarios for the 2019-2030 time horizon, as well as defined based on these scenarios, objectives and goals for the Balanced Scorecard.info:eu-repo/semantics/publishedVersio

Dual-Regulated Lentiviral Vector for Gene Therapy of X-Linked Chronic Granulomatous Disease

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Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients

Adenosine Deaminase (ADA) deficiency is an autosomal recessive variant of severe combined immunodeficiency (SCID) caused by systemic accumulation of ADA substrates. Neurological and behavioral abnormalities observed in ADA-SCID patients surviving after stem cell transplantation or gene therapy represent an unresolved enigma in the field. We found significant neurological and cognitive alterations in untreated ADA-SCID patients as well as in two groups of patients after short- and long-term enzyme replacement therapy with PEG-ADA. These included motor dysfunction, EEG alterations, sensorineural hypoacusia, white matter and ventricular alterations in MRI as well as a low mental development index or IQ. Ada-deficient mice were significantly less active and showed anxiety-like behavior. Molecular and metabolic analyses showed that this phenotype coincides with metabolic alterations and aberrant adenosine receptor signaling. PEG-ADA treatment corrected metabolic adenosine-based alterations, but not cellular and signaling defects, indicating an intrinsic nature of the neurological and behavioral phenotype in ADA deficiency