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Concept: Therapy

396

Background Thrombectomy is currently recommended for eligible patients with stroke who are treated within 6 hours after the onset of symptoms. Methods We conducted a multicenter, randomized, open-label trial, with blinded outcome assessment, of thrombectomy in patients 6 to 16 hours after they were last known to be well and who had remaining ischemic brain tissue that was not yet infarcted. Patients with proximal middle-cerebral-artery or internal-carotid-artery occlusion, an initial infarct size of less than 70 ml, and a ratio of the volume of ischemic tissue on perfusion imaging to infarct volume of 1.8 or more were randomly assigned to endovascular therapy (thrombectomy) plus standard medical therapy (endovascular-therapy group) or standard medical therapy alone (medical-therapy group). The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability) at day 90. Results The trial was conducted at 38 U.S. centers and terminated early for efficacy after 182 patients had undergone randomization (92 to the endovascular-therapy group and 90 to the medical-therapy group). Endovascular therapy plus medical therapy, as compared with medical therapy alone, was associated with a favorable shift in the distribution of functional outcomes on the modified Rankin scale at 90 days (odds ratio, 2.77; P<0.001) and a higher percentage of patients who were functionally independent, defined as a score on the modified Rankin scale of 0 to 2 (45% vs. 17%, P<0.001). The 90-day mortality rate was 14% in the endovascular-therapy group and 26% in the medical-therapy group (P=0.05), and there was no significant between-group difference in the frequency of symptomatic intracranial hemorrhage (7% and 4%, respectively; P=0.75) or of serious adverse events (43% and 53%, respectively; P=0.18). Conclusions Endovascular thrombectomy for ischemic stroke 6 to 16 hours after a patient was last known to be well plus standard medical therapy resulted in better functional outcomes than standard medical therapy alone among patients with proximal middle-cerebral-artery or internal-carotid-artery occlusion and a region of tissue that was ischemic but not yet infarcted. (Funded by the National Institute of Neurological Disorders and Stroke; DEFUSE 3 ClinicalTrials.gov number, NCT02586415 .).

Concepts: Medicine, Blood, Stroke, Therapy, Modified Rankin Scale, Ischemia, Randomness, Disability

367

Low reproducibility rates within life science research undermine cumulative knowledge production and contribute to both delays and costs of therapeutic drug development. An analysis of past studies indicates that the cumulative (total) prevalence of irreproducible preclinical research exceeds 50%, resulting in approximately US$28,000,000,000 (US$28B)/year spent on preclinical research that is not reproducible-in the United States alone. We outline a framework for solutions and a plan for long-term improvements in reproducibility rates that will help to accelerate the discovery of life-saving therapies and cures.

Concepts: Scientific method, Medicine, Life, United States, Therapy, Science, U.S. state, Philosophy of science

168

We have used a peptide-based targeting system to improve lysosomal delivery of acid α-glucosidase (GAA), the enzyme deficient in patients with Pompe disease. Human GAA was fused to the Glycosylation-Independent Lysosomal Targeting (GILT) tag, which contains a portion of insulin-like growth factor II (IGF-II), to create an active, chimeric enzyme with high affinity for the cation-independent mannose 6-phosphate receptor (CI-MPR). GILT-tagged GAA was taken up by L6 myoblasts about 25-fold more efficiently than was recombinant human GAA (rhGAA). Once delivered to the lysosome, the mature form of GILT-tagged GAA was indistinguishable from rhGAA and persisted with a half-life indistinguishable from rhGAA. GILT-tagged GAA was significantly more effective than rhGAA in clearing glycogen from numerous skeletal muscle tissues in the Pompe mouse model. The GILT-tagged GAA enzyme may provide an improved enzyme replacement therapy for Pompe disease patients.

Concepts: Protein, Cell, Golgi apparatus, Muscle, Therapy, Glycogen, Glycogen storage disease, Insulin-like growth factor 2

167

Morquio A syndrome is a lysosomal storage disease associated with mucopolysaccharidosis. It is caused by a deficiency of the lysosomal enzyme, N-acetylgalactosamine-6-sulfate sulfatase, which leads to accumulation of keratan sulfate and condroitin-6 sulfate in multiple organs. Patients present with multisystemic complications involving the musculoskeletal, respiratory, cardiovascular, and digestive systems. Presently, there is no definitive cure, and current management options are palliative. Enzyme replacement therapy and hematopoietic stem cell therapy have been proven effective in certain lysosomal storage diseases, and current investigations are underway to evaluate the effectiveness of these therapies and others for the treatment of Morquio A syndrome. This review discusses the current and emerging treatment options for Morquio A syndrome, citing examples of the treatment of other mucopolysaccharidoses.

Concepts: Cell, Lysosomal storage disease, Therapy, Mucopolysaccharidosis, Lysosomal storage diseases, Morquio syndrome

167

Mesoporous silica-encapsulated gold nanorods (GNRs@mSiO(2)) have great potential both in photothermal therapy and drug delivery. In this paper, we firstly developed GNRs@mSiO(2) as a synergistic therapy tool for delivery heat and drug to the tumorigenic region. We studied the ablation of tumor both in vitro and in vivo by the combination of photothermal therapy and chemotherapy using doxorubicin (DOX)-loaded GNRs@mSiO(2). Significantly greater cell killing was observed when A549 cells incubated with DOX-loaded GNRs@mSiO(2) were irradiated with near-infrared (NIR) illumination, attributable to both GNRs@mSiO(2)-mediated photothermal ablation and cytotoxicity of light-triggered DOX release. We then performed in vivo therapy studies and observed a promising tumor treatment. Compared with chemotherapy or photothermal treatment alone, the combined treatment showed a synergistic effect, resulting in higher therapeutic efficacy. Furthermore, the lower systematic toxicity of GNRs@mSiO(2) has been validated.

Concepts: DNA, Cancer, Oncology, Chemotherapy, Therapy, Efficacy, Doxorubicin, Photothermal Therapy

167

Influenza is a severe disease in humans and animals with few effective therapies available. All strains of influenza virus are prone to developing drug resistance due to the high mutation rate in the viral genome. A therapeutic agent that targets a highly conserved region of the virus could bypass resistance and also be effective against multiple strains of influenza. Influenza uses many individually weak ligand-binding interactions for a high-avidity multivalent attachment to sialic acid-bearing cells. Polymerized sialic acid analogs can form multivalent interactions with influenza, but are not ideal therapeutics due to solubility and toxicity issues. We used liposomes as a novel means for delivery of the glycan sialylneolacto-N-tetraose c (LSTc). LSTc-bearing decoy liposomes form multivalent, polymer-like interactions with influenza virus. Decoy liposomes competitively bind influenza virus in hemagglutination inhibition assays and inhibit infection of target cells in a dose-dependent manner. Inhibition is specific for influenza virus, as inhibition of Sendai virus and respiratory syncytial virus is not observed. In contrast, monovalent LSTc does not bind influenza virus or inhibit infectivity. LSTc decoy liposomes prevent the spread of influenza virus during multiple rounds of replication in vitro and extend survival of mice challenged with a lethal dose of virus. LSTc decoy liposomes co-localize with fluorescently tagged influenza virus, while control liposomes do not. Considering the conservation of the hemagglutinin binding pocket and the ability of decoy liposomes to form high avidity interactions with influenza hemagglutinin, our decoy liposomes have potential as a new therapeutic agent against emerging influenza strains.

Concepts: Microbiology, Sialic acid, Therapy, Influenza, Human respiratory syncytial virus, Orthomyxoviridae, Influenza A virus, Influenzavirus A

166

The way hemodynamic therapies are delivered today in anesthesia and critical care is suboptimal. Hemodynamic variables are not always understood correctly and used properly. The adoption of hemodynamic goal-directed strategies, known to be clinically useful, is poor. Ensuring therapies are delivered effectively is the goal of decision support tools and closed loop systems. Graphical displays (metaphor screens) may help clinicians to better capture and integrate the multivariable hemodynamic information. This may result in faster and more accurate diagnosis and therapeutic decisions. Graphical displays (target screens) have the potential to increase adherence to goal-directed strategies and ultimately improve patients' outcomes, but this remains to be confirmed by prospective studies. Closed loop systems are the ultimate solution to ensure therapies are delivered. However, most therapeutic decisions cannot be based on a limited number of output variables. Therefore, one should focus on the development of systems designed to relieve clinicians from very simple and repetitive tasks. Whether intraoperative goal-directed fluid therapy may be one of these tasks remains to be evaluated.

Concepts: Medicine, Therapy, Classification of Pharmaco-Therapeutic Referrals, Decision theory, Control theory, Decision support system, Graphic design, Medical error

162

Personalized therapy provides the best outcome of cancer care and its implementation in the clinic has been greatly facilitated by recent convergence of enormous progress in basic cancer research, rapid advancement of new tumor profiling technologies, and an expanding compendium of targeted cancer therapeutics.

Concepts: Medicine, Cancer, Oncology, Therapy, Tumor

162

Enzyme replacement therapy for mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo B syndrome) has been hindered by inadequate mannose 6-phosphorylation and cellular uptake of recombinantly produced human α-N-acetyl-glucosamindase (rhNAGLU). We expressed and characterized a modified, recombinant human NAGLU fused to the receptor binding motif of insulin-like growth factor-II (rhNAGLU-IGF-II) to enhance its ability to enter cells using the cation-independent mannose 6-phosphate receptor, which is also the receptor for IGF-II (at a different binding site). RhNAGLU-IGF-II was stably expressed in Chinese hamster ovary cells, secreted and purified to apparent homogeneity. The Km and pH optimum of the fusion enzyme was similar to those reported for rhNAGLU. Both intracellular uptake and confocal microscopy suggested MPS IIIB fibroblasts readily take up the fusion enzyme via receptor-mediated endocytosis that was significantly inhibited (p<0.001) by monomeric IGF-II peptide. Glycosaminoglycan storage was reduced by 60% (p<0.001) to near background levels in MPS IIIB cells after treatment with rhNAGLU-IGF-II, with half-maximal correction at concentrations of 3-12 pM. Similar cellular uptake mechanism via the IGF-II receptor was also demonstrated in two different brain tumor-derived cell lines. Fusion of NAGLU to IGF-II enhanced its cellular uptake while maintaining enzymatic activity, supporting its potential as a therapeutic candidate for MPS IIIB.

Concepts: Protein, Cell, Enzyme, Golgi apparatus, Therapy, Chinese hamster ovary cell, Insulin-like growth factor 2, Mucopolysaccharidosis

154

With the recent regulatory approval of Talimogene laherparepvec (T-VEC) for the treatment of advanced of melanoma in the United States, Europe and Australia, oncolytic virus immunotherapy has earned its place in the clinic. However, the adoption of T-VEC by the U.S. oncology community has been slow, and so far has been largely limited to specialized cancer centers. Limiting factors include the intratumoral route of administration, which is unfamiliar to medical oncologists, biosafety concerns related to the use of a live virus in the clinic, and the explosion of other therapeutic strategies now available for the treatment of advanced melanoma. Herein, we review the development of T-VEC, and suggest how it fits into the in the current clinical treatment paradigm, and provide pearls for drug preparation, administration, and monitoring of response to therapy.

Concepts: Medicine, Oncology, Microbiology, United States, Chemotherapy, Therapy, Oncolytic virus, Viruses