Expert opinion on biological therapy
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Expert Opin Biol Ther · Jan 2010
ReviewDelivery of RNA interference triggers to sensory neurons in vivo using herpes simplex virus.
Pain is a hugely important area of research attracting considerable academic and commercial interest. However, the application of RNA interference (RNAi) to the study of nociceptive processes and the development of new analgesics has been limited by the specific challenges associated with the delivery of RNAi triggers to the cell bodies of sensory neurons in the dorsal root ganglia (DRG). ⋯ The potential to use inducible or tissue-specific promoters and to simultaneously silence multiple gene targets, in addition to recent studies suggesting that artificial miRNAs may have improved safety profiles, hold clear advantages for the use of miRNA-based vectors for gene silencing in sensory neurons.
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Expert Opin Biol Ther · Oct 2009
ReviewPotential application of mesenchymal stem cells in acute lung injury.
Despite extensive research into the pathogenesis of acute lung injury and the acute respiratory distress syndrome (ALI/ARDS), mortality remains high at approximately 40%. Current treatment is primarily supportive, with lung-protective ventilation and a fluid conservative strategy. Pharmacologic therapies that reduce the severity of lung injury in experimental studies have not yet been translated into effective clinical treatment options. ⋯ Recently, MSC have been studied in several in vivo models of lung disease. This review focuses on first describing the existing experimental literature that has tested the use of MSC in models of ALI/ARDS, and then the potential mechanisms underlying their therapeutic use with an emphasis on secreted paracrine soluble factors. The review concludes with a discussion of future research directions required for potential clinical trials.
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Expert Opin Biol Ther · Oct 2009
ReviewFibrinogen concentrate--a potential universal hemostatic agent.
Human fibrinogen concentrates have been commercially available for decades for substitution therapy in hypofibrinogenemia, dysfibrinogenemia and afibrinogenemia. Accumulating new data suggest that fibrinogen plays a critical role in achieving and maintaining hemostasis, particularly in patients suffering from acquired fibrinogen deficiency during massive bleeding, where benefit from early intervention with fibrinogen concentrate appears to be important. ⋯ Pasteurized fibrinogen concentrate is derived from human plasma. Its half life is 2.7 days in patients with congenital fibrinogen deficiency. For congenital and acquired deficiency in vivo recovery rates vary from 60% to 109%. Reportedly, administration of pasteurized fibrinogen in patients with congenital deficiency is efficacious. Acquired deficiency of fibrinogen appears to be an early event in seriously bleeding patients, preceding critical levels of platelets or other coagulation factors. Experimental animal studies, as well as clinical observations suggest a beneficial role of early substitution with fibrinogen in management of critical traumatic and surgical bleeds. Pasteurized fibrinogen concentrate is well tolerated and associated with a low incidence of adverse thrombo-embolic events.
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Expert Opin Biol Ther · Aug 2009
ReviewThe PEPvIII-KLH (CDX-110) vaccine in glioblastoma multiforme patients.
Conventional therapies for glioblastoma multiforme (GBM) fail to target tumor cells exclusively, resulting in non-specific toxicity. Immune targeting of tumor-specific mutations may allow for more precise eradication of neoplastic cells. EGFR variant III (EGFRvIII) is a tumor-specific mutation that is widely expressed in GBM and other neoplasms and its expression enhances tumorigenicity. ⋯ In this review, we summarize our results in GBM patients targeting this mutation in multiple, multi-institutional Phase II immunotherapy trials. These trials demonstrated that a selected population of GBM patients who received vaccines targeting EGFRvIII had an unexpectedly long survival time. Further therapeutic strategies and potential pitfalls of using this approach are discussed.
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The high fibrin specificity of Desmodus rotundus salivary plasminogen activator alpha1 (desmoteplase) renders it a promising candidate for the treatment of acute ischemic stroke. In the DIAS (Desmoteplase in Acute Ischemic Stroke) and DEDAS (Dose Escalation study of Desmoteplase in Acute ischemic Stroke) Phase II studies, doses of 90 microg/kg and 125 microg/kg desmoteplase were reported to have acceptable safety profiles, leading to potentially superior reperfusion compared with placebo, with possible clinical efficacy for up to 9 h after the onset of symptoms in patients with a significant ischemic penumbra selected from magnetic resonance perfusion-diffusion weighted mismatches imaging. However, a Phase III clinical trial (DIAS-2) was unable to detect any benefit from desmoteplase when given 3 - 9 h after stroke onset. ⋯ In this frame, why exactly desmoteplase should have specific advantages over tPA, is not clear. Taken together, these findings may also lead to the disappointing conclusion that vessel recanalization after 4.5 - 5 h from stroke onset may generally be inefficacious for tissue salvage. Nevertheless, other randomized Phase III clinical trials (DIAS-3 and DIAS-4) are currently under way with a planned sample size of 320 patients having vessel occlusion or high-grade stenosis on MRI or CT-angiography in the proximal cerebral arteries.