What is the problem you want to solve, why is it important, what do you propose to do to solve the problem? Maximum of 150 words.

Promising and delivering non-viral vector gene therapies for sickle cell disease
Instruction:
-follow the instructions
-I need copy of all references with highlight the lines which are used.
-Only journal articles.

Promising and delivering non-viral vector gene therapies for sickle cell disease

Maximum 5x A4 pages PLUS reference page(s).

Single sided, 12 point Times New Roman font, lines 1.5 spaced, with 2cm margins.

I need all references which are used and highlighted the lines (necessary).

The title is suggested, so I do not know how will things goes.

Please follow the structure below

I will upload journal articles that may help and if you can use it, it will be better.

Please, make sure that you do not use any unscientific sources only journal articles.

Title: Maximum 10 words, clear, concise, grabs attention.

Summary of your proposal: What is the problem you want to solve, why is it important, what do you propose to do to solve the problem? Maximum of 150 words.

Literature review: Give the reader enough background information to be able to understand the research problem you wish to investigate. Describe the evidence that the problem exists and needs further research; that is, identify the “gap in knowledge” you want to solve.

Research problem and aims: Briefly describe the research problem that you wish to solve. Why is it a problem? What are the specific aims of your project?

Methods: Describe, in general terms only, the experiments that you would do to solve the parts research problem you wish to solve. You will need to describe experiments/methods for each aim.

References: A list of references used in the document. You must cite mainly journal articles, and a minimum of 15 references must be presented.
For personal use. Only reproduce with permission from The Lancet Publishing Group. RAPID REVIEW Lancet 2002; 360: 629–31 Department of Hematology/Oncology, Children’s Hospital Oakland, Oakland, CA 94609, USA (Elliott Vichinsky MD) Correspondence to: Dr Elliott Vichinsky (e-mail: evichinsky@mail.cho.org) In the past decade, understanding of the pathophysiology of sickle cell disease (SCD) and its treatment has progressed. Infections, brain injury, renal disease, pain, and priapism can now be prevented. Complications from pulmonary injury, surgery, and transfusion can be minimised (panel 1). Vaso-occlusion and tissue ischaemia in SCD involve not only the polymerisation of the sickle haemoglobin (Hb S) but also interactions between red cells, endothelium, platelets, leucocytes, and plasma factors.1–3 Polymerisation of Hb S is the most important factor in the sickling cycle, and a rise in fetal haemoglobin (Hb F) decreases intracellular polymerisation of Hb S. Hb F concentrations are inversely related to morbidity in SCD.4 Increasing Hb F is the most clinically studied approach against sickling. Management Sickling can be interrupted at several key pathways (panel 2). Hydroxyurea, the most prescribed therapy for SCD, causes myelosuppressive-induced Hb F synthesis by decreasing terminal differentiation of erythroid stem cells, resulting in improved red-cell survival and decreased sickling. Hydroxyurea is orally active, safe in the short term, and beneficial in most patients.5 Although hydroxyurea halves pain episodes, pulmonary events, and hospitalisations, 40% of treated patients do not respond or have progressive organ failure.3,4,6 Individual reports of responses to short-chain fatty acids (eg, valproic acid) have been dramatic, with almost complete correction of anaemia. These drugs increase Hb F by affecting globin gene-expression, possibly by inhibition of histone deacetylases.4 They are not myelosuppressive or cross-resistant with hydroxyurea. But existing compounds inhibit stem-cell proliferation and are thus unpredictable clinically. Newly developed orally active short-chain fatty acids and pulse therapy of existing agents may not inhibit stem-cell growth. Another agent that modulates Hb F is 5-azacytidine, which may increase gamma-gene expression by hypomethylation of the gamma promoter, but there are tumorigenic concerns about this drug. Decitabine, a safer analogue of azacytidine, increased total Hb and Hb F in patients resistant to hydroxyurea.7 The agents that modulate Hb F (hydroxyurea, short-chain fatty acids, erythropoietin) may be synergistic. Another therapeutic approach aims to prevent polymerisation-induced damage of the red-cell membrane.3 Membrane injury causes cell dehydration and the formation of the rigid dense cells associated with anaemia and vasoocclusion. Several of the transport systems for cell dehydration have been successfully modulated, including the calcium-activated K+ channel, described by Gardos. Sickling-induced increased cytosolic Ca2+ leads to cell dehydration. Clotrimazole, a Gardos-channel blocker, led to decreased sickling events and improved laboratory variables in pilot work.8 Magnesium pidolate, an inhibitor of the pH sensitive K:Cl co-transport system support, is another anticell-dehydration approach with promise.1,3,9,10–12 New therapies in sickle cell disease Elliott Vichinsky Rapid review THE LANCET • Vol 360 • August 24, 2002 • www.thelancet.com 629 Context New therapies have evolved from our improved understanding of the biology of sickle cell disease (SCD) and the availability of a useful transgenic animal model. Several therapeutic options are available that interrupt the sickling process at various key pathways. Nitric oxide (NO) is a critical factor in the pathophysiology of SCD and is a promising antisickling agent with vasodilation properties. NO regulates blood vessel tone, endothelial adhesion, and the severity of ischaemia-reperfusion injury and anaemia in SCD. Although NO is difficult to administer, its precursor, L-arginine, is an oral supplement. Starting point J R Romero and colleagues recently demonstrated in sickle transgenic mice that oral arginine supplementation induced NO production and reduced red-cell density by inhibiting the Gardos channel, which modulates cell hydration and polymerisation of haemoglobin S (Blood 2002; 99: 1103–08). Haemoglobinopathies can be cured by stem-cell transplantation. This therapy is now accepted treatment in symptomatic children. However, most patients lack a genotypically identical family donor. G La Nasa and colleagues demonstrated unrelated-donor stem-cell transplantation may give similar results to related-donor stem-cell transplantation when extended phenotypic matching is used (Blood 2002; 99: 4350–56). This pilot study offers the possibility of cure to patients without a family donor. Where next Although potential opportunities to prevent morbidity in SCD through new therapies are exciting, most patients do not have access to standard multidisciplinary specialty care. Patients require both. For personal use. Only reproduce with permission from The Lancet Publishing Group. Ex-vivo microcirculation studies show that endothelial adherence of sickle cells activates vaso-occlusion. Any adhesive interaction that impairs flow, delaying the transit time of sickle cells, can initiate or amplify intravascular sickling. Many cellular contact sites and plasma factors are now being targeted.2,3,13–16 Sulphasalazine, an inhibitor of nuclear factor kappa-b modifies endothelial activation,1 and in pilot studies reduced the expression of adhesion molecules and E selectin. Antithrombotic therapy is a growing area,2,3 with increasing evidence that hypercoagulation plays an important role in the pathophysiology of SCD. Sickle cells stimulate the coagulation system by increasing platelet activation, thrombin generation, and fibrinolysis. Pilot studies with anticoagulants (acenocoumarol, n3 fatty acids, heparin) showed improvement in coagulation markers, and, anecdotally, pain.17 Several new drugs alter multiple pathological processes in SCD. These drugs are promising, but require extensive studies to determine the most effective method of use. Poloxamer 188 is a nonionic surfactant copolymer that improves microvascular blood flow,18 decreasing viscosity, thrombosis, frictional forces, and inflammation. Its antiadhesive properties result from blocking of hydrophobic adhesive interactions between erythrocytes and vascular endothelium. In a randomised double-blind placebocontrolled phase 2 study, a 48-h infusion of poloxamer 188 reduced pain intensity and analgesic use, which led to a larger placebo-controlled trial of 255 patients with painful sickle-cell crisis.18 There was significant improvement in the treatment group, but this improvement was associated with only a limited reduction in the duration of painful crises. Two groups of patients have an amplified response to poloxamer 188, including children receiving hydroxyurea. These observations are consistent with previous antisickling drug studies, suggesting that children are more responsive to intervention because they have less irreversible organ injury and that combination therapy is better than monotherapy. Nitric oxide (NO) is a critical factor in the pathophysiology of SCD and is a potentially powerful treatment modality.3,19,20 NO regulates blood vessel tone, endothelial adhesion, leucocytes, and platelet activity, important factors in ischaemia-reperfusion injury and sickle-cell-induced ischaemia. In SCD, more adhesion molecules are produced due to decreased availability of NO. In sickle transgenic mice, oral arginine supplementation induced NO production and reduced red-cell density by inhibiting the Gardos channel.21 Whether the low NO concnetrations are because of decreased endothelial production or increased use is unknown. In SCD, low NO concentrations are associated with low L-arginine, the precursor of NO. Pilot studies treating sickle-cell patients with NO have shown promising antisickling activity with vasodilator properties. Clinical trials with L-arginine supplementation appear to correct the NO deficiency and improve pulmonary hypertension. In addition, red-cell adherence to pulmonary endothelium appears to decrease with NO.19,20 NO or arginine supplementation may be synergistic with hydroxyurea, and seems to further increase NO release and decrease adhesives molecules. Transplantation and transfusion Stem-cell transplantation and chronic transfusion can cure or dramatically lessen the severity of SCD.3 The overall survival rate for HLA-identical sibling-donor stem-cell transplantation is 93%, and event-free survival is 82%. Allogeneic bone-marrow transplantation (BMT) is now accepted therapy for symptomatic children. Initially, RAPID REVIEW 630 THE LANCET • Vol 360 • August 24, 2002 • www.thelancet.com Panel 2: Emerging therapeutic agents in SCD Category Mechanism Agent 1) Red-cell Gardos channel inhibition Clotrimazole, rehydration ICA–17403* K:CL co-transport inhibition Mg pidolate Chloride movement blockage NS 1652*, NS 3623* 2) Antiadhesion Red-cell endothelial adhesion RGD peptide Antiadhesion antibodies PAF-induced adhesion Anti-von-Willebrand factor Anti-white-cell adhesion Anti-integrin receptors Endothelial activation Sulphasalazine (inhibitor of NF-kb) 3) Hb F Ribonucleotide reductase Hydroxyurea augmentation Histone deacetylase Short-chain fatty acids DNA hypomethylation 2-deoxy-5-azacytidine Str

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