OBJECTIVE: To evaluate bone ingrowth, integration, and tolerance of a synthetic osteochondral implant in the medial femoral condyle (MFC) of normal horses. STUDY DESIGN: Experimental study. ANIMALS: ...Adult horses (n = 6). METHODS: Horses were anesthetized and bilateral femorotibial arthrotomies were performed for placement of 1 implant consisting of polycarbonate urethane with a titanium base in 1 MFC. The contralateral MFC served as a sham‐operated control without reaming of cartilage or subchondral bone. Lameness evaluations and radiographs were performed pre‐operatively with subsequent monthly lameness exams and radiographs at 6 months. Synovial fluid was collected for analysis from the adjacent femoropatellar joints pre‐operatively and at several intervals post‐operatively. Horses were euthanatized 6 months post‐operatively. Stifles were harvested for gross and histologic evaluations. RESULTS: Two horses were never lame, 2 were mildly lame, and 1 exhibited moderate lameness. Synovial fluid inflammatory parameters of the adjacent femoropatellar joints were not significantly different. No significant changes occurred radiographically over time in either stifle. Histologic assessment of synovium from the medial femorotibial joint revealed no differences in inflammatory changes between implant and sham stifles. Integration and osteoconductivity of the implant were graded as good in 4 and 3 of 5 specimens, respectively. Complications included joint sepsis resulting in euthanasia (1 horse), persistent lameness (1 horse), incisional seromas (4 horses), and incisional dehiscence (2 horses). CONCLUSION: Results of this pilot study indicate that the implant was compatible with placement in the MFC of normal horses. Implant design allowed bone ingrowth within the titanium base and provision of a synthetic articular surface.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The replacement of a proportion of concurrent controls by virtual controls in nonclinical safety studies has gained traction over the last few years. This is supported by foundational work, ...encouraged by regulators, and aligned with societal expectations regarding the use of animals in research. This paper provides an overview of the points to consider for any institution on the verge of implementing this concept, with emphasis given on database creation, risks, and discipline-specific perspectives.
•Implementing virtual controls needs careful preliminary work to design a quality database and digital microscopic slides.•Determining the covariates to select the virtual controls and respecting discipline-specific considerations is critical.•Compliance should be obtained via a stepwise validation process that will factor pre-identified risks.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Ongoing clinical trials for treatment of beta-globinopathies by gene therapy involve the transfer of the beta-globin gene, which requires integration of three to four copies per genome in most target ...cells. This high proviral load may increase genome toxicity, potentially limiting the safety of this therapy and relegating its use to total body myeloablation. We hypothesized that introducing an additional hypersensitive site from the locus control region, the complete sequence of the second intron of the beta-globin gene, and the ankyrin insulator may enhance beta-globin expression. We identified a construct, ALS20, that synthesized significantly higher adult hemoglobin levels than those of other constructs currently used in clinical trials. These findings were confirmed in erythroblastic cell lines and in primary cells isolated from sickle cell disease patients. Bone marrow transplantation studies in beta-thalassemia mice revealed that ALS20 was curative at less than one copy per genome. Injection of human CD34+ cells transduced with ALS20 led to safe, long-term, and high polyclonal engraftment in xenograft experiments. Successful treatment of beta-globinopathies with ALS20 could potentially be achieved at less than two copies per genome, minimizing the risk of cytotoxic events and lowering the intensity of myeloablation.
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Increase of beta-globin expression by gene addition is critical to successfully curing patients with beta-thalassemia and sickle cell disease. Here, Breda and colleagues report genomic features that maximize transgene expression at low genome integration rates, preserving efficacy and safety and potentially reducing the burden of autologous bone marrow transplantation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
“Humanized” immunodeficient mice generated via the transplantation of CD34+ human hematopoietic stem cells (hHSC) are an important preclinical model system. The triple transgenic ...NOD.Cg-PrkdcscidIl2rgtm1Wjl Tg(CMV-IL3,CSF2,KITLG)1Eav/MloySzJ (NSGS) mouse line is increasingly used as recipient for CD34+ hHSC engraftment. NSGS mice combine the features of the highly immunodeficient NSG mice with transgenic expression of the human myeloid stimulatory cytokines GM-CSF, IL-3, and Kit ligand. While generating humanized NSGS (huNSGS) mice from two independent cohorts, we encountered a fatal macrophage activation syndrome (MAS)-like phenotype resulting from the transplantation of CD34+ hHSC. huNSGS mice exhibiting this phenotype declined clinically starting at approximately 10 weeks following CD34+ hHSC engraftment, with all mice requiring euthanasia by 16 weeks. Gross changes comprised small, irregular liver, splenomegaly, cardiomegaly, and generalized pallor. Hematological abnormalities included severe thrombocytopenia and anemia. Pathologically, huNSGS spontaneously developed a disseminated histiocytosis with infiltrates of activated macrophages and hemophagocytosis predominantly affecting the liver, spleen, bone marrow, and pancreas. The infiltrates were chimeric with a mixture of human and mouse macrophages. Immunohistochemistry suggested activation of the inflammasome in both human and murine macrophages. Active Epstein-Barr virus infection was not a feature. Although the affected mice exhibited robust chimerism of the spleen and bone marrow, the phenotype often developed in the face of low chimerism of the peripheral blood. Given the high penetrance and early lethality associated with the MAS-like phenotype here described, we urge caution when considering the use of huNSGS mice for the development of long-term studies.
•NSGS mice engrafted with CD34+ hHSC (huNSGS) develop a macrophage activation syndrome-like phenotype.•Macrophagic inflammation in huNSGS mice contains both human and murine components.•Active EBV infection is not a feature.•The macrophage activation syndrome-like phenotype can develop in the face of low chimerism of the peripheral blood.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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