Biomedical subjects

David Lee

Publications and source records attributed to David Lee.

At least 37 records · Page 2Linked to original sources

PubMed2006

Emerging antiangiogenic agents in lung cancer.

The success of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab in numerous tumor types including non-small-cell lung cancer (NSCLC) has spurred the development of additional novel antiangiogenic agents with distinct mechanisms of action. These include the small-molecule receptor tyrosine kinase (TK) inhibitors ZD6474, sorafenib, sunitinib malate, and AG-013736, all of which inhibit VEGF receptor TK activity. Because of the structural similarity of the different receptor TKs, these receptor TK inhibitors inhibit multiple receptors in addition to VEGF receptor. Vascular endothelial growth factor Trap, a novel, high-affinity molecule with specificity to the VEGF molecule, was generated as a fusion molecule of the VEGF receptor extracellular domain and the Fc portion of immunoglobulin (Ig) G1. Data from phase I/II trials have indicated the clinical feasibility of these agents, which are currently being investigated in phase II/III trials.

Angiogenesis Inhibitors↗

PubMed2006

Clinical development of SRC tyrosine kinase inhibitors in lung cancer.

Src tyrosine kinases regulate a large number of important mechanisms in normal and cancerous cells, are overexpressed in a broad range of tumors including lung cancer, and thus represent a potential target for cancer therapy. Preclinical experiments indicate that small-molecule inhibitors of Src block tumor growth, metastasis, and angiogenesis. Phase I data from healthy volunteers also suggest that inhibitors of Src prevent bone resorption. Several phase II trials with small-molecule inhibitors of Src are under way or have been initiated in lung cancer and in other malignancies, as discussed herein.

Benzodioxoles↗

PubMed2005

Increased apolipoprotein C-III levels associated with insulin resistance contribute to dyslipidemia in normoglycemic and diabetic subjects from a triethnic population.

Despite the major role of insulin in regulating apolipoprotein C-III (apo C-III) production, little is known about the relationship between apo C-III and insulin resistance. We examined this relationship, and the association of apo C-III with dyslipidemia, in a triethnic sample of 168 subjects with normoglycemia or type 2 diabetes. African-Americans had lower triglycerides (1.21 +/- 0.11 mmol/l) compared with Hispanics (2.01 +/- 0.14 mmol/l) and white non-Hispanics (1.83 +/- 0.15 mmol/l), regardless of gender and type 2 diabetes status (P < 0.01), but this difference was partially accounted for by ethnic difference in apo C-III levels. Metabolic syndrome was associated with high apo C-III (> 14 mg/dl) in Hispanics (OR = 5.6; 95%CI: 1.3-23.4) and white non-Hispanics (OR = 6.9; 95%CI: 1.3-36.4), but not in African-Americans. Apo C-III was the best predictor of triglycerides (R2 = 0.54, P < 0.001), after accounting for demographic and clinical variables. We found an inverse relationship between apo C-III levels and low-density lipoprotein (LDL) particle size in the type 2 diabetes subjects with (r = -0.36, P = 0.02) and without (r = -0.47, P = 0.02) the metabolic syndrome, but in normoglycemic subjects an inverse relationship was evident only in metabolic syndrome subjects (r = -0.52, P < 0.01). These results suggest that higher apo C-III may contribute to the increased cardiovascular risk in subjects with insulin resistance and type 2 diabetes through its effects on triglycerides and LDL particle size.

Adult↗

PubMed2005

DNA extraction and analysis from processed coffee beans.

The authenticity of coffee is an important issue for both producers and consumers. Premium Arabica material is especially prone to being adulterated, and a number of different techniques have been employed to determine the quality of both roasted and instant coffee. Currently, assessment of coffee authenticity relies on chemical methods which can discriminate between coffee species, but not varieties. Several genetic markers are available for assessing coffee origin, but their suitability to testing commercial coffee is limited by the ability to extract DNA from highly processed beans. In this paper, we demonstrate that PCR-grade DNA may be obtained from roasted beans and even instant coffee. This would allow analysis of commercial samples, provided that suitable markers for species/variety identification are found.

Coffea↗

PubMed2005

N-terminal insertion and C-terminal ankyrin-like repeats of alpha-latrotoxin are critical for Ca2+-dependent exocytosis.

Alpha-latrotoxin, a potent stimulator of exocytosis from neurons and neuroendocrine cells, has been studied intensively, but the mechanisms of its actions are poorly understood. Here, we developed a new method to generate active recombinant alpha-latrotoxin and conducted a structure/function analysis of the toxin in stimulating Ca2+-dependent exocytosis. alpha-Latrotoxin consists of a conserved N-terminal domain and C-terminal ankyrin-like repeats. After cleavage of an N-terminally fused purification tag of glutathione S-transferase (GST), the recombinant toxin strongly stimulated exocytosis, whereas the GST-fused toxin was much less potent. The GST-fused toxin bound to the receptors [neurexin 1alpha; CL1 (CIRL/latrophilin 1)] as efficiently as did the GST-cleaved toxin but was much less effective in inserting into the plasma membrane and inducing cation conductance. The toxin with deletion of the last two ankyrin-like repeats still bound the receptors but could neither stimulate exocytosis nor induce cation conductance efficiently. The abilities of the mutated toxins to stimulate exocytosis correlated well with their abilities to induce cation conductance, but not their binding to the receptors. Our results indicate that (1) C-terminal ankyrin-like repeats and a free (unfused) N terminus are both required for the toxin to form pores, which is essential for Ca2+-dependent exocytosis, and (2) receptor binding alone is not sufficient to stimulate Ca2+-dependent exocytosis.

Animals↗

PubMed2005

Effect of a second-generation venous catheter impregnated with chlorhexidine and silver sulfadiazine on central catheter-related infections: a randomized, controlled trial.

BACKGROUND: Central venous catheter-related infections are a significant medical problem. Improved preventive measures are needed. OBJECTIVE: To ascertain 1) effectiveness of a second-generation antiseptic-coated catheter in the prevention of microbial colonization and infection; 2) safety and tolerability of this device; 3) microbiology of infected catheters; and 4) propensity for the development of antiseptic resistance. DESIGN: Multicenter, randomized, double-blind, controlled trial. SETTING: 9 university-affiliated medical centers. PATIENTS: 780 patients in intensive care units who required central venous catheterization. INTERVENTION: Patients received either a standard catheter or a catheter coated with chlorhexidine and silver sulfadiazine. MEASUREMENTS: The authors assessed catheter colonization and catheter-related infection, characterized microbes by molecular typing, and determined their susceptibility to antiseptics. Patient tolerance of the catheter was monitored. RESULTS: Patients with the 2 types of catheters had similar demographic features, clinical interventions, laboratory values, and risk factors for infection. Antiseptic catheters were less likely to be colonized at the time of removal compared with control catheters (13.3 vs. 24.1 colonized catheters per 1000 catheter-days; P < 0.01). The center-stratified Cox regression hazard ratio for colonization controlling for sampling design and potentially confounding variables was 0.45 (95% CI, 0.25 to 0.78). The rate of definitive catheter-related bloodstream infection was 1.24 per 1000 catheter-days (CI, 0.26 to 3.62 per 1000 catheter-days) for the control group versus 0.42 per 1000 catheter-days (CI, 0.01 to 2.34 per 1000 catheter-days) for the antiseptic catheter group (P = 0.6). Coagulase-negative staphylococci and other gram-positive organisms were the most frequent microbes to colonize catheters. Noninfectious adverse events were similar in both groups. Antiseptic susceptibility was similar for microbes recovered from either group. LIMITATIONS: The antiseptic catheter was not compared with an antibiotic-coated catheter, and no conclusion can be made regarding its effect on bloodstream infection. CONCLUSIONS: The second-generation chlorhexidine-silver sulfadiazine catheter is well tolerated. Antiseptic coating appears to reduce microbial colonization of the catheter compared with an uncoated catheter.

Aged↗

PubMed2005

Aspirin induces platelet receptor shedding via ADAM17 (TACE).

Aspirin is effective in the therapy of cardiovascular diseases, because it causes acetylation of cyclooxygenase 1 (COX-1) leading to irreversible inhibition of platelets. Additional mechanisms can be suspected, because patients treated with other platelet COX inhibitors such as indomethacin do not display an increased bleeding tendency as observed for aspirin-treated patients. Recently, aspirin and other anti-inflammatory drugs were shown to induce shedding of L-selectin in neutrophils in a metalloproteinase-dependent manner. Therefore, we investigated the effects of aspirin on the von Willebrand Factor receptor complex glycoprotein (GP) Ib-V-IX, whose lack or dysfunction causes bleeding in patients. As quantified by fluorescence-activated cell sorting analysis in whole blood, aspirin, but not its metabolite salicylic acid, induced dose-dependent shedding of human and murine GPIbalpha and GPV from the platelet surface, whereas other glycoproteins remained unaffected by this treatment. Biotinylated fragments of GPV were detected by immunoprecipitation in the supernatant of washed mouse platelets, and the expression level of GPIbalpha was decreased in these platelets as measured by Western blot analysis. Although shedding occurred normally in COX-1-deficient murine platelets, shedding was completely blocked by a broad-range metalloproteinase inhibitor and, more importantly, in mouse platelets expressing an inactive form of ADAM17. Shed fragments of GPIbalpha and GPV were elevated in the plasma of aspirin-injected mice compared with animals injected with control buffer. These data demonstrate that aspirin at high concentrations induces shedding of GPIbalpha and GPV by an ADAM17-dependent mechanism and that this process can occur in vivo.

ADAM Proteins↗

PubMed2005

C-reactive protein is elevated in obese patients with the metabolic syndrome.

C-reactive protein (CRP) is associated with increased risk for cardiovascular disease and diabetes. Few studies have evaluated the importance of CRP in those with the cluster of cardiovascular risk factors known as the metabolic syndrome (MS). We studied 190 overweight subjects (83 men and 107 women), aged 25-75 years, screened for glucose intolerance, in order to assess whether CRP levels vary according to the presence of MS, and to examine the relationship between CRP levels and metabolic variables. The prevalence of the Adult Treatment Panel III MS was 36.8%. Subjects with the MS had a higher degree of insulin resistance (IR), measured by the homeostasis model assessment (HOMA) method (5.4+/-0.4 versus 3.6+/-0.3, p<0.001) and higher frequency of glucose intolerance (78.3% versus 44.4%, p<0.001) than those without the MS. CRP values were increased among those with the MS (4.85+/-0.47 mg/l versus 3.34+/-0.36 mg/l, p<0.05). CRP correlated with waist circumference (r=0.28, p<0.001) and body mass index (r=0.38, p<0.001) in both men and women; however the relationship of CRP with HOMA(IR) was only evident in men (r=0.37, p<0.01) while the association with free fatty acids (FFA) was only significant in women (r=0.20, p<0.05), even after adjusting for age, hispanic ethnicity and glucose tolerance status. Abdominal obesity (elevated waist circumference) was the single most important MS component associated with increased CRP levels (>3mg/dl) (OR=3.1, 95% C.I.: 1.4-10.1), followed by female gender and smoking. These results confirm that CRP levels are elevated in MS subjects at risk for glucose intolerance. In addition waist circumference, HOMA(IR) and FFA levels are associated with CRP levels, suggesting potential roles of obesity, insulin resistance and lipolysis in the development of the subclinical inflammation associated with the MS.

Adult↗

PubMed2005

Identification and distribution of protein families in 120 completed genomes using Gene3D.

Using a new protocol, PFscape, we undertake a systematic identification of protein families and domain architectures in 120 complete genomes. PFscape clusters sequences into protein families using a Markov clustering algorithm (Enright et al., Nucleic Acids Res 2002;30:1575-1584) followed by complete linkage clustering according to sequence identity. Within each protein family, domains are recognized using a library of hidden Markov models comprising CATH structural and Pfam functional domains. Domain architectures are then determined using DomainFinder (Pearl et al., Protein Sci 2002;11:233-244) and the protein family and domain architecture data are amalgamated in the Gene3D database (Buchan et al., Genome Res 2002;12:503-514). Using Gene3D, we have investigated protein sequence space, the extent of structural annotation, and the distribution of different domain architectures in completed genomes from all kingdoms of life. As with earlier studies by other researchers, the distribution of domain families shows power-law behavior such that the largest 2,000 domain families can be mapped to approximately 70% of nonsingleton genome sequences; the remaining sequences are assigned to much smaller families. While approximately 50% of domain annotations within a genome are assigned to 219 universal domain families, a much smaller proportion (< 10%) of protein sequences are assigned to universal protein families. This supports the mosaic theory of evolution whereby domain duplication followed by domain shuffling gives rise to novel domain architectures that can expand the protein functional repertoire of an organism. Functional data (e.g. COG/KEGG/GO) integrated within Gene3D result in a comprehensive resource that is currently being used in structure genomics initiatives and can be accessed via http://www.biochem.ucl.ac.uk/bsm/cath/Gene3D/.

Amino Acid Sequence↗

PubMed2005

MorphiDex (morphine sulfate/dextromethorphan hydrobromide combination) in the treatment of chronic pain: three multicenter, randomized, double-blind, controlled clinical trials fail to demonstrate enhanced opioid analgesia or reduction in tolerance.

While many pre-clinical and clinical studies have suggested that the addition of N-methyl-D-aspartate (NMDA) receptor antagonists, such as dextromethorphan (DM), to opioid analgesics, such as morphine (MS), may enhance the analgesic effects and prevent the tolerance that may result from chronic opioid administration, others have not. The potential for reduced doses, enhanced opioid analgesia, and decreased analgesic tolerance associated with the MS/DM combination were evaluated in a series of three large, randomized, double-blind, parallel group, phase 3, multicenter trials each of 3 months duration in patients with chronic, non-malignant, non-neuropathic pain. To evaluate these unique endpoints, novel study designs were employed. In Study A, patients received fixed doses of MS or MS/DM, based on the stable dose of MS/DM attained during a Run-in period; changes from baseline in average daily pain intensity were compared. In Studies B and C, patients self-titrated doses of MS or MS/DM, based on stable doses of MS or other opioids attained during Run-in periods, to maintain pain relief; percentage changes from baseline in MS (or MS-equivalent) doses were compared. No statistically significant differences between treatment groups in any primary or secondary efficacy variables were demonstrated in any trial. These results suggest that adding the NMDA antagonist, dextromethorphan, to opioids does not add any clinical benefit.

Adult↗

PubMed2005

Long-term outcome of postorchiectomy surveillance for Stage I testicular seminoma.

PURPOSE: To examine the long-term outcome and patterns of relapse in clinical Stage I testicular seminoma managed with surveillance alone after radical inguinal orchiectomy. METHODS AND MATERIALS: This was a prospective, single-arm study. Patients with Stage I testicular seminoma were treated with surveillance alone in accordance with regular, predefined, schedules and investigations. RESULTS: The study accrued a total of 88 patients between 1985 and 1996. The median age at diagnosis was 34 years. The median tumor size was 3.5 cm. The median follow-up as of June 2003 was 12.1 years. Only 3 patients were lost to follow-up. Of the 88 patients, 71 remained free of relapse and 17 did not. The actuarial relapse-free rate was 83%, 80%, and 80% at 5, 10, and 15 years, respectively. Most relapses (15 of 17) were below the diaphragm. Of the 17 patients with relapse, 14 were treated with radiotherapy and 3 with combination chemotherapy. Only 1 had a second relapse and was further salvaged by chemotherapy. All 17 relapsed patients remained free of recurrence after salvage treatment. None died of seminoma. The statistically significant predictive factor for relapse on the Cox proportional hazards model was the presence of rete testis invasion (hazard ratio 3.5, p = 0.03). CONCLUSION: Surveillance with the reservation of radiotherapy or chemotherapy for salvage of relapse is a safe alternative to upfront postoperative adjuvant therapy for Stage I testicular seminoma.

Adult↗

PubMed2005

A GM-CSF/CD40L producing cell augments anti-tumor T cell responses.

BACKGROUND: Tumors evade T cell-mediated rejection despite the presence of tumor associated antigens (TAAs) and T cells specific for these TAAs in cancer patients. Therapeutic tumor vaccines are being developed to prevent this evasion. Previous reports revealed that anti-tumor T cell responses could be activated in mice when granulocyte macrophage-colony stimulating factor (GM-CSF) or CD40L are produced at tumor vaccine sites. We sought to test the hypothesis that production of GM-CSF and CD40L by a bystander cell line could induce an anti-tumor T cell response in an in vitro human model. MATERIALS AND METHODS: The K562 cell line was stably transfected with the human GM-CSF and CD40L genes. The effect of this cell line on T cell responses was tested in a human autologous mixed tumor cell/lymph node cell model using tissue from a series of cancer patients. RESULTS: There was no significant anti-tumor T cell response when human lymphocytes derived from tumor-draining lymph nodes were stimulated with autologous tumor cells in vitro. However, significant anti-tumor T cell responses were observed when bystander cells transfected with CD40L and GM-CSF were added to the cultures. CONCLUSIONS: A fully autologous human model consisting of tumor cells as stimulator cells and tumor-draining lymph nodes as responder cells can be used to test immunotherapeutic strategies. T cells in these lymph nodes are unresponsive to autologous tumor cells, but this lack of responsiveness can be reversed in the presence of GM-CSF and CD40L. These data provide a rationale for testing tumor cell vaccines incorporating GM-CSF- and CD40L-expressing bystanders in clinical trials.

Bystander Effect↗

PubMed2005

The CATH Domain Structure Database and related resources Gene3D and DHS provide comprehensive domain family information for genome analysis.

The CATH database of protein domain structures (http://www.biochem.ucl.ac.uk/bsm/cath/) currently contains 43,229 domains classified into 1467 superfamilies and 5107 sequence families. Each structural family is expanded with sequence relatives from GenBank and completed genomes, using a variety of efficient sequence search protocols and reliable thresholds. This extended CATH protein family database contains 616,470 domain sequences classified into 23,876 sequence families. This results in the significant expansion of the CATH HMM model library to include models built from the CATH sequence relatives, giving a 10% increase in coverage for detecting remote homologues. An improved Dictionary of Homologous superfamilies (DHS) (http://www.biochem.ucl.ac.uk/bsm/dhs/) containing specific sequence, structural and functional information for each superfamily in CATH considerably assists manual validation of homologues. Information on sequence relatives in CATH superfamilies, GenBank and completed genomes is presented in the CATH associated DHS and Gene3D resources. Domain partnership information can be obtained from Gene3D (http://www.biochem.ucl.ac.uk/bsm/cath/Gene3D/). A new CATH server has been implemented (http://www.biochem.ucl.ac.uk/cgi-bin/cath/CathServer.pl) providing automatic classification of newly determined sequences and structures using a suite of rapid sequence and structure comparison methods. The statistical significance of matches is assessed and links are provided to the putative superfamily or fold group to which the query sequence or structure is assigned.

Databases, Nucleic Acid↗

PubMed2005

The paradox of normal serum albumin in anorexia nervosa: a case report.

OBJECTIVE: Anorexia nervosa (AN) is associated with marked decreases in caloric intake and a corresponding reduction in body weight due to abnormal self body image. Although counterintuitive, hypoalbuminemia and vitamin deficiencies are not expected consequences of this disorder. Etiologic considerations for hypoalbuminemia are discussed. METHOD: The case report of a patient with AN and marked hypoalbuminemia is presented and a focused literature review is reported. RESULTS: Hypoalbuminemia was initially attributed to starvation. However, occult infection was ultimately responsible. Serum albumin concentration normalized with antibiotic therapy despite minimal restoration of body weight. DISCUSSION: Hypoalbuminemia should not be considered a characteristic feature of AN even in the setting of progressive weight loss. The presence of other potentially life-threatening conditions should be sought, as reduced serum albumin concentration is a marker of inflammation in AN.

Anorexia Nervosa↗

PubMed2005

Scientific Grid activities and PKI deployment in the Cybermedia Center, Osaka University.

The Cybermedia Center (CMC), Osaka University, is a research institution that offers knowledge and technology resources obtained from advanced researches in the areas of large-scale computation, information and communication, multimedia content and education. Currently, CMC is involved in Japanese national Grid projects such as JGN II (Japan Gigabit Network), NAREGI and BioGrid. Not limited to Japan, CMC also actively takes part in international activities such as PRAGMA. In these projects and international collaborations, CMC has developed a Grid system that allows scientists to perform their analysis by remote-controlling the world's largest ultra-high voltage electron microscope located in Osaka University. In another undertaking, CMC has assumed a leadership role in BioGrid by sharing its experiences and knowledge on the system development for the area of biology. In this paper, we will give an overview of the BioGrid project and introduce the progress of the Telescience unit, which collaborates with the Telescience Project led by the National Center for Microscopy and Imaging Research (NCMIR). Furthermore, CMC collaborates with seven Computing Centers in Japan, NAREGI and National Institute of Informatics to deploy PKI base authentication infrastructure. The current status of this project and future collaboration with Grid Projects will be delineated in this paper.

Computational Biology↗

PubMed2005

Assessment of resident surgical skills: is testing feasible?

OBJECTIVE: We have previously shown that in a single residency program objective structured assessment of technical skills (OSATS) is a reliable and valid method of assessing surgical competency. Our goal was to establish feasibility of this evaluation instrument when administered at multiple residency programs throughout the US, and assess the impact of a laboratory-based surgical curriculum on results. STUDY DESIGN: An OSATS exam was administered to 116 residents from 5 residency programs. One of the residency programs had participated in a comprehensive surgical curriculum over a 4-year period of time. The exam consisted of 3 open and 3 laparoscopic tasks. Residents were graded by both a blinded and unblinded examiner with task-specific checklist, global rating scale, pass/fail assessment, and tasks were timed. All tasks were performed on life-like models. RESULTS: Examinations were successfully completed at all sites. Each exam required 90 minutes of resident time. Reliability indices calculated with Cronbach's alpha were .97 for overall global rating and .95 for checklists. Interrater reliability between blinded and unblinded examiners ranged from .71 to .97 for individual tasks and was .95 overall. Assessment of construct validity (the ability to distinguish among residency levels) found significant differences among the residents for both blinded and unblinded examiners for all evaluation outcomes except time. For the test overall, the global rating scale showed significant differences among all 4 residency levels. The checklist showed significant differences at three levels (PGY3-4 >PGY2 >PGY1). Approximate cost for replaceable items was 40 US dollars to 150 per resident depending on which tasks were chosen. Comparison of scores between residents who received a laboratory-based curriculum and those who did not revealed significantly higher scores and shorter time to complete tasks for the group who received additional training. CONCLUSION: Large-scale testing has confirmed that OSATS is an objective, reliable, and valid method to assess surgical skills, and can easily be administered in most residency programs. A laboratory-based surgical curriculum improved test results and reduced time to complete tasks.

Clinical Competence↗

PubMed2005

Correlation of office-based cystoscopy and cytology with histologic diagnosis: how good is the reference standard?

OBJECTIVES: To evaluate the accuracy of cystoscopy and cytology in predicting the histopathologic features of suspicious cystoscopic lesions. METHODS: We reviewed the bladder biopsy records at two institutions from July 2001 to July 2004. Intraoperative biopsies were performed for positive (papillary or sessile) (n = 155) and equivocal (n = 101) lesions found during office cystoscopy. The specimens were submitted for histopathologic analysis, and the results were correlated with the preceding office-based cystoscopy and cytology findings. RESULTS: Malignancy was found in 27 (26.7%) of 101 equivocal lesions and 128 (82.5%) of 155 sessile or papillary lesions. Of the 72 biopsies performed for equivocal lesions in patients with a history of transitional cell carcinoma (TCC), 24 (33%) had malignancy compared with 3 (10.3%) of 29 biopsies performed in patients without a history of TCC. For patients with no history of TCC and equivocal lesions, cytology was able to identify all neoplasms (100% sensitivity) and negative cytology always predicted a normal biopsy result (100% negative predictive value). However, for patients with a history of TCC and equivocal lesions, cytology had a sensitivity and negative predictive value of 81.8% and 88.2%, respectively. CONCLUSIONS: Our findings suggest that patients without a history of TCC who have an equivocal lesion at cystoscopy may avoid an unnecessary operation if they have normal cytology findings. A large number of patients with equivocal cystoscopic findings undergo unnecessary biopsies in the operating room, and future studies should be performed to assess the value of other bladder markers in predicting oncologic status in this setting.

Cystoscopy↗

PubMed2005

Liver-directed neonatal gene therapy prevents cardiac, bone, ear, and eye disease in mucopolysaccharidosis I mice.

Mucopolysaccharidosis I (MPS I) due to deficient alpha-L-iduronidase (IDUA) activity results in accumulation of glycosaminoglycans in many cells. Gene therapy could program liver to secrete enzyme with mannose 6-phosphate (M6P), and enzyme in blood could be taken up by other cells via the M6P receptor. Newborn MPS I mice were injected with 10(9) (high dose) or 10(8) (low dose) transducing units/kg of a retroviral vector (RV) expressing canine IDUA. Most animals achieved stable expression of IDUA in serum at 1240 +/- 147 and 110 +/- 31 units/ml, respectively. At 8 months, untreated MPS I mice had aortic insufficiency, increased bone mineral density (BMD), and reduced responses to sound and light. In contrast, MPS I mice that received high-dose RV had normal echocardiograms, BMD, auditory-evoked brain-stem responses, and electroretinograms. This is the first report of complete correction of these clinical manifestations in any model of mucopolysaccharidosis. Biochemical and pathologic evaluation confirmed that storage was reduced in these organs. Mice that received low-dose RV and achieved 30 units/ml of serum IDUA activity had no or only partial improvement. We conclude that high-dose neonatal gene therapy with an RV reduces some major clinical manifestations of MPS I in mice, but low dose is less effective.

Animals↗