TSRI scientists develop first drug candidate that neutralizes disease-causing RNA repeats

Top, Venn diagram of substructures in compounds that were found to bind to RNA from the fluorescence screening assay showed in Fig. 1c. Data were compiled by using compounds that had a P value of <0.001 for binding to the RNA hairpins. Bottom, structures of compounds 1 and 2 that were the most avid for binding to AUAU and AAUU RNA hairpins.

In an important new study with implications for the treatment of dozens of incurable diseases, scientists from the Florida campus of The Scripps Research Institute (TSRI) have for the first time created a drug candidate that attacks and neutralizes the RNA structure that causes an incurable progressive, inherited disease involving a gradual loss of control over body movement.

The study, which was published June 1, 2016 in Nature Communications, showed the compound significantly improved several aspects of cells taken directly from patients with spinocerebellar ataxia type 10 (SCA10), a form of spinocerebellar ataxia.

“More than 30 diseases, all of them incurable, are caused by RNA repeats,” said TSRI Professor Matthew Disney, who led the study. “By a thorough basic science investigation, we identified small molecules that target RNA base pairs precisely. We then leveraged this information to design the first drug candidate that binds to disease-causing defects in SCA10. Application of the drug candidate returns certain aspects of those cells to healthy levels—it’s like the defect is not even there.”

SCA10 is caused by what is called a pentanucleotide repeat (a genetic sequence of five nucleotides repeated many more times than normal) affecting the mitochondria, the cell’s energy source. The new drug candidate, known as 2AU-2, targets these repeats by binding to RNA base pairs.

“The potent bioactivity of 2AU-2 to moderate the structurally induced toxicity in SCA10 strongly suggests that base-pair-targeting RNA modules could have broad applicability in our effort to develop other compounds that target different RNAs,” said TSRI Research Associate Wang-Yong Yang, the first author of the study. “More than 70 percent of RNA secondary structure is made up of base pairing.”

The Disney group has developed new tools to identify optimal interactions between RNA structures and drug candidates targeting them. A database of these interactions has already been used to design several small molecule drug candidates.

“We are in the process of developing tools that allow one to design small molecules to target any RNA structural motif in a complex cellular environment. That environment can contain millions of other RNAs. In this study, Wang-Yong has done an exceptional job tackling this previously-thought-to-be-impossible molecular recognition problem,” Disney said.

Pathogenic RNA repeats contribute to disorders including Huntington’s disease, fragile X-associated tremor ataxia syndrome and myotonic dystrophy type 1 and 2.

Ref : http://www.nature.com/ncomms/2016/160601/ncomms11647/full/ncomms11647.html

FDA Approves Odefsey (emtricitabine, rilpivirine and tenofovir alafenamide) for the Treatment of HIV-1 Infection

Gilead Sciences, Inc announced that the U.S. Food and Drug Administration (FDA) has approved Odefsey (emtricitabine 200 mg/rilpivirine 25 mg/tenofovir alafenamide 25 mg or R/F/TAF) for the treatment of HIV-1 infection in certain patients. Emtricitabine and tenofovir alafenamide are from Gilead Sciences and rilpivirine is from Janssen Sciences Ireland UC, one of the Janssen Pharmaceutical Companies of Johnson & Johnson (Janssen). Odefsey is Gilead’s second TAF-based regimen to receive FDA approval and represents the smallest pill of any single tablet regimen for the treatment of HIV.

Emtricitabine  Rilpivirine  Tenofovir alafenamide

Odefsey is indicated as a complete regimen for the treatment of HIV-1 infection in patients 12 years of age and older who have no antiretroviral treatment history and HIV-1 RNA levels less than or equal to 100,000 copies per mL. Odefsey is also indicated as replacement for a stable antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) for at least six months with no history of treatment failure and no known substitutions associated with resistance to the individual components of Odefsey. No dosage adjustment of Odefsey is required in patients with estimated creatinine clearance greater than or equal to 30 mL per minute.

Odefsey has a boxed warning in its product label regarding the risks of lactic acidosis/severe hepatomegaly with steatosis, and post treatment acute exacerbation of hepatitis B.

TAF is a novel targeted prodrug of tenofovir that has demonstrated high antiviral efficacy similar to and at a dose less than one-tenth that of Gilead’s Viread (tenofovir disoproxil fumarate, TDF). TAF has also demonstrated improvement in surrogate laboratory markers of renal and bone safety as compared to TDF in clinical trials in combination with other antiretroviral agents. Data show that because TAF enters cells, including HIV-infected cells, more efficiently than TDF, it can be given at a much lower dose and there is 90 percent less tenofovir in the bloodstream.

FDA Approves Odefsey (emtricitabine, rilpivirine and tenofovir alafenamide) for the Treatment of HIV-1 Infection

EC approves expanded use of Daklinza (daclatasvir) for patients with chronic HCV and HIV co-infection

Daclatasvir formerly BMS-790052, trade name Daklinza) is a drug for the treatment of hepatitis C (HCV). It was developed by Bristol-Myers Squibb and was approved in Europe on 22 August 2014. Daklinza gained its FDA approval on July 24, 2015 in the United States; it is approved for Hepatitis C genotype 3 infections.  

A generic version of daclatasvir is expected to be approved in India before the end of 2015. 

Daclatasvir inhibits the HCV nonstructural protein NS5A.  Recent research suggests that it targets two steps of the viral replication process, enabling rapid decline of HCV RNA. Daclatasvir has been tested in combination regimens with pegylated interferon and ribavirin,  as well as with other direct-acting antiviral agents including asunaprevir and sofosbuvir....

Now....

EC approves expanded use of Daklinza (daclatasvir) for patients with chronic HCV and HIV co-infection: Bristol-Myers Squibb today announced that the European Commission has approved the expanded use of Daklinza, a first-in-class oral, once-a-day pill used in combination with other treatments as an option for adult patients with chronic hepatitis C virus infection who are co-infected with HIV or who have had a prior liver transplant.

Cancer drug can neutralize toxic RNA that causes myotonic dystrophy

A group of researchers has shown for the first time in cells and in a mouse model that a drug used to treat cancer can neutralize the toxic RNA that causes the prolonged muscle contractions and other symptoms of myotonic dystrophy type 1, the most common form of adult-onset muscular dystrophy. The researchers report their findings today Dec. 10, 2015 in the journal Cell Reports. (actinomycin-D)

"This finding opens a new avenue for a therapeutic strategy for this disease," said Andrew Berglund, Ph.D., a professor of biochemistry and molecular biology in the University of Florida College of Medicine. "This is the first evidence that specifically inhibiting transcription can be effective in knocking down the toxic material that causes the disease."

In myotonic dystrophy and other related neurological disorders, the symptoms stem from repeated individual nucleotides, or "building blocks," in the RNA in muscle tissue cells that can build up over time. These repeats, called CTG expansions in myotonic dystrophy type 1, become 'toxic' when transcribed from DNA. The expansions disrupt the RNA binding proteins responsible for splicing, the 'editing' needed so that the RNA can create appropriate proteins that allow muscles to function properly.

Cancer drug can neutralize toxic RNA that causes myotonic dystrophy

Investigational antiviral drug effectively treats Lassa virus infection in guinea pigs

We know that, Favipiravir, also known as T-705 or Avigan, is an experimental antiviral drug being developed by Toyama Chemical of Japan with activity against many RNA viruses. Like some other experimental antiviral drugs (T-1105 and T-1106), it is a pyrazinecarboxamide derivative. Favipiravir is active against influenza viruses, West Nile virus, yellow fever virus, foot-and-mouth disease virus as well as other flaviviruses, arenaviruses, bunyaviruses and alphaviruses.[1Activity against enteroviruses and Rift Valley fever virus has also been demonstrated.

The mechanism of its actions is thought to be related to the selective inhibition of viral RNA-dependent RNA polymerase.[4] Favipiravir does not inhibit RNA or DNA synthesis in mammalian cells and is not toxic to them.[1]

In 2014, favipiravir was approved in Japan for stockpiling against influenza pandemics

Favipiravir, an investigational antiviral drug currently being tested in West Africa as a treatment for Ebola virus disease, effectively treated Lassa virus infection in guinea pigs, according to a new study from National Institutes of Health (NIH) scientists and colleagues. Lassa fever is endemic to West Africa and affects about 300,000 people annually, killing roughly 5,000. In some parts of Sierra Leone and Liberia, it is believed nearly 15 percent of people admitted to hospitals have Lassa fever, according to the Centers for Disease Control and Prevention. No vaccine or licensed treatment exists for Lassa fever, although ribavirin, licensed for hepatitis C treatment, has been used with limited success. In the new study, published Oct. 12, 2015, in Scientific Reports, favipiravir not only effectively treated guinea pigs infected with Lassa virus, it also worked better than ribavirin.

Two days after infecting groups of guinea pigs with a lethal dose of Lassa virus, the scientists treated the rodents daily for two weeks with either ribavirin, low doses of favipiravir, or high doses of favipiravir. They also evaluated the effect of high-dose favipiravir in the rodents that began treatment five, seven or nine days after infection. All of the animals that received high-dose favipiravir were completely protected from lethal infection; animals treated seven or nine days after infection had begun showing signs of disease, but their conditions quickly improved when treatment began. Those animals in the low-dose favipiravir group showed mild to moderate signs of disease, but those symptoms resolved after about one week of treatment. The animals treated with ribavirin appeared normal during the treatment phase but developed severe disease shortly after treatment ended.

Investigational antiviral drug effectively treats Lassa virus infection in guinea pigs

Antiviral agent protects rhesus monkeys from deadly Ebola virus

Rhesus monkeys were completely protected from the deadly Ebola virus when treated three days after infection with a compound that blocks the virus's ability to replicate. These encouraging preclinical results suggest the compound, known as GS-5734, should be further developed as a potential treatment, according to research findings to be presented tomorrow at the IDWeek conference.

Travis Warren, Ph.D., a principal investigator at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), said the work is a result of the continuing collaboration between USAMRIID and Gilead Sciences of Foster City, Calif. Scientists at the Centers for Disease Control and Prevention (CDC) also contributed by performing initial screening of the Gilead Sciences compound library to find molecules with promising antiviral activity.

The initial work identified the precursor to GS-5734, a small-molecule antiviral agent, which led to the effort by Gilead and USAMRIID to further refine, develop and evaluate the compound. Led by USAMRIID Science Director Sina Bavari, Ph.D., the research team used cell culture and animal models to assess the compound's efficacy against several pathogens, including Ebola virus.

In animal studies, treatment initiated on day 3 post-infection with Ebola virus resulted in 100 percent survival of the monkeys. They also exhibited a substantial reduction in viral load and a marked decrease in the physical signs of disease, including internal bleeding and tissue damage.

"The compound, which is a novel nucleotide analog prodrug, works by blocking the viral RNA replication process," said Warren. "If the virus can't make copies of itself, the body's immune system has time to take over and fight off the infection."

In cell culture studies, GS-5734 was active against a broad spectrum of viral pathogens. These included Lassa virus, Middle East Respiratory Syndrome (MERS) virus, Marburg virus, and multiple variants of Ebola virus, including the Makona strain causing the most recent outbreak in West Africa.

Ref : https://idsa.confex.com/idsa/2015/webprogram/Paper54208.html

Antiviral agent protects rhesus monkeys from deadly Ebola virus

Xuriden (uridine triacetate) now approved for patients with hereditary orotic aciduria

The U.S. Food and Drug Administration approved Xuriden (uridine triacetate), the first FDA-approved treatment for patients with hereditary orotic aciduria. Hereditary orotic aciduria is a rare metabolic disorder, which has been reported in approximately 20 patients worldwide.

Hereditary orotic aciduria is inherited from a recessive gene. The disease is due to a defective or deficient enzyme, which results in the body being unable to normally synthesize uridine, a necessary component of ribonucleic acid (RNA). Signs and symptoms of the disease include blood abnormalities (anemia, decreased white blood cell count, decreased neutrophil count), urinary tract obstruction due to the formation of orotic acid crystals in the urinary tract, failure to thrive, and developmental delays.

"Today's approval and rare pediatric disease priority review voucher underscore the FDA's commitment to making treatments available to patients with rare diseases," said Amy G. Egan, M.D., M.P.H., deputy director of the Office of Drug Evaluation III in the FDA's Center for Drug Evaluation and Research (CDER). "Prior to Xuriden's approval, patients with this rare disorder had no approved treatment options."

The FDA granted Xuriden orphan drug designation because it treats a rare disease. Orphan drug designation provides financial incentives, like clinical trial tax credits, user fee waivers, and eligibility for market exclusivity to promote rare disease drug development. Xuriden was also granted priority review. An FDA priority review provides for an expedited review of drugs for serious diseases or conditions that may offer major advances in treatment. The manufacturer of Xuriden was granted a rare pediatric disease priority review voucher – a provision that encourages development of new drugs and biologics for the prevention and treatment of rare pediatric diseases.

Xuriden is an orally administered product intended to replace uridine. Xuriden is approved as oral granules that can be mixed with food or in milk or infant formula, and is administered once daily.

The safety and effectiveness of Xuriden were evaluated in a single arm, six-week, open-label trial in four patients with hereditary orotic aciduria, ranging in age from three to 19 years of age, and in a six-month extension phase of the trial. The study assessed changes in the patients' pre-specified hematologic parameters during the trial period. At both the six-week and six-month assessments, Xuriden treatment resulted in stability of the hematologic parameters in all four clinical trial patients. The safety and effectiveness of uridine replacement therapy were further supported by case reports from the published literature.

Xuriden (uridine triacetate) now approved for patients with hereditary orotic aciduria

Novel molecule inhibits cancer-causing transcription factors

A novel molecule designed by scientists at the University of Massachusetts Medical School and the University of Virginia inhibits progression of a hard-to-treat form of recurring acute myeloid leukemia (AML) in patient tissue. The small molecule is one of the first designed to specifically target a cancer-causing transcription factor. Previously thought to be an undruggable target, this strategy may be used to design other novel molecules that can specifically inhibit cancer-causing transcription factors. Details of the work were published in Science.

Transcription factors are single- or multi-protein complexes that regulate transcription of DNA into messenger RNA and gene expression by binding to regions on the genome next to a gene. Mutations in transcription factors can result in altered gene expression programs that give way to new, cancer-causing functions. Although these aberrant transcription factors are promising targets for new therapeutics, the complexity of interrupting very specific protein-to-protein interactions has made it difficult to find small molecules or design drugs that treat these cancers.

"When we look at inhibitors, they usually target an enzyme or receptor. There aren't a lot of good examples of transcription factor inhibitors in clinical trials," said Lucio H. Castilla, PhD, associate professor of molecular, cell and cancer biology and co-leader of the study. "Here, we've used our extensive knowledge of a mutant transcription factor found in a subset for acute myeloid leukemia patients to design a molecule that can specifically sequester only the oncogenic mutant. This leaves the normal transcription factor to bind to the DNA and restore gene expression.".......

Ref : http://www.sciencemag.org/content/347/6223/779.abstract?sid=73b04258-783e-43e4-8e1d-09fe5eb7d331

Novel molecule inhibits cancer-causing transcription factors

RNA molecule can be manipulated to generate more neurons from neural stem cells

A research team at UC San Francisco has discovered an RNA molecule called Pnky that can be manipulated to increase the production of neurons from neural stem cells.

The research, led by neurosurgeon Daniel A. Lim, MD, PhD, and published on March 19, 2015 in Cell Stem Cell, has possible applications in regenerative medicine, including treatments of such disorders as Alzheimer's disease, Parkinson's disease and traumatic brain injury, and in cancer treatment.

Pnky is one of a number of newly discovered long noncoding RNAs (lncRNAs), which are stretches of 200 or more nucleotides in the human genome that do not code for proteins, yet seem to have a biological function.

The name, pronounced "Pinky," was inspired by the popular American cartoon series Pinky and the Brain. "Pnky is encoded near a gene called 'Brain,' so it sort of suggested itself to the students in my laboratory," said Lim. Pnky also appears only to be found in the brain, he noted.

Co-first authors Alex Ramos, PhD, and Rebecca Andersen, who are students in Lim's laboratory, first studied Pnky in neural stem cells found in mouse brains, and also identified the molecule in neural stem cells of the developing human brain. They found that when Pnky was removed from stem cells in a process called knockdown, neuron production increased three to four times.

"It is remarkable that when you take Pnky away, the stem cells produce many more neurons," said Lim, an assistant professor of neurological surgery and director of restorative surgery at UCSF. "These findings suggest that Pnky, and perhaps lncRNAs in general, could eventually have important applications in regenerative medicine and cancer treatment."

RNA molecule can be manipulated to generate more neurons from neural stem cells

Kinex Pharmaceuticals doses first actinic keratosis patient with KX2-391 ointment

Kinex Pharmaceuticals announced today that the first actinic keratosis patient has been dosed with KX2-391 ointment in Austin, Texas.

KX2-391 (KX01), a dual Src/pre-tubulin inhibitor, is a small molecule drug that has excellent skin penetration when formulated as a topical ointment. The pre-tubulin activity causes hyperproliferating cells to undergo apoptosis due to a disruption of the tubulin dynamics needed for these cells to pass through mitosis. Actinic Keratosis (AK) is a very common skin disease that appears as rough, dry, scaly patches or growths that form on the skin when the skin is badly damaged by ultraviolet rays from the sun or through indoor tanning. Ultraviolet rays can cause damage to DNA and RNA leading to keratinocyte mutations and uncontrolled growth. Reduction of the tumor suppressor p53 level has also been implicated in the unchecked proliferation of dysplastic keratinocytes. KX2-391 also potently increases p53 levels during unchecked proliferation thereby potentially addressing the dysregulation of p53 in AK.

Dr. Rudolf Kwan, Chief Medical Officer of Kinex Pharmaceuticals commented "Actinic Keratosis is a common dermatological problem with long term overexposure to the sun's ultraviolet light. If left untreated, AK can progress to squamous cell carcinoma, a type of skin cancer. Once a patient is afflicted with AK lesions, they tend to continue getting new AK lesions for life. We are hopeful to offer a new treatment option for these patients."

Kinex Pharmaceuticals doses first actinic keratosis patient with KX2-391 ointment

Isis Pharmaceuticals begins ISIS-DMPK Rx clinical study in DM1 patients

Isis Pharmaceuticals, Inc. (NASDAQ: ISIS) announced  that it has initiated a study for ISIS-DMPKRx in patients with Myotonic Dystrophy Type 1 (DM1). DM1 is a rare genetic neuromuscular disease caused by the production of toxic dystrophia myotonica-protein kinase (DMPK) RNA in cells. ISIS-DMPKRx is specifically designed to reduce toxic DMPK RNA.

"The Myotonic Dystrophy Foundation is pleased that Isis is advancing to the next phase of clinical trials for ISIS-DMPKRx," said Molly White, executive director of the Myotonic Dystrophy Foundation. "Myotonic Dystrophy, the most common form of muscular dystrophy, is a devastating disease with no therapeutic option. Myotonic dystrophy research has accelerated significantly in the last 10 years, helping bring about the innovative science behind ISIS-DMPKRx, a drug that specifically targets the genetic defect that causes myotonic dystrophy type 1. We applaud Isis for investing in and leading drug development efforts for myotonic dystrophy type 1, and we appreciate the commitment Isis Pharmaceuticals has made to improve the lives of patients in our community."

"We have an innovative and productive partnership with Biogen Idec in developing drugs to treat severe and rare diseases, like DM1. In just under two and a half years, we have been able to discover and complete early development on ISIS-DMPKRx, which includes completing a Phase 1 single ascending-dose study in healthy volunteers. Today we advance this program into patients," said B. Lynne Parshall, chief operating officer at Isis. "The speed at which we have advanced ISIS-DMPKRx highlights the productive and collaborative nature of our partnership."

Isis Pharmaceuticals begins ISIS-DMPK Rx clinical study in DM1 patients

Resveratrol in red wine inhibits formation of inflammatory factors that activate cardiovascular diseases

In continuation of my update on resveratrol 

A natural substance present in red wine, resveratrol, inhibits the formation of inflammatory factors that trigger cardiovascular diseases. This has been established by a research team at the Department of Pharmacology of the University Medical Center of Johannes Gutenberg University of Mainz (JGU) working in collaboration with researchers of the Friedrich Schiller University in Jena and the University of Vienna. Their results have recently been published in the scientific journal Nucleic Acids Research.

Despite the fact that they eat more fatty foods, the French tend to less frequently develop cardiac diseases than Germans. This so-called French Paradox is attributed to the higher consumption of red wine in France and it has already been the subject of various studies in the past. A number of research projects have actually demonstrated that the natural product resveratrol, present in red wine, has a protective effect against cardiovascular diseases. But what exactly is the reason for this? It seems that at least part of the protective effect can be explained by the fact that resveratrol inhibits the formation of inflammatory factors, a conclusion reached by the research team of Junior Professor Andrea Pautz and Professor Hartmut Kleinert of the Mainz University Medical Center following collaboration in a joint project with Professor Oliver Werz of the Friedrich Schiller University in Jena and Professor Verena Dirsch of the University of Vienna. In fact, the researchers discovered that the natural substance binds to the regulator protein KSRP and activates it. KSRP reduces the stability of messenger RNA (mRNA) in connection with a number of inflammatory mediators and thus inhibits their synthesis.

Resveratrol in red wine inhibits formation of inflammatory factors that activate cardiovascular diseases

Scientists devise powerful algorithm to improve effectiveness of research technology harnessing RNAi

In continuation of my update on RNAi

Scientists at Cold Spring Harbor Laboratory (CSHL) have devised a powerful algorithm that improves the effectiveness of an important research technology harnessing RNA interference, or RNAi.

Discovered in the late 1990s, RNAi is a naturally occurring biological mechanism in which short RNA molecules bind to and "interfere" with messages sent by genes that contain instructions for protein production. Such interference can prevent a gene from being expressed. In addition to helping regulate gene expression, the RNAi pathway in many species, including humans, acts to defend the genome from parasitic viruses and transposons.

Harnessed by scientists since the mid-2000s, RNAi has provided a way to artificially "knock down" the expression of specific genes. By preventing a gene or genes from being activated in a model organism such as a mouse, for instance, much can be learned by inference about gene function. RNAi-based technology also has been extremely useful as tool in drug discovery.

Scientists devise powerful algorithm to improve effectiveness of research technology harnessing RNAi

Study: RNAi silencing strategy blocks production of mutant huntingtin protein

In continuation of my update on RNAi

A targeted gene silencing strategy blocks production of the dysfunctional huntingtin (Htt) protein, the cause of Huntington's disease, a fatal, inherited neurodegenerative disorder. The effectiveness of this RNA interference (RNAi) approach in reducing levels of mutant Htt protein and disease symptoms in a mouse model of the disease is described in Human Gene Therapy, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. The article is available free on the Human Gene Therapy website.

Lisa Stanek and coauthors from Genzyme (Framingham, MA) used an adeno-associated viral (AAV) vector to deliver a targeted nucleic acid sequence called a small interfering RNA (siRNA) into the cells of affected mice. The siRNA selectively binds to the mutated gene, blocking disease-causing Htt production. The authors present data demonstrating the ability to deliver the therapeutic RNAi into the cells, reduce mutant Htt levels, and impact behavioral deficits in the mice without causing any noticeable neurotoxicity, in their article "Silencing Mutant Huntingtin by Adeno-Associated Virus-Mediated RNA Interference Ameliorates Disease Manifestations in the YAC128 Mouse Model of Huntington's Disease."

"The Genzyme group uses state-of-the-art delivery technology and a gene silencing approach to generate very promising preclinical data for Huntington's disease," says James M. Wilson, MD, PhD, Editor-in-Chief of Human Gene Therapy, and Director of the Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.

Study: RNAi silencing strategy blocks production of mutant huntingtin protein

Compound reverses symptoms of Alzheimer's disease in mice

"It reversed learning and memory deficits and brain inflammation in mice that are genetically engineered to model Alzheimer's disease," Farr said. "Our current findings suggest that the compound, which is called antisense oligonucleotide (OL-1), is a potential treatment for Alzheimer's disease."

Farr cautioned that the experiment was conducted in a mouse model. Like any drug, before an antisense compound could be tested in human clinical trials, toxicity tests need to be completed.

Antisense is a strand of molecules that bind to messenger RNA, launching a cascade of cellular events that turns off a certain gene.

In this case, OL-1 blocks the translation of RNA, which triggers a process that keeps excess amyloid beta protein from being produced. The specific antisense significantly decreased the over expression of a substance called amyloid beta protein precursor, which normalized the amount of amyloid beta protein in the body. Excess amyloid beta protein is believed to be partially responsible for the formation of plaque in
the brain of patients who have Alzheimer's disease.

Scientists tested OL-1 in a type of mouse that overexpresses a mutant form of the human amyloid beta precursor gene. Previously they had tested the substance in a mouse model that has a natural mutation causing it to overproduce mouse amyloid beta. Like people who have Alzheimer's disease, both types of mice have age-related impairments in learning and memory, elevated levels of amyloid beta protein that stay in the brain and increased inflammation and oxidative damage to the hippocampus  the part of the brain responsible for learning and memory.

"To be effective in humans, OL-1 would need to be effective at suppressing production of human amyloid beta protein," Farr said.

Scientists compared the mice that were genetically engineered to overproduce human amyloid beta protein with a wild strain, which served as the control. All of the wild strain received random antisense, while about half of the genetically engineered mice received random antisense and half received OL-1. 

The mice were given a series of tests designed to measure memory, learning and appropriate behavior, such as going through a maze, exploring an unfamiliar location and recognizing an object. 

Scientists found that learning and memory improved in the genetically engineered mice that received OL-1 compared to the genetically engineered mice that received random antisense. Learning and memory were the same among genetically engineered mice that received OL-1 and wild mice that received random antisense.

They also tested the effect of administering the drug through the central nervous system, so it crossed the blood brain barrier to enter the brain directly, and of giving it through a vein in the tail, so it circulated through the bloodstream in the body. They found where the drug was injected had little effect on learning and memory.

Ref http://iospress.metapress.com/content/px72758w0158103u/?issue=4&genre=article&spage=1005&issn=1387-2877&volume=40

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Compound
reverses symptoms of Alzheimer's disease in mice  

Scientists have found a potential cure for Ebola (Science Alert)

Ebola and related viruses cause hemorrhagic fever and death through organ failure, and can have a mortality rate of up to 90%, among the highest of any known human disease.  But researchers working in a high-contaminant biological laboratory maintained by USAMRIID at Fort Detrick in Maryland, US, may have found a potential cure.

The scientists have discovered a molecule, named BCX4430, (see structure) which looks a lot like the "A" that makes up DNA: adenosine. Adenosine is one of four base pairs in DNA, and is also used in the genomes of RNA-based viruses,  such as Ebola. But because BCX4430 looks so much like Adenosine, the scientists found that members of the Filoviridae virus family, such as Ebola, can accidentally use it as a building block when trying to grow inside our cells

  
In the study, the team gave Macaque monkeys effected with the deadly Marburg virus (a close relative to Ebola) two doses for BCX4430 a day  for 14 days.

The monkeys who weren't given any of the treatment were dead by day 12, whereas all but one monkey who was given BCX4430 survived, even if they only received treatment 48 hours after they were infected.

Luckily, only virus cells appear to be tricked into using BCX4430, and human and monkey cells do just fine with the molecule around. In vitro experiments
also suggest that BCX4430 could potentially be used against a wide range of
viruses, including SARS, influenza, measles and dengue.
It's too early to get excited just yet, with no human trials yet conducted. But the newly discovered molecule holds the greatest potential we've ever seen for curing these terrifying diseases.

http://www.nature.com/nature/journal/vaop/ncurrent/fig_tab/nature13027_F1.html

Scientists
have found a potential cure for Ebola (Science Alert)

Combined therapy could repair and prevent damage in Duchenne muscular dystrophy, study suggests

Results from a clinical trial of eteplirsen, {RNA, [P-deoxy-P-(dimethylamino)](2',3'-dideoxy-2',3'-imino-2',3'-seco)(2'a→5')(C-m5U-   C-C-A-A-C-A-m5U-C-A-A-G-G-A-A-G-A-m5U-G-G-C-A-m5U-m5U-m5U-C-m5U-A-G),    5'-[P-[4-[[2-[2-(2-hydroxyethoxy) ethoxy]ethoxy] carbonyl]-1-piperazinyl]-N,N-   dimethylphosphonamidate]}  a drug designed to treat Duchenne muscular dystrophy, suggest that the therapy allows participants to walk farther than people treated with placebo and dramatically increases production of a protein vital to muscle growth and health. The study, led by a team in The Research Institute at Nationwide Children's Hospital, is the first of its kind to show these results from an exon-skipping drug -- a class of therapeutics that allows cells to skip over missing parts of the gene and produce protein naturally....

Combined therapy could repair and prevent damage in Duchenne muscular dystrophy, study suggests

Ref http://onlinelibrary.wiley.com/doi/10.1002/ana.23982/abstract

Scripps Florida Scientists Devise New Way to Dramatically Raise RNA Treatment Potency

"We're trying to make tools that can target any RNA motif," said Matthew Disney, a TSRI associate professor who authored the research with a research associate in his lab, Lirui Guan. "This study completely validates our design -- it validates that our compound targets the desired RNA sequence in a complex cellular environment that contains many hundreds of thousands of RNAs."

While targeting DNA has been used as a therapeutic strategy against cancer, few similar approaches have been attempted for disease-associated RNAs.

In the new study, the scientists created a small molecule that binds to the genetic defect in RNA that causes myotonic dystrophy type 1 and improves associated defects in cell culture.

Myotonic dystrophy type 1 involves a type of RNA defect known as a "triplet repeat," a series of three nucleotides repeated more times than normal in an individual's genetic code. In this case, the repetition of the cytosine-uracil-guanine (CUG) in the RNA sequence leads to disease by binding to a particular protein, MBNL1, rendering it inactive and resulting in a number of protein-splicing abnormalities.

To achieve the increase in the drug candidate's potency, Disney and his colleagues attached a reactive molecule (a derivative of chlorambucil, (see structure below) a chemotherapy drug that has been used to treatment a form of leukemia) to the small molecule they had identified. As a result, the new compound not only binds to the target, it becomes a permanent part of the target -- as if it were super glued to it, Disney said. Once attached, it switches off the CUG defect and prevents the cell from turning it back on.

Disney was surprised at the approximately 2,500-fold improvement in potency with the new approach.

"I was shocked by the increase," he said. "This takes the potency into the realm where one would like to see if the compound were to have real therapeutic potential."

As a result, the new compound, known as 2H-4-CA, is the most potent compound known to date that improves DM1-associated splicing defects. Importantly, 2H-4-CA does not affect the alternative splicing of a transcript not regulated by MBNL1, demonstrating selectivity for the CUG repeat and suggesting that it might have minimal side effects. "We can now use this approach to attach reactive molecules to other RNA targeted small molecules," Disney said.

The reactive molecule model also provides a potentially general method to identify cellular targets of RNA-directed small molecules. Such probes could also identify unintended targets, information that could be used to design and identify compounds with improved selectivity in an approach similar to activity-based profiling, Disney said.

Scripps Florida Scientists Devise New Way to Dramatically Raise RNA Treatment Potency

The ribosome: New target for antiprion medicines

New research results from Uppsala University, Sweden, show that the key to treating neurodegenerative prion diseases such as mad cow disease and Creutzfeldt-Jakob disease may lie in the ribosome, the protein synthesis machinery of the cell. The results were recently published in the Journal of Biological Chemistry.

"We have now shown that the protein folding activity of the ribosome (PFAR) is most likely involved in prion propagation and thus, can be a specific target for antiprion medicines. If we understand the mechanism fully, we will be able to find ways to stop that too.," says Suparna Sanyal, senior lecturer at the Department of Cell and Molecular Biology, Uppsala University .

The ribosome is the protein synthesis machinery of the cell. The mechanism of protein synthesis by the ribosome is well characterized, while PFAR is a rather recent discovery. PFAR is a ribosomal RNA dependent function of the large subunit of the ribosome irrespective of its source. The PFAR center closely overlaps the peptidyl transferase center although the nucleobases responsible for these two functions are not all common.

"Our results show that two prion inhibitors 6-aminophenanthridine (left struct) and guanabenz acetate (right struct) implement antiprion activity by binding to ribosomal RNA and inhibiting PFAR. Thus, the ribosome and more specifically PFAR is the new target for antiprion medicines. Furthermore, we have developed an in vitro PFAR assay, which can be used as a platform for screening prion inhibitors in a high-throughput fashion. This assay is much more time and cost-effective than standard prion assays," says Suparna Sanyal....

 The ribosome: New target for antiprion medicines

 

Scientists Uncover How Grapefruits Provide a Secret Weapon in Medical Drug Delivery...

Lipids (right panel first three tubes) derived from grapefruit. GNVs can efficiently deliver a variety of therapeutic agents, including DNA, RNA (DIR-GNVs), proteins and anti-cancer drugs (GNVs-Drugs) as demonstrated in this study. University of Louisville researchers have uncovered how to create nanoparticles using natural lipids derived from grapefruit, and have discovered how to use them as drug delivery vehicles.

"These nanoparticles, which we've named grapefruit-derived nanovectors (GNVs), are derived from an edible plant, and we believe they are less toxic for patients, result in less biohazardous waste for the environment, and are much cheaper to produce at large scale than nanoparticles made from synthetic materials," Zhang said.

The researchers demonstrated that GNVs can transport various therapeutic agents, including anti-cancer drugs, DNA/RNA and proteins such as antibodies. Treatment of animals with GNVs seemed to cause less adverse effects than treatment with drugs encapsulated in synthetic lipids.

"Our GNVs can be modified to target specific cells -- we can use them like missiles to carry a variety of therapeutic agents for the purpose of destroying diseased cells," he said. "Furthermore, we can do this at an affordable price."

The therapeutic potential of grapefruit derived nanoparticles was further validated through a Phase 1 clinical trial for treatment of colon cancer patients. So far, researchers have observed no toxicity in the patients who orally took the anti-inflammatory agent curcumin encapsulated in grapefruit nanoparticles.

Ref : http://www.nature.com/ncomms/journal/v4/n5/full/ncomms2886.html