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At least 775 records · Page 43Linked to original sources
PubMed1998

A longitudinal study of calcium regulation in a nonhuman primate model of parenteral nutrition.

The question of whether parenteral nutrition adversely affects calcium regulation remains unclear. Human studies of this question have been confounded by uncontrolled variables including the degree to which food is ingested orally; gut absorption; underlying disease; medication adversely affecting bone, including steroids; and aluminum contamination of parenteral nutrients. The present study was undertaken to examine whether parenteral nutrition adversely affects calcium regulation in a nonhuman primate model that allows for control of underlying clinical variables and mobility. With use of this model, it was possible to show weight maintenance and positive nitrogen and calcium balances with parenteral nutrition. There was no demonstrable effect of the animals' wearing a jacket and tether system or of catheterization on calcium regulation. Calciuria in response to parenteral nutrition was elevated initially but diminished by 2 wk of therapy. The calciuria observed resulted from an increased urine-filtered calcium load. Calcium balance with parenteral nutrition was preserved by a diminished fraction of calcium filtered by the kidney being excreted in the urine. The present study suggests that negative calcium balance produced by parenteral nutrition may result from abnormal renal tubular function or disruption of normal parathyroid hormone regulation.

Administration, Oral↗
PubMed2004

Use of recombinant cytokines for optimized induction of antiviral immunity against SIV in the nonhuman primate model of human AIDS.

Outbreaks of infectious diseases such as HIV and the much televised and attention-getting outbreaks of diseases such as Ebola, Hantaviruses, and the most recent outbreak of SARS have induced a significant new interest in the formulations and more importantly the science of vaccinology, which has previously to a large extent been conducted empirically. Our laboratory has focused on the use of recombinant nonhuman primate cytokines as adjunctive therapies for inducing antigen-specific immune responses in monkeys because most recombinant human cytokines appear to be immunogenic. This article provides a summary of our work with such cytokines, which includes attempts to define optimum dosing schedules that lead to optimal primary and lasting memory antigen-specific immune responses.

Acquired Immunodeficiency Syndrome↗
PubMed1991

A protective thermoplast splint for the forearm and hand in nonhuman primates.

A custom-made thermoplastic splint was developed for the protection of the upper extremity after experimental surgery. It was used in 39 cases for a duration of 12-79 days. Complications were minimal and transient. The cast was easy to make, in one piece and inexpensive. Frequent removal for wound inspection was simple. This splint provides a good immobilization and protection of the arm and hand in the nonhuman primate.

Animals↗
PubMed1983

Failure of hypercholesterolemic serum to stimulate collagen synthesis in aortic smooth muscle cells from two species of nonhuman primates having different rates of collagen synthesis.

African green monkeys develop atherosclerotic lesions that are more fibrous than those found in rhesus monkeys. The purpose of this study was to determine if this difference in collagen content could be related to a specific effect of a serum component on collagen synthesis by cells of the arterial wall or to inherent differences in the arterial smooth muscle cells from these two nonhuman primate species. Aortic smooth muscle cells were grown in tissue culture from both rhesus and African green monkeys and incubated for up to 48 hr with different concentrations of serum from normal or hypercholesterolemic animals. Collagen synthesis was determined by measuring the conversion of radiolabeled proline to hydroxyproline. Total protein synthesis was determined from the incorporation of radiolabeled proline into total proteins. Hypercholesterolemic serum from either species did not stimulate collagen or total protein synthesis in either African green or rhesus monkey smooth muscle cells. This was true even though under the same conditions other studies have shown that hypercholesterolemic serum produces an increase in cellular cholesteryl ester content. This suggests that hypercholesterolemia per se is not directly responsible for the stimulation of collagen synthesis typically seen in atherosclerotic lesions. African green monkey smooth muscle cells synthesized from 1.7 to 3.4 times more collagen than did rhesus monkey smooth muscle cells, while total protein synthesis was similar for both cell types. This suggests that the greater amounts of collagen present in the atherosclerotic lesions from African green monkeys may be in part the result of an inherently greater potential of their smooth muscle cells to synthesize collagen.

Animals↗
PubMed2005

Effects of JAK3 inhibition with CP-690,550 on immune cell populations and their functions in nonhuman primate recipients of kidney allografts.

BACKGROUND: Janus Kinase (JAK) 3 is a tyrosine kinase essential for proper signal transduction downstream of selected cytokine receptors and for robust T-cell and natural killer cells activation and function. JAK3 inhibition with CP-690,550 prevents acute allograft rejection. To provide further insight into the mechanisms of efficacy, we investigated the immunomodulatory effects of CP-690,550 in vitro and in vivo in nonhuman primates. METHODS: Pharmacodynamic assessments of lymphocyte activation, function, proliferation and phenotype were performed in three settings: in vitro in whole blood isolated from untransplanted cynomolgus monkeys (cynos), in vivo in blood from untransplanted cynos dosed with CP-690,550 for 8 days, and in vivo in blood from transplanted cynos immunosuppressed with CP-690,550. Cell surface activation markers expression, IL-2- enhanced IFN-gamma production, lymphocyte proliferation and immune cell phenotype analyzes were performed with multiparametric flow cytometry. RESULTS: In vitro exposure to CP-690,550 resulted in significant reduction of IL-2-enhanced IFN-gamma production by T-cells (maximum inhibition of 55-63%), T-cell surface expression of CD25 (50% inhibitory concentration (IC50); 0.18 microM) and CD71 (IC50; 1.6 microM), and T-cell proliferative capacities measured by proliferating cell nuclear antigen expression (IC50; 0.87 microM). Similar results were observed in animals dosed with CP-690,550. In addition, transplanted animals displayed significant reduction of NK cell (90% from baseline) and T-cell numbers whereas CD8 effector memory T-cell populations were unaffected. CONCLUSIONS: Potent in vitro and in vivo immunomodulatory effects of the JAK3 inhibitor CP-690,550 likely contribute to its efficacy in the prevention of organ allograft rejection.

Animals↗
PubMed2004

Comparison of retroviral transduction efficiency in CD34+ cells derived from bone marrow versus G-CSF-mobilized or G-CSF plus stem cell factor-mobilized peripheral blood in nonhuman primates.

Hematopoietic stem cells (HSCs) are ideal targets for genetic manipulation in the treatment of several congenital and acquired disorders affecting the hematopoietic compartment. Although G-CSF-mobilized peripheral blood CD34(+) cells are the favored source of hematopoietic stem cells in clinical transplantation, this source of stem cells does not provide meaningful engraftment levels of genetically modified cells compared with G-CSF + stem cell factor (SCF)-mobilized cells in nonhuman primates. Furthermore, the use of G-CSF mobilization can have disastrous consequences in patients with sickle cell disease, a long-held target disorder for HSC-based gene therapy approaches. We therefore conducted a study to compare the levels of genetically modified cells attainable after retroviral transduction of CD34(+) cells collected from a bone marrow (BM) harvest with CD34(+) cells collected from a leukapheresis product after mobilization with G-CSF (n = 3) or G-CSF in combination with SCF (n = 3) in the rhesus macaque autologous transplantation model. Transductions were performed using retroviral vector supernatant on fibronectin-coated plates for 96 hours in the presence of stimulatory cytokines. BM was equal to or better than G-CSF-mobilized peripheral blood as a source of HSCs for retroviral transduction. Although the highest marking observed was derived from G-SCF + SCF-mobilized peripheral blood in two animals, marking in the third originated only from the BM fraction. These results demonstrate that steady-state BM is at least equivalent to G-CSF-mobilized peripheral blood as a source of HSCs for retroviral gene transfer and the only currently available source for patients with sickle cell disease.

Anemia, Sickle Cell↗
PubMed2001

SIB-1553A, (+/-)-4-[[2-(1-methyl-2-pyrrolidinyl)ethyl]thio]phenol hydrochloride, a subtype-selective ligand for nicotinic acetylcholine receptors with putative cognitive-enhancing properties: effects on working and reference memory performances in aged rodents and nonhuman primates.

Preclinical and clinical data have suggested the potential use of nicotinic acetylcholine receptor (nAChR) ligands for treating cognitive dysfunction associated with neurodegenerative diseases, such as Alzheimer's disease. SIB-1553A, (+/-)-4-[[2-(1-methyl-2-pyrrolidinyl)ethyl]thio]phenol hydrochloride, a novel nAChR ligand with predominant agonist subtype selectivity for beta4 subunit-containing human neuronal nAChRs, was tested in a variety of cognitive paradigms in aged rodents and nonhuman primates after acute and repeated administration. Subcutaneous administration of SIB-1553A improved delayed nonmatching to place performance in aged mice. In aged rhesus monkeys, intramuscular and oral administration of SIB-1553A improved choice accuracy in a delayed matching to sample task. SIB-1553A improved performances in these spatial and nonspatial working memory tasks but was less effective at improving performances in spatial reference memory tasks (i.e., aged rodents exposed to a discrimination task in a T-maze or trained to locate a hidden platform in a water maze). These data suggest that SIB-1553A has a predominant effect on attention/working memory processes. SIB-1553A also induced the release of acetylcholine in the hippocampus of aged rats and was equally effective whether administered acutely or repeatedly (6 weeks of daily subcutaneous administration). Thus, rats repeatedly treated with SIB-1553A exhibit neither tolerance nor sensitization to the effects of the compound. The SIB-1553A-induced cognitive improvement may be in part related to an increase in cholinergic function. The present study provides additional support for the use of subtype-selective nAChR ligands as a potential therapy for the symptomatic treatment of specific cognitive deficits (such as attention/working memory deficits) associated with aging and neurological diseases.

Aging↗
PubMed1992

Effects of intravenous IL-8 administration in nonhuman primates.

IL-8, a cytokine known for its potent and specific neutrophil activation and chemoattractant properties, has been recently detected in the circulation during septic shock, endotoxemia, and after IL-1 alpha administration. Because of its observed in vitro actions, it has been hypothesized that IL-8 may contribute to the dynamics of circulating granulocytes and to the pathologic sequelae seen in sepsis. Here, human rIL-8 is administered to healthy nonhuman primates as a single i.v. injection or as a continuous 8-h i.v. infusion. We demonstrate that both methods of i.v. administration result in a rapid but transient, severe granulocytopenia, followed by a granulocytosis that persists as long as IL-8 levels are detectable in the circulation. There were no hemodynamic changes after IL-8 administration, and animals remained clinically stable during the 24-h observation period. No detectable circulating TNF-alpha, IL-1 beta, or IL-6 response was induced by either IL-8 administration regimen. Histopathologic examination revealed mild to moderate neutrophilic margination in lung, liver, and spleen, of greater severity in baboons receiving the 8-h infusion. There was no associated neutrophilic infiltration or tissue injury. Thus, IL-8 modulates circulating granulocyte dynamics and likely directs their actions, but when administered i.v. to healthy animals, either as a bolus dose or as a continuous infusion for up to 8 h, does not induce the hemodynamic and metabolic aberrations or the acute organ damage seen during sepsis.

Animals↗
PubMed2001

Effect of probenecid on ventricular cerebrospinal fluid methotrexate pharmacokinetics after intralumbar administration in nonhuman primates.

PURPOSE: Intrathecal methotrexate (MTX) achieves high concentrations in the cerebrospinal fluid (CSF) following intralumbar administration. However, peak ventricular CSF MTX concentrations are highly variable and are < 10% of those achieved with intraventricular dosing. The objectives of this study were to evaluate the effect of intralumbar and intravenous probenecid on ventricular CSF MTX concentrations after intralumbar administration of MTX, and to compare the pharmacokinetics of MTX after intralumbar and intraventricular administration. METHODS: Nonhuman primates (Macaca mulatta) with permanently implanted catheters in the lateral and fourth ventricles received 0.5 mg intraventricular (lateral ventricle) MTX, or 0.5 mg intralumbar MTX with and without intralumbar or intravenous probenecid. Animals were kept prone for 1 h after MTX administration, and ventricular CSF was sampled up to 48 h from a fourth ventricular Ommaya reservoir. MTX concentrations were measured using the dihydrofolate reductase enzyme inhibition assay. Area under the ventricular CSF MTX concentration-time curve (AUC) was used as a measure of MTX exposure. RESULTS: Peak ventricular CSF MTX concentrations and AUCs were highly variable after intralumbar MTX administration. Ventricular CSF MTX AUCs increased by a mean of 3.2-fold after the addition of intralumbar probenecid. Intravenous administration of probenecid did not result in an increase in ventricular CSF MTX AUCs. Asymptomatic pleocytosis was observed in all animals after intralumbar probenecid administration. Ventricular CSF MTX concentrations and AUCs were less variable after intraventricular administration of MTX. CONCLUSION: The administration of intralumbar but not intravenous probenecid increases the ventricular CSF MTX exposure after intralumbar MTX administration.

Animals↗
PubMed2007

Calorie restriction in nonhuman primates: assessing effects on brain and behavioral aging.

Dietary caloric restriction (CR) is the only intervention repeatedly demonstrated to retard the onset and incidence of age-related diseases, maintain function, and extend both lifespan and health span in mammals, including brain and behavioral function. In 70 years of study, such beneficial effects have been demonstrated in rodents and lower animals. Recent results emerging from ongoing studies of CR in humans and nonhuman primates suggest that many of the same anti-disease and anti-aging benefits observed in rodent studies may be applicable to long-lived species. Results of studies in rhesus monkeys indicate that CR animals (30% less than controls) are healthier than fully-fed counterparts based on reduced incidence of various diseases, exhibit significantly better indices of predisposition to disease and may be aging at a slower rate based on analysis of selected indices of aging. The current review discusses approaches taken in studies of rhesus monkeys to analyze age-related changes in brain and behavioral function and the impact of CR on these changes. Approaches include analyses of gross and fine locomotor performance as well as brain imaging. In a related study it was observed that short-term CR (6 months) in adult rhesus monkeys can provide protection against a neurotoxic insult. Increasing interest in the CR paradigm will expand its role in demonstrating how nutrition can modulate the rate of aging and the mechanisms responsible for this modulation.

Aging↗
PubMed1993

Platelet involvement in experimental immune complex-mediated glomerulonephritis in the nonhuman primate.

Abundant glomerular platelet deposition is a hallmark of certain animal models of immune complex (IC)-mediated glomerulonephritis (GN). By contrast, conspicuous platelet deposition is uncommon in the IC-GN seen in humans. This could result from intrinsic differences between human and animal platelets, which are known to be present. To assess whether abundant glomerular platelet deposition can occur in humans with IC-GN, the present studies were undertaken in nonhuman primates (cynomolgus monkeys, CYN), with active experimental IC-GN induced by 12 weeks of daily intravenous infusion of bovine gamma globulin (BGG). CYN are appropriate for these studies because, like humans, CYN platelets do not express the C3b receptor but do express receptors for the Fc region of IgG (FcR gamma II). Furthermore, in this model of IC-GN, which is indistinguishable from IC-GN seen in humans, it is possible to time the biopsy to coincide with a period of peak activity of the GN. The present studies proceeded as follows: ten CYN were studied before and after intravenous infusion of BGG sufficient to achieve conditions near antigen/antibody equivalence for circulating precipitating antibody to BGG. The infusion of BGG, which was given over 10 minutes, resulted in an acute reduction in circulating platelets (mean 43% +/- 5 SE, P < 0.001). However, renal biopsies performed before and five minutes after the acute reduction in circulating platelets showed that relatively few of the platelets removed from the circulation lodged in glomeruli (platelets/glomerular cross section: 0.2 +/- 0.06 before BGG vs. 0.88 +/- 0.31 after BGG, P = 0.035). In five of the CYN studied under the above protocol, autologous platelets were labeled with 111In and reinfused into the CYN just prior to the BGG infusion. These studies confirmed the paucity of platelet deposition in kidney but showed major uptake of the 111In-labeled platelets by liver and spleen (mean +/- SE 111In CPM/mg of tissue: kidney cortex 18 +/- 8, liver 132 +/- 42, and spleen 808 +/- 127, P = 0.038, comparing kidney to liver or spleen by paired t-test). Thus, the platelets removed from the circulation were taken up at the sites which are also the principal sites of IC uptake (liver and spleen), and over the time interval that coincides with the period of maximum uptake of IC by liver and spleen, after BGG infusion. In vitro studies, discussed herein, showed that BGG anti-BGG IC bind to CYN platelets via FcR gamma II.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1999

Efficient and durable gene marking of hematopoietic progenitor cells in nonhuman primates after nonablative conditioning.

Optimization of mobilization, harvest, and transduction of hematopoietic stem cells is critical to successful stem cell gene therapy. We evaluated the utility of a novel protocol involving Flt3-ligand (Flt3-L) and granulocyte colony-stimulating factor (G-CSF) mobilization of peripheral blood stem cells and retrovirus transduction using hematopoietic growth factors to introduce a reporter gene, murine CD24 (mCD24), into hematopoietic stem cells in nonhuman primates. Rhesus macaques were treated with Flt3-L (200 microgram/kg) and G-CSF (20 microgram/kg) for 7 days and autologous CD34(+) peripheral blood stem cells harvested by leukapheresis. CD34(+) cells were transduced with an MFGS-based retrovirus vector encoding mCD24 using 4 daily transductions with centrifugations in the presence of Flt3-L (100 ng/mL), human stem cell factor (50 ng/mL), and PIXY321 (50 ng/mL) in serum-free medium. An important and novel feature of this study is that enhanced in vivo engraftment of transduced stem cells was achieved by conditioning the animals with a low-morbidity regimen of sublethal irradiation (320 to 400 cGy) on the day of transplantation. Engraftment was monitored sequentially in the bone marrow and blood using both multiparameter flow cytometry and semi-quantitative DNA polymerase chain reaction (PCR). Our data show successful and persistent engraftment of transduced primitive progenitors capable of giving rise to marked cells of multiple hematopoietic lineages, including granulocytes, monocytes, and B and T lymphocytes. At 4 to 6 weeks posttransplantation, 47% +/- 32% (n = 4) of granulocytes expressed mCD24 antigen at the cell surface. Peak in vivo levels of genetically modified peripheral blood lymphocytes approached 35% +/- 22% (n = 4) as assessed both by flow cytometry and PCR 6 to 10 weeks posttransplantation. In addition, naïve (CD45RA(+) and CD62L(+)) CD4(+) and CD8(+) cells were the predominant phenotype of the marked CD3(+) T cells detected at early time points. A high level of marking persisted at between 10% and 15% of peripheral blood leukocytes for 4 months and at lower levels past 6 months in some animals. A cytotoxic T-lymphocyte response against mCD24 was detected in only 1 animal. This degree of persistent long-lived, high-level gene marking of multiple hematopoietic lineages, including naïve T cells, using a nonablative marrow conditioning regimen represents an important step toward the ultimate goal of high-level permanent transduced gene expression in stem cells.

Animals↗
PubMed2002

Strategies for preclinical evaluation of dendritic cell subsets for promotion of transplant tolerance in the nonhuman primate.

A role for dendritic cells (DC) as critical regulators of immune reactivity has become increasingly recognized. There is evidence in rodent models that donor-derived DC, particularly in the immature state, can prolong organ allograft survival and even induce donor-specific tolerance. To allow the potential tolerogenic properties of these cells to be evaluated more fully with a view to clinical testing, it is necessary to identify DC subsets in nonhuman primates. We have identified the putative rhesus monkey equivalents of circulating human DC subset precursors as lineage(-), HLA-DR(+), CD123(lo),CD11c(hi)(pDC1) and lineage(-), HLA-DR(+), CD123(hi),CD11c(lo)(pDC2). Testing of these DC populations both in vitro and in vivo, as well as in transplant models in combination with conventional or experimental immunosuppressive reagents, will aid the development of novel strategies for the promotion of allo-antigen specific tolerance in transplantation.

Animals↗
PubMed2001

Measurement of plasma metabolites of (S)-5-[123I]iodo-3-(2-azetidinylmethoxy)pyridine (5-IA-85380), a nicotinic acetylcholine receptor imaging agent, in nonhuman primates.

The iodinated analog (S)-5-[123I]iodo-3-(2-azetidinylmethoxy)pyridine of A-85380 is a new potential SPECT tracer specific for the alpha4beta2 subtype nicotinic acetylcholine receptors, which play an important role in neurodegenerative diseases and in tobacco dependence. To evaluate the possibility of using this tracer for the in vivo quantification of these receptors, an accurate measurement of the plasma concentration of the parent compound is necessary. In human or nonhuman primate whole blood as well as in plasma, the parent compound is only stable for approximately 5 min, after which it decomposes. The radioligand is stable in the injection solution and in protein-free ( >30 K M.W.) plasma ultrafiltrate for at least 18 h. To preserve the parent compound in plasma the radioactive plasma must be mixed with equal volumes of acetonitrile within 5 min after its collection or, alternatively, radioactive blood should be collected and mixed with sodium azide (3 mg/ml blood). The in vivo metabolism of [123I]5-IA resulted in two components: a radiometabolite that is less lipophilic than the parent compound and a polar radiometabolite that is not free radioiodide because of the absence of radioactivity accumulation in the thyroid.

Animals↗
PubMed1999

Comprehensive MR imaging protocol for stroke management: tissue sodium concentration as a measure of tissue viability in nonhuman primate studies and in clinical studies.

PURPOSE: To investigate sodium magnetic resonance (MR) imaging for monitoring tissue viability in stroke. MATERIALS AND METHODS: A comprehensive MR imaging protocol used to measure apparent diffusion coefficient and perfusion parameters was extended to include sodium imaging. Tissue sodium concentration was estimated by using a two-compartment model. This protocol lasted less than 45 minutes. These parameters were followed over the first 6 hours in a nonhuman primate model (n = 2) of acute embolic stroke without or with thrombolytic therapy. This protocol was used in patients in whom acute (< 24 hours, n = 11) or nonacute (> or = 24 hours, n = 31) stroke was ultimately confirmed. RESULTS: The animal model showed abnormal diffusion and perfusion parameters in the lesion immediately after embolization, and these remained abnormal for over 6 hours. Tissue sodium concentration increased with time (5.7 mmol/L/h) unless halted with thrombolytic therapy. Regions with sodium concentrations over 70 mmol/L were histochemically verified as being infarcted. In patients in whom stroke older than 6 hours was clinically confirmed, sodium concentrations over 70 mmol/L were found in the appropriate brain regions. CONCLUSION: Tissue sodium concentration provides a sensitive measure of tissue viability that is complementary to the diagnostic role of diffusion and perfusion imaging for ischemic insult.

Adult↗
PubMedDate not supplied

Atherosclerosis. Chronic effects of fish oil and a therapeutic diet in nonhuman primates.

Prolonged testing of marine fish oil (FO) as a dietary supplement is necessary because of widespread claims that it is antiatherogenic. The basis for such claims is inadequate because atherogenesis is chronic and may not respond to short-term changes induced by dietary treatments. A proven (vervet) model of atherosclerosis promoted by an atherogenic diet (AD) was used to test dietary supplementation with Atlantic pilchard FO for 20 months in 47 omnivorous nonhuman primates. Responses were controlled against known favorable effects of changing from the AD to a therapeutic diet (TD). Compliance was achieved, and tissue responses to the FO dose were confirmed. Compromise of reflex vasoconstriction by atherosclerosis was demonstrated for the first time in the model. Aortic, peripheral, coronary, and cerebral atherosclerosis were assessed by light microscopy and computerized image analysis. No component of atherosclerosis regressed after dietary FO, and several deteriorated. After a change to the TD, stainable lipid was cleared from aortas and there were few lipophages, but advanced atherosclerosis was not reduced. Male vervets developed more severe atherosclerosis than did females, and the association among aortic, peripheral, and coronary atherosclerosis was positive in males. Females were resistant to coronary atherosclerosis. Only mild cerebral atherosclerosis was detected. In conclusion, the FO used was not antiatherogenic in the model, and there is a need for caution. The TD regresses some components of atherosclerosis, but it was not effective against fibrosis, mineralization, and cholesterol crystals within 20 months.

Animals↗
PubMed2001

Acceleration of fracture healing in nonhuman primates by fibroblast growth factor-2.

One of the greatest needs in the clinical bone field is a bioactive agent to stimulate bone formation. We previously reported that fibroblast growth factor-2 (FGF-2) exhibited strong anabolic actions on bone formation in models of rodents and dogs. Aiming at a clinical application, this study was undertaken to clarify the effect of a single local application of recombinant human FGF-2 on fracture healing in nonhuman primates. After a fracture was created at the midshaft of the right ulna of animals and stabilized with an intramedullary nail, gelatin hydrogel alone (n = 10) or gelatin hydrogel containing 200 microg FGF-2 (n = 10) was injected into the fracture site. Although 4 of 10 animals treated with the vehicle alone remained in a nonunion state even after 10 weeks, bone union was complete at 6 weeks in all 10 animals treated with FGF-2. Significant differences in bone mineral content and density at the fracture site between the vehicle and FGF-2 groups were seen at 6 weeks and thereafter. FGF-2 also increased the mechanical property of the fracture site. We conclude that FGF-2 accelerates fracture healing and prevents nonunion in primates, and therefore propose that it is a potent bone anabolic agent for clinical use.

Alkaline Phosphatase↗
PubMed1995

Long-term in vivo expression of the human glucocerebrosidase gene in nonhuman primates after CD34+ hematopoietic cell transduction with cell-free retroviral vector preparations.

Successful gene transfer into stem cells would provide a potentially useful therapeutic modality for treatment of inherited and acquired disorders affecting hematopoietic tissues. Coculture of primate bone marrow cells with retroviral producer cells, autologous stroma, or an engineered stromal cell line expressing human stem cell factor has resulted in a low efficiency of gene transfer as reflected by the presence of 0.1-5% of genetically modified cells in the blood of reconstituted animals. Our experiments in a nonhuman primate model were designed to explore various transduction protocols that did not involve coculture in an effort to define clinically useful conditions and to enhance transduction efficiency of repopulating cells. We report the presence of genetically modified cells at levels ranging from 0.1% (granulocytes) to 14% (B lymphocytes) more than 1 year following reconstitution of myeloablated animals with CD34+ immunoselected cells transduced in suspension culture with cytokines for 4 days with a retrovirus containing the glucocerebrosidase gene. A period of prestimulation for 7 days in the presence of autologous stroma separated from the CD34+ cells by a porous membrane did not appear to enhance transduction efficiency. Infusion of transduced CD34+ cells into animals without myeloablation resulted in only transient appearance of genetically modified cells in peripheral blood. Our results document that retroviral transduction of primate repopulating cells can be achieved without coculture with stroma or producer cells and that the proportion of genetically modified cells may be highest in the B-lymphoid lineage under the given transduction conditions.

Animals↗