Day: 02/10/2012

Optogenetic therapy for retinitis pigmentosa.

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Retinitis pigmentosa (RP) refers to a diverse group of progressive, hereditary diseases of the retina that lead to incurable blindness and affect two million people worldwide. Artificial photoreceptors constructed by gene delivery of light-activated channels or pumps (‘optogenetic tools’) to surviving cell types in the remaining retinal circuit has been shown to restore photosensitivity in animal models of RP at the level of the retina and cortex as well as behaviorally. The translational potential of this optogenetic approach has been evaluated using in vitro studies involving post-mortem human retinas. Here, we review recent developments in this expanding field and discuss the potential and limitations of optogenetic engineering for the treatment of RP.

Source: Gene therapy

 

 

Novel adeno-associated viral vectors for retinal gene therapy.

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Vectors derived from adeno-associated virus (AAV) are currently the most promising vehicles for therapeutic gene delivery to the retina. Recently, subretinal administration of AAV2 has been demonstrated to be safe and effective in patients with a rare form of inherited childhood blindness, suggesting that AAV-mediated retinal gene therapy may be successfully extended to other blinding conditions. This is further supported by the great versatility of AAV as a vector platform as there are a large number of AAV variants and many of these have unique transduction characteristics useful for targeting different cell types in the retina including glia, epithelium and many types of neurons. Naturally occurring, rationally designed or in vitro evolved AAV vectors are currently being utilized to transduce several different cell types in the retina and to treat a variety of animal models of retinal disease. The continuous and creative development of AAV vectors provides opportunities to overcome existing challenges in retinal gene therapy such as efficient transfer of genes exceeding AAV’s cargo capacity, or the targeting of specific cells within the retina or transduction of photoreceptors following routinely used intravitreal injections. Such developments should ultimately advance the treatment of a wide range of blinding retinal conditions.

Source: Gene therapy

 

 

Gene supplementation therapy for recessive forms of inherited retinal dystrophies.

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Over the last decade, gene supplementation therapy for inherited retinal degeneration has come of age. Early proof-of-concept studies in animal models of disease showed modest, but genuine improvements in retinal function and/or survival. Further development of the vectors used for gene transfer to the retina has led to better treatment efficacy in a wide variety of animal models, leading in 2008 to the initiation of three clinical trials for Leber congenital amaurosis caused by retinal pigment epithelium 65 deficiency. The results from these trials suggest that the treatment of inherited retinal dystrophy by gene therapy can be safe and effective. Here, we examine the progress of gene supplementation therapy in the retina, and discuss the potential for using gene therapy to treat different forms of inherited retinal degeneration.

Source: Gene therapy

 

Ocular gene delivery using lentiviral vectors

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Substantial advances in our understanding of lentivirus lifecycles and their various constituent proteins have permitted the bioengineering of lentiviral vectors now considered safe enough for clinical trials for both lethal and non-lethal diseases. They possess distinct properties that make them particularly suitable for gene delivery in ophthalmic diseases, including high expression, consistent targeting of various post-mitotic ocular cells in vivo and a paucity of associated intraocular inflammation, all contributing to their ability to mediate efficient and stable intraocular gene transfer. In this review, the intraocular tropisms and therapeutic applications of both primate and non-primate lentiviral vectors, and how the unique features of the eye influence these, are discussed. The feasibility of therapeutic targeting using these vectors in animal models of both anterior and posterior ophthalmic disorders has been established, and has, in combination with substantial progress in enhancing lentiviral vector bio-safety over the past two decades, paved the way for the first human ophthalmic clinical trials using lentivirus-based gene transfer vectors.

Source: Gene therapy

 

Gene therapy for retinal ganglion cell neuroprotection in glaucoma.

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Glaucoma is the leading cause of irreversible blindness worldwide. The primary cause of glaucoma is not known, but several risk factors have been identified, including elevated intraocular pressure and age. Loss of vision in glaucoma is caused by the death of retinal ganglion cells (RGCs), the neurons that convey visual information from the retina to the brain. Therapeutic strategies aimed at delaying or halting RGC loss, known as neuroprotection, would be valuable to save vision in glaucoma. In this review, we discuss the significant progress that has been made in the use of gene therapy to understand mechanisms underlying RGC degeneration and to promote the survival of these neurons in experimental models of optic nerve injury.

Source: Gene therapy

 

 

Gene therapy for retinal ganglion cell neuroprotection in glaucoma .

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Glaucoma is the leading cause of irreversible blindness worldwide. The primary cause of glaucoma is not known, but several risk factors have been identified, including elevated intraocular pressure and age. Loss of vision in glaucoma is caused by the death of retinal ganglion cells (RGCs), the neurons that convey visual information from the retina to the brain. Therapeutic strategies aimed at delaying or halting RGC loss, known as neuroprotection, would be valuable to save vision in glaucoma. In this review, we discuss the significant progress that has been made in the use of gene therapy to understand mechanisms underlying RGC degeneration and to promote the survival of these neurons in experimental models of optic nerve injury.

Source: Gene therapy

 

 

 

Gene transfer for ocular neovascularization and macular edema.

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Diseases complicated by abnormal growth of vessels or excessive leakage are the most prevalent cause of moderate or severe vision loss in developed countries. Recent progress unraveling the molecular pathogenesis of several of these disease processes has led to new drug therapies that have provided major benefits to patients. However, those treatments often require frequent intraocular injections, and despite monthly injections, some patients have a suboptimal response. Gene transfer of antiangiogenic proteins is an alternative approach that has the potential to provide long-term suppression of neovascularization (NV) and/or excessive vascular leakage in the eye. Studies in animal models of ocular NV have demonstrated impressive results with a number of transgenes, and a clinical trial in patients with advanced neovascular age-related macular degeneration has provided proof-of-concept. Two ongoing clinical trials, one using an adeno-associated viral (AAV) vector to express a vascular endothelial growth factor-binding protein and another using a lentiviral vector to express endostatin and angiostatin, will provide valuable information that should help to inform future trials and provide a foundation on which to build.

Source: Gene therapy

 

U-Shaped Association Between Potassium Level and Acute-MI Mortality.

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Hypokalemia was associated with increased mortality, but so were serum potassium levels 4.5 mEq/L, suggesting that repletion measures should be moderated.

On the basis of small studies with surrogate outcomes, current practice guidelines for managing ST-elevation myocardial infarction (STEMI) recommend maintaining a potassium level greater than 4.0 mEq/L. To explore the association of potassium levels with mortality, investigators used the Cerner Health Facts database to conduct a retrospective cohort study involving 38,689 patients with biomarker-confirmed acute MI and one or more serum potassium level measurements during hospitalization (mean number of measurements, 5.9). Mean admission potassium level was 4.2 mEq/L, and levels remained fairly constant during hospitalization.

In-hospital mortality was 6.9%. Mortality was lowest (4.8%) in patients with postadmission potassium levels of 3.5 to <4.0 mEq/L and similar (5.0%) in patients with postadmission potassium levels of 4.0 to <4.5 mEq/L. However, in-hospital mortality was twice that rate (10%) in patients with postadmission potassium levels of 4.5 to <5.0 mEq/L and continued to rise with higher potassium levels. In-hospital mortality was also significantly increased (13%) at potassium levels less than 3.5 mEq/L. The U-shaped association persisted after multivariable adjustment and did not differ between patients who received potassium supplementation during hospitalization and those who did not. In-hospital ventricular fibrillation or cardiac arrest occurred in 1707 patients (4.4%); rates of these events were relatively flat across a wide range of potassium levels and were substantively increased only in patients with the lowest or highest mean potassium levels (<3 or 5.0 mEq/L).

Comment: These findings confirm that hypokalemia is associated with worse outcome in patients with acute myocardial infarction; moreover, they reveal a similar adverse effect of hyperkalemia. As editorialists note, the fact that mortality was not affected by potassium supplementation suggests that potassium level may be a marker of severity of illness or of other underlying conditions. Nonetheless, a serum potassium target somewhat lower and narrower than that currently recommended for these patients seems reasonable.

Source:Journal Watch Cardiology .

Oral HPV Infection Is Common.

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Such infection — associated with a form of oropharyngeal squamous cell carcinoma — is present in 6.9% of the U.S. population aged 14 to 69.

Although the incidence of oropharyngeal squamous cell carcinomas linked to alcohol and tobacco use has been declining in the U.S., the incidence of such cancers linked to human papillomavirus (HPV) — primarily HPV type 16 — is increasing. Now, researchers have reported the results of the first population-based study of oral HPV prevalence in the U.S.

As part of the U.S. National Health and Nutrition Examination Survey performed in 2009 and 2010, individuals aged 14 to 69 were questioned about their sexual behaviors. They were also asked to perform a 30-second oral rinse to provide samples for HPV DNA polymerase chain reaction and type-specific hybridization.

Among 5501 participants, the prevalence of oral HPV infection was 6.9% overall (3.7% for high-risk HPV types, 1.0% for HPV-16). Prevalence showed a bimodal pattern by age, with a small peak for individuals aged 30 to 34 and a larger peak for those aged 60 to 64. The rate was higher for men than for women (10.1% vs. 3.6%; P<0.001), and for participants who reported ever having had sex than for those who reported having had no sexual activity (7.5% vs. 0.9%; P<0.001). In multivariate analyses, risk for oral HPV infection was associated with age, gender, lifetime number of sexual partners, and current smoking (including intensity).

Comment: No studies have assessed HPV vaccine efficacy against oral HPV infection. The present findings support the need for such trials and suggest the possibility of particular benefit for men.

Source: Journal Watch Infectious Diseases

A Common Y-Chromosome Variant May Explain Increased CVD Risk in Men.

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Common European variants of the Y chromosome seem linked to inflammatory responses — and thus to cardiovascular risk — according to research published in the Lancet.

Investigators examined Y chromosomes in two groups of subjects. In the first group, chromosomal markers were compared between men with confirmed coronary disease and healthy controls. They found a common variant called haplogroup I to be significantly more common in men with coronary disease.

The second group included men at high risk for coronary disease. Those who suffered a coronary event were compared with those who did not. Again, haplogroup I was significantly more common among those suffering an event. In addition, traditional coronary risk factors did not differ between cases and controls.

The authors conclude that the presence of haplogroup I increased coronary risk by 50%.

An analysis of macrophage RNA transcripts showed differences related to inflammatory response, which seemed exaggerated in those with haplogroup I.

Sorce:Lancet