Targeting Epigenetics – Not Just Drugs for Cancer

Epigenetics is effectively the study of changes in gene function by covalent modifications. Such modifications result in a stably heritable phenotype that does not involve a change in DNA sequence. There are effectively 2 routes by which such covalent changes can be effected; first by methylation of C5 cytosine bases located 5’ to guanosines. This route is referred to as the cytosine methylation code. In addition, the histone component of chromosomes can be covalently modified at the N-terminus, the so-called histone code.

Epigenetics is effectively the study of changes in gene function by covalent modifications. Such modifications result in a stably heritable phenotype that does not involve a change in DNA sequence. There are effectively 2 routes by which such covalent changes can be effected; first by methylation of C5 cytosine bases located 5’ to guanosines. This route is referred to as the cytosine methylation code. In addition, the histone component of chromosomes can be covalently modified at the N-terminus, the so-called histone code.

Epigenetic modification has been the focus of a great deal of interest as targets for the development of anti-cancer drugs. Indeed, there has been some great progress in identifying compounds that can interfere with the epigenetic process and potentially with the disease itself. Such epigenetic approaches have unique properties in the search for novel cancer drugs, in that they can modulate properties of tumours that represent major obstacles in treatment that occur as a result of their adaptive properties, such as metastasis and angiogenesis, amongst others.

The major classes of compounds showing promise at the moment are the DNA methyltransferase (DNMT) inhibitors, histone deacetylase (HDAC) inhibitors and aurora kinase inhibitors, representatives of which have been through clinical trial and have been licensed by the FDA. There is a degree of current focus upon the development of 2nd generation drugs targeting the epigenetic process through enzymes that are capable of mediating restricted histone modification.

Although the epigenetic approach has been largely directed at the development of oncology drugs, there is growing interest in their use in other indications. Of particular interest is their use in CNS indications, diabetes and inflammatory disorders. In this issue of Drug Discovery Today Editor’s Choice, we have provided free downloads of some recent significant articles involved with epigenetics, drugs targeted against it and the use of compounds derived from this approach to the treatment of cancer and non-oncology indications. The first of the 3 downloads is: Epigenetic therapies for non-oncology indications by Jonathan D. Best and Nessa Carey and this article deals with the scope of potential epigenetic drugs in the treatment of a wide range of diseases. The authors highlight some of the issues around the  development of compounds for these indications, not least the availability of appropriate in vivo models.

Second in the series of our trio of downloads is the article by José L. Medina-Franco and Thomas Caulfield entitled, “Advances in the computational development of DNA methyltransferase inhibitors”. This review highlights the most up-to-date findings on the virtual screening of compounds and how computational approaches can interlink with other discovery efforts in the search for the optimal compound.

Source: Drug discovery today

An Overview of Creatine Supplements

In their quest to run farther, jump higher, and outlast the competition, many athletes have turned to a variety of performance-enhancing drugs and supplements. Creatine is the most popular of these substances, believed to enhance muscle mass and help athletes achieve bursts of strength.

Part of the reason for creatine’s popularity might be its accessibility. Creatine powder, tablets, energy bars, and drink mixes are available without a doctor’s prescription at drug stores, supermarkets, nutrition stores, and over the Internet.

Although creatine is a natural substance, it hasn’t been well-studied over the long-term. Researchers still aren’t sure what effects it might have on the body, particularly in young people, or how effective it might be.

Will Vitamins & Supplements Help You Reach Your Goals?

What Is Creatine?

Creatine is a natural substance that turns into creatine phosphate in the body. Creatine phosphate helps make a substance called adenosine triphosphate (ATP). ATP provides the energy for muscle contractions.

The body produces some of the creatine it uses. It also comes from protein-rich foods such as meat or fish.

How Is Creatine Used?

Back in the 1970s, scientists discovered that taking creatine in supplement form might enhance physical performance. In the 1990s, athletes started to catch on, and creatine became a popular sports supplement. According to studies, 8% of adolescents take creatine. The supplement is particularly popular among high school, college, and professional athletes, especially football and hockey players, wrestlers, and gymnasts. An estimated 40% of college athletes and up to half of professional athletes say they use creatine supplements.

Creatine is thought to improve strength, increase lean muscle mass, and help the muscles recover more quickly during exercise. This muscular boost may help athletes achieve bursts of speed and energy, especially during short bouts of high-intensity activities such as weight lifting or sprinting. However, scientific research on creatine has been mixed. Although some studies have found that it does help improve performance during short periods of athletic activity, there is no evidence that creatine helps with endurance sports. Research also shows that not everyone’s muscles respond to creatine; some people who use it see no benefit.

Despite the popularity of creatine among young people, there has been very little research conducted in children under age 18. Of those studies, a few have suggested a positive effect but the overall evidence is inconclusive. In one study, teenage swimmers performed better after taking creatine; in another study, it helped high school soccer players sprint, dribble, and jump more effectively.

Researchers are studying whether creatine might also be useful for treating certain health conditions caused by weakened muscles, including:

  • Heart failure and heart attack
  • Huntington’s disease
  • Neuromuscular disorders, including muscular dystrophy and amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease)

Creatine is also being studied as a way to lower cholesterol in people with abnormally high levels. Although early research has been promising, it’s too early to say for sure whether creatine is effective for any of these conditions.

How Safe Is Creatine?

Just because creatine is natural, doesn’t necessarily mean that it is safe. Supplements aren’t held to the same standards by the FDA as medications, which means you can’t always know exactly what’s in your supplement, or in what amounts.

Researchers still don’t know the long-term effects of taking creatine supplements, especially in young people. Adolescents who take creatine often do so without their doctor’s advice, which can cause them to take more than the recommended dose.

Although most healthy people can take it with no problem, creatine can, in rare cases, have adverse effects, particularly when used in excess. Side effects can include:

  • Weight gain
  • Anxiety
  • Breathing difficulty
  • Diarrhea
  • Fatigue
  • Fever
  • Headache
  • Kidney problems
  • Nausea, vomiting
  • Rash
  • Stomach upset

Certain drugs, including diabetes medications, acetaminophen, and diuretics, can have dangerous interactions with creatine. Taking the stimulants caffeine and ephedra with creatine can increase the risk of side effects.

Creatine isn’t recommended for people with kidney or liver disease, or diabetes. Others who should avoid taking it are children under age 18 and women who are pregnant or nursing. Also don’t use creatine if you are taking any medication or supplement that could affect your blood sugar, because creatine may also affect blood sugar levels.

If you do take creatine, drink enough water to prevent dehydration.

No matter how healthy you are, let your doctor know before you take creatine or any other supplement.

source: webMD

FDA Approves New Device for Treatment of Brain Aneurysms

The FDA approved yesterday a new device for treating large brain aneurysms without invasive surgery. The Pipeline Embolization Device — a platinum and nickel-cobalt mesh tube that is threaded up to the brain through a leg artery — works by cutting blood flow to the aneurysm, reducing the chance of rupture.

Approval was based on a study of 108 patients between ages 21 and 75. One year after the device was implanted, 70% of aneurysms remained blocked off without stenosis of the artery.

Source: FDA press release


Progesterone Gel Lowers Risk for Preterm Birth in Women with a Short Cervix

In women with a short cervix during the second trimester of pregnancy, use of a vaginal progesterone gel essentially halves the risk for preterm birth, according to an NIH- and industry-funded study published in Ultrasound in Obstetrics & Gynecology.

Some 450 asymptomatic women with a cervix length between 10 and 20 mm at roughly 19 to 24 weeks’ gestation were randomized to use a vaginal progesterone gel or placebo daily until 37 weeks’ gestation, rupture of the membranes, or delivery. Women using progesterone were significantly less likely than those using placebo to deliver before 33 weeks (9% vs. 16%), as well as before 28 weeks (5% vs. 10%).

In addition, neonatal morbidity and mortality were lower with progesterone. Treatment side effects did not differ between the groups.

The authors calculate that 14 women with a short cervix would need to be treated to prevent one preterm birth.

Source: Ultrasound in Obstetrics & Gynecology article


Improved antibiotic-free plasmid vector design by incorporation of transient expression enhancers

Methods to improve plasmid-mediated transgene expression are needed for gene medicine and gene vaccination applications. To maintain a low risk of insertional mutagenesis-mediated gene activation, expression-augmenting sequences would ideally function to improve transgene expression from transiently transfected intact plasmid, but not from spurious genomically integrated vectors. We report herein the development of potent minimal, antibiotic-free, high-manufacturing-yield mammalian expression vectors incorporating rationally designed additive combinations of expression enhancers. The SV40 72 bp enhancer incorporated upstream of the cytomegalovirus (CMV) enhancer selectively improved extrachromosomal transgene expression. The human T-lymphotropic virus type I (HTLV-I) R region, incorporated downstream of the CMV promoter, dramatically increased mRNA translation efficiency, but not overall mRNA levels, after transient transfection. A similar mRNA translation efficiency increase was observed with plasmid vectors incorporating and expressing the protein kinase R-inhibiting adenoviral viral associated (VA)1 RNA. Strikingly, HTLV-I R and VA1 did not increase transgene expression or mRNA translation efficiency from plasmid DNA after genomic integration. The vector platform, when combined with electroporation delivery, further increased transgene expression and improved HIV-1 gp120 DNA vaccine-induced neutralizing antibody titers in rabbits. These antibiotic-free vectors incorporating transient expression enhancers are safer, more potent alternatives to improve transgene expression for DNA therapy or vaccination.

source: nature gene therapy

Down-modulation of cancer targets using locked nucleic acid (LNA)-based antisense oligonucleotides without transfection

Usually, small interfering RNAs and most antisense molecules need mechanical or chemical delivery methods to down-modulate the targeted mRNA. However, these delivery approaches complicate the interpretations of biological consequences. We show that locked nucleic acid (LNA)-based antisense oligonucleotides (LNA–ONs) readily down-modulate genes of interest in multiple cell lines without any delivery means. The down-modulation of genes was quick, robust, long-lasting and specific followed by potent down-modulation of protein. The efficiency of the effect varied among the 30 tumor cell lines investigated. The most robust effects were found in those cells where nuclear localization of the LNA–ON was clearly observed. Importantly, without using any delivery agent, we demonstrated that HER3 mRNA and protein could be efficiently down-modulated in cells and a tumor xenograft model. These data provide a simple and efficient approach to identify potential drug targets and animal models. Further elucidation of the mechanism of cellular uptake and trafficking of LNA–ONs may enhance not only the therapeutic values of this platform but also antisense molecules in general.

source: nature gene therapy


Pivotal role of leptin-hypothalamus signaling in the etiology of diabetes uncovered by gene therapy: a new therapeutic intervention?

The incidence of diabetes mellitus has soared to epidemic proportion worldwide. The debilitating chronic hyperglycemia is caused by either lack of insulin as in diabetes type 1 or its ineffectiveness as in diabetes type 2. Frequent replacement of insulin with or without insulin analogs for optimum glycemic control are the conventional cumbersome therapies. Recent application of leptin gene transfer technology has uncovered the participation of adipocytes-derived leptin-dependent hypothalamic neural signaling in glucose homeostasis and demonstrated that a breakdown in this communication due to leptin insufficiency in the hypothalamus underlies the etiology of chronic hyperglycemia. Reinstatement of central leptin sufficiency by hyperleptinemia produced either by intravenous leptin infusion or a single systemic injection of recombinant adenovirus vector encoding leptin gene suppressed hyperglycemia and evoked euglycemia only transiently in rodent models of diabetes type 1. In contrast, stable restoration of leptin sufficiency, solely in the hypothalamus, with biologically active leptin transduced by an intracerebroventicular injection of recombinant adeno-associated virus vector encoding leptin gene (rAAV-lep) abolished hyperglycemia and imposed euglycemia through the extended duration of experiment by stimulating glucose disposal in the periphery in models of diabetes type 1. Further, similar hypothalamic leptin transgene expression abrogated chronic hyperglycemia and hyperinsulinemia, the predisposing risk factors of the age and environmentally acquired diabetes type 2, and instituted euglycemia by independently activating relays that stimulate glucose metabolism and repress hyperinsulinemia and improve insulin sensitivity in the periphery. Consequently, this durable antidiabetic efficacy of one time rAAV-lep neurotherapy offers a potential novel substitute for insulin therapy following preclinical trials in subhuman primates and humans.

source: nature gene therapy


Analysis Finds Self-Managed Anticoagulant Therapy Safe

Self-management of vitamin K antagonist therapy confers a lower risk for thromboembolism and no increase in major bleeding, according to an Annals of Internal Medicine meta-analysis.

Researchers examined data from 22 trials (mostly from Europe) that examined the outcome of patient self-management of anticoagulant therapy (consisting of vitamin K antagonists). Self-management involved either home-based measurement of prothrombin times and reporting results to a clinician, or measuring and then self-adjusting dosages to keep within a specified international normalized ratio. Controls received usual care.

The pooled results show no increase in risk for major bleeding with self-management and a 40% reduction in risk for major thromboembolism.

Source:Annals of Internal Medicine article


Long Work Hours Add to Coronary Disease Risk

In estimating patients’ risk for coronary heart disease, factoring in the length of their workday adds modestly, but significantly, to the sensitivity of their Framingham score, according to an Annals of Internal Medicine report.

Using a cohort of some 7000 British civil servants without apparent coronary disease at baseline, researchers gathered information to ascertain Framingham risk scores as well as the number of hours worked in a typical day. Follow-up lasted a median of 12 years. After adjustment for Framingham scores, participants working 11 or more hours per day had a 67% increased risk for coronary disease, compared with those working the normal 7 or 8 hours.

The authors caution that “further testing is needed to confirm the added value of information on long working hours for clinical decision making.”

Source: Annals of Internal Medicine article