673. Threshold of Normal Stem Cells for Successful Correction of Murine β-Thalassemia
Bibliographic record
Abstract
To achieve a permanent correction of the β-thalassemia phenotype, it is necessary to establish basic criteria to serve as reference. Using the hemi-βthal mouse deleted from the two adult genes in the β-globin locus on a homogenous genetic background, we have shown that not only red blood cells (RBCs) have a shortened half-life but also that the late erythroid precursors have cellular and structural anomalies resulting in severe ineffective erythropoiesis. Based on this characterization, we hypothesized that bone marrow transplantation of normal donor cells into a thalassemic recipient would have a strong selective advantage and predominate upon erythroid differentiation and maturation. Our aim was to determine the minimal percent of normal bone marrow cells that is necessary to engraft for a future curative gene therapy approach. We have used a Competitive Repopulating Assay by transplanting lethally irradiated recipient mice with a fixed number of bone marrow cells containing reciprocal proportions of normal and hemi-βthal cells ranging from 5 to 100%. The assays were designed to generate 11 chimeric groups of hemi-βthal mice with at least 5 mice per group transplanted with normal and hemi-βthal bone marrow cells. Analysis of 95 hemi-βthal recipient mice followed for short and long-term post-transplantation (2 months to >1 year) were carried out by various cellular, molecular and physio-pathologic evaluation. These analyses showed that a chimerism of 19–24 % normal engrafted cells, determined by the Gpi1a marker, produced 40–50% of normal RBCs in the peripheral blood. Interestingly, the osmotic fragility of the RBCs from the chimeric hemi-βthal groups displayed a two-step lysis corresponding to the chimerism of the two RBC populations. The hematological parameters of the 19–24% chimeric hemi-βthal mice were significantly improved with increase hemoglobin of 3–4 g/dl and mean cell volume (MCV) reaching normal range. With 19% chimerism, RBC half-life was increased by at least 60% relative to control and their morphology was significantly ameliorated. Similarly, bone marrow and splenic erythropoiesis was improved with increasing chimerism. Consequent to the normalization of RBC half-life and splenic erythropoiesis, the pathology of chimeric mice showed a significant decrease in splenomegaly and in extramedullary splenic hematopoiesis/erythropoiesis. Furthermore, the lifespan of the chimeric mice was increased to normal life expectancy even with 24% chimerism, suggesting a general improvement of the mice physiology. Hence these results determined a two-fold selective advantage of normal RBC relative to thalassemic cells. Altogether, these results established a therapeutic range of 19–24% of engrafted normal/modified bone marrow cells for a physiologic impact and for a significant long-term correction of hemi-βthal mouse condition in vivo.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".