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Fertility challenges for women with sickle cell disease.
Ghafuri DL, Stimpson SJ, Day ME, James A, DeBaun MR, Sharma D
(2017) Expert Rev Hematol 10: 891-901
MeSH Terms: Anemia, Sickle Cell, Blood Transfusion, Chronic Pain, Female, Fertility, Fertility Preservation, Genetic Therapy, Hematopoietic Stem Cell Transplantation, Humans, Hydroxyurea, Infertility, Pregnancy, Primary Ovarian Insufficiency, Reproductive Health, Transplantation Conditioning
Show Abstract · Added November 9, 2018
INTRODUCTION - Sickle cell disease (SCD) represents one of the most common monogenic blood disorders worldwide, with an incidence of over 300,000 newborns affected per year. Reproductive challenges for men and women with SCD have been previously reviewed; however, evidence-based strategies to prevent and manage infertility and increase fecundity are lacking in women with SCD, which is one of the most important factors for quality of life. Areas covered: This review article summarizes the known risk factors for infertility, low fecundity, and premature menopause related to SCD. Expert commentary: Women with SCD have unique risk factors that may impact their ability to conceive, including chronic inflammation, oxidative stress, transfusion-related hemochromatosis, and ovarian sickling, causing ischemia and reperfusion injury to the ovary. Contraception is strongly recommended while on hydroxyurea therapy during reproductive years and discontinuing hydroxyurea for family planning and during pregnancy based on teratogenicity in animal studies. Hematopoietic stem cell transplantation (HSCT), the only curative therapy, sometimes involves conditioning regimens containing alkylating agents and total body irradiation that contribute to infertility and premature ovarian failure. Prior to HSCT or gene therapy, we strongly recommend referral to a reproductive endocrinologist to discuss fertility preservation and surrogacy options for all women with SCD.
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Translational Advances in the Field of Pulmonary Hypertension Molecular Medicine of Pulmonary Arterial Hypertension. From Population Genetics to Precision Medicine and Gene Editing.
Austin ED, West J, Loyd JE, Hemnes AR
(2017) Am J Respir Crit Care Med 195: 23-31
MeSH Terms: Forecasting, Gene Editing, Genetic Therapy, Genetics, Population, Humans, Hypertension, Pulmonary, Male, Precision Medicine, Translational Medical Research
Added February 21, 2017
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9 MeSH Terms
Erythropoietin Slows Photoreceptor Cell Death in a Mouse Model of Autosomal Dominant Retinitis Pigmentosa.
Rex TS, Kasmala L, Bond WS, de Lucas Cerrillo AM, Wynn K, Lewin AS
(2016) PLoS One 11: e0157411
MeSH Terms: Animals, Cell Death, Dependovirus, Disease Models, Animal, Erythropoietin, Gene Transfer Techniques, Genetic Therapy, Humans, Mice, Opsins, Point Mutation, Retinal Cone Photoreceptor Cells, Retinitis Pigmentosa, Vision, Ocular
Show Abstract · Added April 2, 2019
PURPOSE - To test the efficacy of systemic gene delivery of a mutant form of erythropoietin (EPO-R76E) that has attenuated erythropoietic activity, in a mouse model of autosomal dominant retinitis pigmentosa.
METHODS - Ten-day old mice carrying one copy of human rhodopsin with the P23H mutation and both copies of wild-type mouse rhodopsin (hP23H RHO+/-,mRHO+/+) were injected into the quadriceps with recombinant adeno-associated virus (rAAV) carrying either enhanced green fluorescent protein (eGFP) or EpoR76E. Visual function (electroretinogram) and retina structure (optical coherence tomography, histology, and immunohistochemistry) were assessed at 7 and 12 months of age.
RESULTS - The outer nuclear layer thickness decreased over time at a slower rate in rAAV.EpoR76E treated as compared to the rAAV.eGFP injected mice. There was a statistically significant preservation of the electroretinogram at 7, but not 12 months of age.
CONCLUSIONS - Systemic EPO-R76E slows death of the photoreceptors and vision loss in hP23H RHO+/-,mRHO+/+ mice. Treatment with EPO-R76E may widen the therapeutic window for retinal degeneration patients by increasing the number of viable cells. Future studies might investigate if co-treatment with EPO-R76E and gene replacement therapy is more effective than gene replacement therapy alone.
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Erythropoietin either Prevents or Exacerbates Retinal Damage from Eye Trauma Depending on Treatment Timing.
Bricker-Anthony C, D'Surney L, Lunn B, Hines-Beard J, Jo M, Bernardo-Colon A, Rex TS
(2017) Optom Vis Sci 94: 20-32
MeSH Terms: Animals, Blast Injuries, Cell Survival, Dependovirus, Disease Models, Animal, Erythropoietin, Eye Injuries, Ferritins, Genetic Therapy, Genetic Vectors, Green Fluorescent Proteins, In Situ Nick-End Labeling, Injections, Intramuscular, Injections, Intraperitoneal, Mice, Mice, Inbred BALB C, Mice, Inbred DBA, NADPH Oxidases, Oxidative Stress, Polymerase Chain Reaction, Retina, Retinal Diseases, Time Factors, Vision Disorders, Wounds, Nonpenetrating
Show Abstract · Added April 2, 2019
PURPOSE - Erythropoietin (EPO) is a promising neuroprotective agent and is currently in Phase III clinical trials for the treatment of traumatic brain injury. The goal of this study was to determine if EPO is also protective in traumatic eye injury.
METHODS - The left eyes of anesthetized DBA/2J or Balb/c mice were exposed to a single 26 psi overpressure air-wave while the rest of the body was shielded. DBA/2J mice were given intraperitoneal injections of EPO or buffer and analyses were performed at 3 or 7 days post-blast. Balb/c mice were given intramuscular injections of rAAV.EpoR76E or rAAV.eGFP either pre- or post-blast and analyses were performed at 1 month post-blast.
RESULTS - EPO had a bimodal effect on cell death, glial reactivity, and oxidative stress. All measures were increased at 3 days post-blast and decreased at 7-days post-blast. Increased retinal ferritin and NADPH oxygenases were detected in retinas from EPO-treated mice. The gene therapy approach protected against axon degeneration, cell death, and oxidative stress when given after blast, but not before.
CONCLUSIONS - Systemic, exogenous EPO and EPO-R76E protects the retina after trauma even when initiation of treatment is delayed by up to 3 weeks. Systemic treatment with EPO or EPO-R76E beginning before or soon after trauma may exacerbate protective effects of EPO within the retina as a result of increased iron levels from erythropoiesis and, thus, increased oxidative stress within the retina. This is likely overcome with time as a result of an increase in levels of antioxidant enzymes. Either intraocular delivery of EPO or treatment with non-erythropoietic forms of EPO may be more efficacious.
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Virus-mediated EpoR76E gene therapy preserves vision in a glaucoma model by modulating neuroinflammation and decreasing oxidative stress.
Hines-Beard J, Bond WS, Backstrom JR, Rex TS
(2016) J Neuroinflammation 13: 39
MeSH Terms: Animals, Calcium-Binding Proteins, Cholera Toxin, Cytokines, Dependovirus, Disease Models, Animal, Erythropoietin, Evoked Potentials, Visual, Fluorescein Angiography, Gene Expression Regulation, Genetic Therapy, Glaucoma, Ki-67 Antigen, Mice, Mice, Inbred DBA, Microfilament Proteins, Microglia, Oxidative Stress, Photic Stimulation, Retina, Transduction, Genetic
Show Abstract · Added April 2, 2019
BACKGROUND - Glaucoma is a complex neurodegeneration and a leading cause of blindness worldwide. Current therapeutic strategies, which are all directed towards lowering the intraocular pressure (IOP), do not stop progression of the disease. We have demonstrated that recombinant adeno-associated virus (rAAV) gene delivery of a form of erythropoietin with attenuated erythropoietic activity (EpoR76E) can preserve retinal ganglion cells, their axons, and vision without decreasing IOP. The goal of this study was to determine if modulation of neuroinflammation or oxidative stress played a role in the neuroprotective activity of EPO.R76E.
METHODS - Five-month-old DBA/2J mice were treated with either rAAV.EpoR76E or a control vector and collected at 8 months of age. Neuroprotection was assessed by quantification of axon transport and visual evoked potentials. Microglia number and morphology and cytokine and chemokine levels were quantified. Message levels of oxidative stress-related proteins were assessed.
RESULTS - Axon transport and visual evoked potentials were preserved in rAAV.EpoR76E-treated mice. The number of microglia was decreased in retinas from 8-month-old rAAV.EpoR76E-treated mice, but proliferation was unaffected. The blood-retina barrier was also unaffected by treatment. Levels of some pro-inflammatory cytokines were decreased in retinas from rAAV.EpoR76E-treated mice including IL-1, IL-12, IL-13, IL-17, CCL4, and CCL5. TNFα messenger RNA (mRNA) was increased in retinas from 8-month-old mice compared to 3-month-old controls regardless of treatment. Expression of several antioxidant proteins was increased in retinas of rAAV.EpoR76E-treated 8-month-old mice.
CONCLUSIONS - Treatment with rAAV.EpoR76E preserves vision in the DBA/2J model of glaucoma at least in part by decreasing infiltration of peripheral immune cells, modulating microglial reactivity, and decreasing oxidative stress.
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Pharmacological Treatments for Autism Spectrum Disorder: Will Emerging Approaches Yield New Treatments?
Gogliotti RG, Conn PJ
(2016) Neuropsychopharmacology 41: 376-7
MeSH Terms: Animals, Autism Spectrum Disorder, Drug Delivery Systems, Genetic Therapy, Humans, Insulin-Like Growth Factor I, Receptor, Metabotropic Glutamate 5, Receptors, GABA-B, Treatment Outcome
Added February 18, 2016
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Virus-mediated EpoR76E Therapy Slows Optic Nerve Axonopathy in Experimental Glaucoma.
Bond WS, Hines-Beard J, GoldenMerry YL, Davis M, Farooque A, Sappington RM, Calkins DJ, Rex TS
(2016) Mol Ther 24: 230-239
MeSH Terms: Animals, Axons, Dependovirus, Disease Models, Animal, Erythropoietin, Genetic Therapy, Genetic Vectors, Glaucoma, Humans, Intraocular Pressure, Mice, Mutation, Optic Nerve
Show Abstract · Added February 4, 2016
Glaucoma, a common cause of blindness, is currently treated by intraocular pressure (IOP)-lowering interventions. However, this approach is insufficient to completely prevent vision loss. Here, we evaluate an IOP-independent gene therapy strategy using a modified erythropoietin, EPO-R76E, which has reduced erythropoietic function. We used two models of glaucoma, the murine microbead occlusion model and the DBA/2J mouse. Systemic recombinant adeno-associated virus-mediated gene delivery of EpoR76E (rAAV.EpoR76E) was performed concurrent with elevation of IOP. Axon structure and active anterograde transport were preserved in both models. Vision, as determined by the flash visual evoked potential, was preserved in the DBA/2J. These results show that systemic EpoR76E gene therapy protects retinal ganglion cells from glaucomatous degeneration in two different models. This suggests that EPO targets a component of the neurodegenerative pathway that is common to both models. The efficacy of rAAV.EpoR76E delivered at onset of IOP elevation supports clinical relevance of this treatment.
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Beyond traditional pharmacology: new tools and approaches.
Gurevich EV, Gurevich VV
(2015) Br J Pharmacol 172: 3229-41
MeSH Terms: Animals, Biological Products, Cell- and Tissue-Based Therapy, Genetic Therapy, Humans, Pharmacology, Protein Engineering, Signal Transduction
Show Abstract · Added February 12, 2015
Traditional pharmacology is defined as the science that deals with drugs and their actions. While small molecule drugs have clear advantages, there are many cases where they have proved to be ineffective, prone to unacceptable side effects, or where due to a particular disease aetiology they cannot possibly be effective. A dominant feature of the small molecule drugs is their single mindedness: they provide either continuous inhibition or continuous activation of the target. Because of that, these drugs tend to engage compensatory mechanisms leading to drug tolerance, drug resistance or, in some cases, sensitization and consequent loss of therapeutic efficacy over time and/or unwanted side effects. Here we discuss new and emerging therapeutic tools and approaches that have potential for treating the majority of disorders for which small molecules are either failing or cannot be developed. These new tools include biologics, such as recombinant hormones and antibodies, as well as approaches involving gene transfer (gene therapy and genome editing) and the introduction of specially designed self-replicating cells. It is clear that no single method is going to be a 'silver bullet', but collectively, these novel approaches hold promise for curing practically every disorder.
© 2015 The British Pharmacological Society.
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8 MeSH Terms
Characterization of vector-based delivery of neurogenin-3 in murine diabetes.
Phillips N, Kay MA
(2014) Hum Gene Ther 25: 651-61
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cellular Reprogramming, Diabetes Mellitus, Experimental, Genetic Therapy, Genetic Vectors, Hyperglycemia, Insulin-Secreting Cells, Mice, Nerve Tissue Proteins
Show Abstract · Added October 19, 2016
Treatment of type 1 diabetes with gene transfer-induced cellular reprogramming requires a pancreatic transcription factor such as Neurogenin-3 (Ngn3) and as of yet unknown component of the adenoviral particle. Despite intensive study, there are many unsolved processes related to the mechanisms and physiological parameters related to diabetes correction using this approach. While we confirm that systemic delivery of adenovirus (Ad)-Ngn3 provides long-lasting correction of streptozotocin (STZ)-induced hyperglycemia and restoration of growth curves, we found that insulin levels and glucose tolerance tests are not fully restored. By altering the innate and antigen-specific immune responses, we establish that the former likely plays some role in the reprogramming process. Interestingly, Ad-hNgn3 therapy in diabetic animals appeared to protect them from secondary STZ challenge. The resistance to secondary STZ response was more pronounced at later time points, indicating that a period of cell maturation and/or expansion may be required in order to promote lasting correction. More importantly, these results suggest that the long-term reprogrammed cells are not fully reprogrammed into β-cells, which in the case of autoimmune diabetes may be advantageous in a long-term treatment strategy. Finally, we show that the prophylactic administration of Ad-hNgn3 before diabetic induction protected mice from developing hyperglycemia, demonstrating the potential for reducing or eliminating disease progression should treatment be initiated early or before onset of symptoms.
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10 MeSH Terms
Genomics of alternative splicing: evolution, development and pathophysiology.
Gamazon ER, Stranger BE
(2014) Hum Genet 133: 679-87
MeSH Terms: Alternative Splicing, Biological Evolution, Databases, Genetic, Genetic Therapy, Genetic Variation, Genome, Human, Genomics, Humans, Muscular Dystrophy, Duchenne, Myelodysplastic Syndromes, Oligonucleotides, Antisense, Software, Transcriptome, beta-Thalassemia
Show Abstract · Added April 13, 2017
Alternative splicing is a major cellular mechanism in metazoans for generating proteomic diversity. A large proportion of protein-coding genes in multicellular organisms undergo alternative splicing, and in humans, it has been estimated that nearly 90 % of protein-coding genes-much larger than expected-are subject to alternative splicing. Genomic analyses of alternative splicing have illuminated its universal role in shaping the evolution of genomes, in the control of developmental processes, and in the dynamic regulation of the transcriptome to influence phenotype. Disruption of the splicing machinery has been found to drive pathophysiology, and indeed reprogramming of aberrant splicing can provide novel approaches to the development of molecular therapy. This review focuses on the recent progress in our understanding of alternative splicing brought about by the unprecedented explosive growth of genomic data and highlights the relevance of human splicing variation on disease and therapy.
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14 MeSH Terms