Alternative Treatments for Diabetes

Never need insulin injections again!

A peptide synthesized by Israeli researchers provides a radically improved weapon against Type 1 diabetes, stopping it at its source.

Israeli drug maker Teva Pharmaceutical Industries and Clal Biotechnology Industries (CBI) have more than $40 million riding on an Israeli-innovated treatment for Type 1 diabetes now in advanced clinical trials in about 115 medical centers on five continents.

Teva owns the license and worldwide market rights to DiaPep277, a trademarked peptide first synthesized in 1994 by Prof. Irun Cohen at Israel’s Weizmann Institute of Science. This synthetic peptide – a chemical link extracted from a long protein chain – seems to halt the progression of this form of the disease, which used to be called “juvenile” diabetes.

Both Type 1 and Type 2 diabetes result from problems with insulin, a hormone produced by the pancreas to convert sugar, starches and other foods into energy for all the body’s functions. Type 1, accounting for about five percent of the estimated 220 million worldwide cases of diabetes, is caused by an abnormal immune response that kills the insulin-producing beta cells in the pancreas. Until now, nobody has found a way to address the root cause of this serious immune system foul-up, so patients must take daily injections of insulin.

“There have been many approaches to try to treat this disease, because it’s very complicated – partly genetic and partly environmental,” explains Shlomo Dagan, CEO of Andromeda Biotech, the Yavne-based company developing DiaPep277. “The immune system itself is very complicated and we still do not understand its full mechanism of action.”

DiaPep277 is derived from a human protein that modulates the immune system, says Dagan, who has a doctorate in immunology from Weizmann and formerly worked for several biotech companies in Israel and the United States.

Testing on four continents

Andromeda’s radically different approach to diabetes provides hope for children and adults at an early stage of Type 1 diabetes as well as people at high risk of developing it, or in whom the disease is progressing slowly. “The goal is preservation rather than treatment,” Dagan says. “If you still have some [insulin-producing] cells left functioning, we can preserve them with this substance.”

Diabetes patients aged 16 to 45 have been receiving DiaPep277 injections once every three months since 2005 in the first Phase III studies conducted at 40 medical centers in Europe, South Africa and Israel. The subjects are tested regularly over a two-year period to measure their ability to secrete insulin. This study will conclude in a few months.

Last year, Andromeda began the confirmatory Phase III trials concentrating on patients from ages 20 to 45 within six months of diagnosis. Dagan explains that two independent studies are necessary in order to win regulatory approval, and this second trial also will allow researchers to evaluate differences between results in teens and adults. The newer study is going on at hospitals in Israel, three Canadian provinces, many US states, and in Europe and Eastern Europe.

This is currently the largest and most advanced study ever involving Type 1 diabetes patients. Other potential treatments are far behind, in early stages of clinical development. “We are willing to continue with patients who want to try it for another two or three years,” says Dagan. The formal conclusion of the second study is targeted for early 2014.

The product is several years away from pharmacy shelves, but he expects that when it’s commercially available it would be administered the same way as in the testing period, once every three months by injection.

Betting on DiaPep277

Though Andromeda Biotech has fewer than 10 employees, the operation behind getting DiaPep277 into the marketplace involves hundreds of people, from the testing centers on up the ladder to CBI, which owns of 84% of the company it founded in 2007 to develop and commercialize the peptide. Teva holds the remaining 16% of Andromeda.

The advanced study’s steering committee is composed of doctors Itamar Raz, Hadassah Medical Center, Jerusalem; Paolo Pozzilli, Università Campus Bio-Medico di Roma, Rome; Thomas Linn, Universitätsklinikum Giessen, Germany; Francois Bonnici, New Groote Schuur Hospital, Capetown; and Philip Raskin, University of Texas Southwestern Medical Center at Dallas.

By Avigayil Kadesh
9/06/2011
Article Source

Researchers have overcome a major challenge to treating brain diseases by engineering an experimental molecular therapy that crosses the blood-brain barrier to reverse neurological lysosomal storage disease in mice.

Posted online in PNAS Early Edition on Feb. 4, the study was led by scientists at Cincinnati Children’s Hospital Medical Center. “This study provides a non-invasive procedure that targets the blood-brain barrier and delivers large-molecule therapeutic agents to treat neurological lysosomal storage disorders,” said Dao Pan, PhD, principal investigator on the study and researcher in the Cancer and Blood Diseases Institute at Cincinnati Children’s. “Our findings will allow the development of drugs that can be tested for other brain diseases like Parkinson’s and Alzheimer’s.” The scientists assembled the large molecular agents by merging part of a fatty protein called apolipoprotein E (apoE) with a therapeutic lysosomal enzyme called a-L-idurondase (IDUA). Naming the agents IDUAe1 and IDUAe2, researchers used them initially to treat laboratory cultured human cells of the disease mucopolysaccharidosis type I (MPS I). They also tested the agents on mouse models of MPS I.

MPS I is one of the most common lysosomal storage diseases to affect the central nervous system, which in severe form can become Hurler syndrome. In humans, patients can suffer from hydrocephalus, learning delays and other cognitive deficits. If not treated, many patients die by age 10. Lysosomes are part of a cell’s internal machinery, serving as a waste disposal system that helps rid cells of debris to retain normal function. In lysosomal storage diseases like MPS I, enzymes needed to dissolve debris are missing, allowing debris to build up in cells until they malfunction. In MPS I, cells lack the IDUA enzyme, allowing abnormal accumulation of a group of large molecules called glycosaminoglycans in the brain and other organs. Researchers in the current study used the new therapeutic procedure to deliver IDUA to brain cells. But first they had to successfully engineer the therapy to carry IDUA through the blood-brain barrier to diseased brain cells.

The blood-brain barrier is a physiological blockade that alters the permeability of tiny blood vessels called capillaries in the brain. Its purpose is to protect the brain by preventing certain drugs, pathogens and other foreign substances from entering brain tissues. The barrier has also been a persistent roadblock to treating brain disease with drugs. The scientists experimented with a set of derivative components of the fatty protein apoE, which binds to fat receptors on endothelial cells that form the inside surface of capillaries in the blood-brain barrier. They discovered that tagging some of the apoE components to the IDUA enzyme allowed the modified protein to attach to endothelial cells and cross through the cells to reach brain tissues.

Researchers injected experimental IDUAe1 into the tail veins of MPS I mouse models. The tests showed that – unlike currently available un-modified enzyme treatments – the modified enzyme penetrated the blood-brain barrier and entered brain neurons and astrocytes in a dose-dependent manner. The researchers also reported that brain cells in the treated mice exhibited normalized levels of the glycosaminoglycans and the lysosomal enzyme beta-hexosaminidase. With continued treatment through hematopoietic stem cell gene therapy, normalized levels persisted until the end of a five-month observation period, researchers said.

The scientists are continuing their preclinical studies to further verify the use of the experimental IDUA-based agents for treating MPS I, cautioning that results in laboratory mice may face additional challenges when translating to clinical application in humans. Researchers are also testing whether the large-molecule therapeutic procedure used in the current study can be leveraged to develop other neurotherapeutic agents that cross the blood-brain barrier. Also collaborating on the study was Roscoe O. Brady, MD, a researcher and scientist emeritus at the National Institute of Neurological Disorders and Stroke. Journal reference: Proceedings of the National Academy of Sciences search and more info website Provided by Cincinnati Children’s Hospital Medical Center search and more info website.

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Abstract

Osteoarthritis (OA) affects over 40 million people annually. We evaluated interleukin-1 receptor antagonist (IL-1ra) gene transfer in an equine model based on IL-1ra protein therapy which inhibits inflammation through blocking IL-1. Using the self-complementary adeno-associated virus (scAAV)IL-1ra equine gene as a starting construct, we optimized the transgene cassette by analyzing promoters (cytomegalovirus (CMV) versus chicken β-actin hybrid (CBh)), coding sequences (optimized versus unoptimized), vector capsid (serotype 2 versus chimeric capsid), and biological activity in vitro. AAV serotypes 2 and 2.5 CMV scAAVoptIL-1ra were tested in equine joints.

We evaluated two doses of scAAVIL-1ra, scAAVGFP, and saline. We developed a novel endoscopy procedure and confirmed vector-derived transgene expression (GFP) in chondrocytes 6 months post-injection. AAVIL-1ra therapeutic protein levels were 200–800 ng/ml of synovial fluid over 23 and 186 days, respectively. No evidence of intra-articular toxicity was detected and no vector genomes were found in contralateral joints based on GFP fluorescence microscopy and quantitative PCR. Finally, we assayed vector-derived IL-1ra activity based on functional assays which supported anti-inflammatory activity of our protein. These studies represent the first large animal intra-articular gene transfer approach with a therapeutic gene using scAAV and demonstrate high levels of protein production over extended time supporting further clinical investigation using scAAV gene therapy for OA.

Introduction

Osteoarthritis (OA) is a progressive and debilitating joint disease for which there is no cure. It affects over 40 million people annually and is responsible for tremendous financial burdens on health systems especially in societies with growing populations of elderly and obese individuals.1 Furthermore, the disease negatively affects younger, active individuals that participate in high demand sports and suffer from post-traumatic arthritis or overuse syndrome.2 The proinflammatory cytokine primarily responsible for many of the pathological features of OA is interleukin-1β (IL-1β).3 IL-1β has been found to be upregulated in synovial tissues and cartilage and a strong correlation has been consistently found with levels of IL-1β and osteoarthritic changes such as cartilage degeneration and presence of inflammation.1 Initially, treatment for OA consisted of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors, which reduced symptoms of pain and inflammation, caused by IL-1β but did not deter progression of OA.4,5 In addition, with prolonged use, these drugs can be associated with gastrointestinal disorders and cardiovascular ischemic events that can sometimes even lead to the demise of the patient.6

In the last two decades, researchers have sought to explore pharmaceuticals that can not only control symptoms of OA but also slow the progression and even prevent or stop degeneration of the joint thus bypassing the need of inevitable joint replacement. Although drugs such as hyaluronan and glucosamine/chondroitin sulfate have been somewhat disease modifying, they have not alleviated symptoms as effectively as originally forecasted.7,8,9,10,11 A logical target for blocking effects of IL-1β is the molecule IL-1 receptor antagonist (IL-1ra). This molecule is the natural inhibitor of IL-1β and competes with IL-1β for occupancy of the IL-1 cell surface receptors but cannot initiate cellular signals when bound to these receptors.3 Studies have revealed that the IL-1ra concentration is low in inflamed joints and a level of tenfold to 1,000-fold excess of IL-1ra over IL-1β is required to effectively block all of the available IL-1 receptors enough to inhibit joint degeneration.12,13,14 Autologous-conditioned serum, harvested from patient’s blood, is a biological treatment that has high levels of constitutive IL-1ra concentrations and has been met with varying degrees of success in both humans and horses suffering from OA.15,16 One reason may be that levels of IL-1ra protein are not high enough and not sustained for periods required to inhibit ongoing inflammation.16

Gene transfer using viral vectors to initiate therapeutic levels of IL-1ra or growth factors in joints is a promising approach and “proof of concept” in delivering therapeutic genes to joints by direct in vivo injection.17,18,19,20,21 Various viral vectors have been utilized for intra-articular gene therapy including adenovirus, retrovirus, lentivirus and adeno-associated virus (AAV).17,19,22,23 Adenoviral vectors have resulted in significant elevations of protein (IL-1ra, insulin-like growth factor-I) when injected intra-articularly; however, levels only remain elevated for 14–21 days and adenoviral vectors themselves can cause significant inflammation due to their immunogenic stimulation.17,18,24 Retroviral vectors have also significantly increased protein levels, however; these vectors do not efficiently transduce nondividing cells and therefore are less suited for joint tissues where cell turnover is low.22 Lentiviral vectors based on integration into the chromosome, offers the potential of long-term expression for OA; however, when injected into the knee joints of immunocompetent rats, the results demonstrate a sharp decrease in protein expression at ~20 days and therefore may not be the vector of choice for long-term protein production for direct intra-articular injections.23 AAV has been studied and validated to result in significant elevations in protein expression.19,25 Kay et al. compared single-stranded AAV to self-complementary AAV (scAAV) and reported a 25-fold greater transgene expression level for scAAV confirming that second strand DNA synthesis can be a major impediment to transduction efficiency in the joint.19 Furthermore, in Kay et al. scAAV not only resulted in dramatically increased transduction efficiency when compared with the single-stranded AAV but also did not reveal a difference in transduction between normal and inflamed articular environments suggesting that scAAV may be an appropriate vector in OA. Suitability of scAAV vectors intra-articularly was further confirmed in equine joints when transduction efficiency of AdGFP, rAAV, and scAAV were compared over a period of 8 weeks.26 Goodrich et al. compared scAAV serotypes in synoviocytes and chondrocytes in vitro and revealed the importance of serotype affinity in that significant differences existed in transduction efficiencies in both synoviocytes and chondrocytes which are the main cell types in joints.27 Serotype 6 was better in chondrocytes and serotype 3 in synoviocytes whereas serotype 2 was best in both chondrocytes and synoviocytes.27 This was also revealed by Sun et al. where various serotypes of scAAVFIX resulted in differing factor IX levels in the joints of mice.28

In addition to varying serotype efficiencies intra-articularly, various promoters may also change protein production.29 Few studies have been performed to investigate optimal use of promoters to enhance transgene expression intra-articularly but existing data suggest different promoters may play an important role in maximizing protein expression and variability exists with different promoters.30,31 Furthermore, optimization of transgene cassette often enhances therapeutic output of protein through favoring codon usage to exploit amino acyl-transfer RNA molecules that are most abundant in mammalian cells.29

Regardless of promising results seen in vitro, protein expression in cell culture may not always represent protein expression in vivo due to unforeseen immunity, transduction efficiency, and species differences. Since gene therapeutic vectors targeted for OA should produce protein levels for long periods of time (over 4 months), the objective of this study was to optimize variables of our scAAV vector such as promoter and transgene, first in vitro and then, using our optimized promoter and transgene, compare our two best scAAV serotypes in vivo to explore the application of scAAV gene therapy in an equine model.11,18,32 We hypothesized that we could optimize promoter and transgene in vitro and test this vector in vivo to determine efficacy of transgene production in the equine joint. This is the first study to report significant protein elevations for up to 6 months using scAAV in large animal (equine) joints.

Below is a new photo in front of our new RCT Clinic during our recent visit from Senator Claudia Pavlovich Arellano in Rocky Point. Accompanying us was also the Mayor of Puerto Panasco and other regional officials and clinic owners.

From the left to right in the picture are:

1. Mayor of Puerto Penasco: Prof. Gerardo Figueroa Zazueta
2. Business Associate: Luis Barrios
3. Technical Secretary of the Political Council in PRI Sonora: Lic. Roberto Sanchez Cereso
4. Mrs. Myriam Truesdell
5. RCT Clinic CEO: Hans Truesdell
6. Senator for the State of Sonora: Lic. Claudia Pavlovich Arellano
7. Mrs. Mireyda Castro
8. RCT Clinic Dr. Oscar Eduardo Castro Castro

By LESLIE H. LANG
UNC-CH School of Medicine

CHAPEL HILL — Injections of protein fragments prevented the development of type-I diabetes in a strain of mice prone to the disease, according to scientists at the University of North Carolina at Chapel Hill. The peptide injections also prevented progression to diabetes in mice on the verge of clinical disease.

The findings published Aug. 1 in the Journal of Immunology suggest for the first time that peptide-based immunotherapy may benefit people at risk of type-I diabetes. This form of diabetes is an autoimmune disease in which the body’s own immune T cells target and destroy insulin-producing beta cells in the pancreas.

“We’re taking fragments, or peptides, of GAD65, a protein produced by beta cells, and using them to divert the immune system,” said Dr. Roland Tisch, assistant professor of microbiology and immunology at the UNC-CH School of Medicine. Tisch has conducted pioneering diabetes immunotherapy research.

“Our work takes advantage of the highly specific recognition by the immune system of beta cells,” he said.

He noted that type-I diabetes is thought to involve an imbalance between two types of T cells: Th1 and Th2.

“Under normal physiological conditions, it’s thought there’s a functional balance between Th1s and Th2s, and that they regulate one another’s function and development,” he said. “But in type-I diabetes, there appears to be a skewing towards Th1 development. And that’s thought to be a contributing factor toward induction and progression of disease.”

The new study aimed to re-establish that functional balance between Th1 and Th2 in a strain of mice that spontaneously develop diabetes. In a series of experiments, non-obese diabetic (NOD) mice, 12 weeks old, were given injections of GAD65 peptides. The researchers hoped that some injections might prompt the immune system to produce Th2 cells.

“We were trying to immunize NOD mice under certain conditions to induce GAD65-specific Th2 cells, which in turn would suppress the activity of Th1 cells,” Tisch said.

The animals at the age studied were not overtly diabetic, but were poised to become diabetic.

“The pancreas was heavily inflamed, the autoimmune process was basically in full gear, the animals were just about to become overtly diabetic,” Tisch said. “So we were able to show that by immunizing NOD mice at this particular stage with a certain panel of GAD65 peptides, we could effectively induce Th2 cells and prevent further progression of disease. The animals do not develop overt diabetes.”

Why use peptides and not the whole protein? According to the UNC-CH researcher, several reasons apply. “It’s a relatively large protein and there’s always the possibility that you may induce a cross-reactive response with another protein expressed somewhere in the body, and elicit an unwanted immune response,” Tisch explained.

He added, “However, if you use peptides, and the peptides essentially consist of only 16 to 20 amino acids, you minimize that possibility of cross-reaction with other cell proteins. In addition, peptides are far easier to work with, they’re less costly to generate and can be stored quite easily relative to intact native proteins.”

The researcher emphasized that not any GAD65 peptide could induce the protective effect.

“Of a panel of five different peptides, only two were shown to mediate that effect,” he said.

That the non-obese diabetic mice studied already showed signs of significant autoimmunity has implications for clinical trials. In their journal report, Tisch and his co-authors conclude: “These findings may be of importance in designing prophylactic therapies for humans included in diabetes prevention trials, since such individuals are currently selected on the basis of having developed significant levels of beta cell autoimmunity.”

Co-authors of the report are UNC-CH postdoctoral researcher Dr. Bo Wang and Dr. David V. Serreze of the Jackson Laboratory in Bar Harbor, Maine. This study was funded by grants from the National Institute of Allergy and Infectious Diseases and the Juvenile Diabetes Foundation.

Source Article

2011 BioMed Research

- Abstract -

Background: Multiple myeloma (MM) is a B-cell malignancy that is largely incurable and is characterized by the accumulation of malignant plasma cells in the bone marrow. Apigenin, a common flavonoid, has been reported to suppress proliferation in a wide variety of solid tumors and hematological cancers; however its mechanism is not well understood and its effect on MM cells has not been determined.

Results: in this study, we investigated the effects of apigenin on MM cell lines and on primary MM cells. Cell viability assays demonstrated that apigenin exhibited cytotoxicity against both MM cell lines and primary MM cells, but not against normal peripheral blood mononuclear cells.

Together inase assays, immunoprecipitation and western blot analysis showed that apigenin inhibited CK2 kinase activity, decreased phosphorylation of Cdc37, disassociated the l~lsp9O/Cdc37/client complex and induced the degradation of multiple kinase clients, including R|Pi, Src, Raf-i, Cdl<4 and AKT.

By depleting these kinases, apigenin suppressed both constitutive and inducible activation of STAT3, ERK, AKT and NF-KB. The treatment also down regulated the expression of the antiapoptotic proteins Mcl—i, Bcl-2, Bcl-xL, XIAP and Survivin, which ultimately induced apoptosis in MM cells.

In addition, apigenin had a greater effects in depleting Hsp9O clients when used in combination with the Hsp9O inhibitor geldanamycin and the histone deacetylase inhibitor vorinostat.

Conclusions: Our results suggest that the primary mechanisms by which apigenin kill MM cells is by targeting the trinity of CK2—Cdc37-Hsp9O, and this observation reveals the therapeutic potential of apigenin in treating multiple myeloma.

Read the Entire 14 Page Multiple Myeloma Report

Download PDF Here

Published:  Monday, October 24^th, 2011
Download the complete Report Here.

In this publication we will give you a general overview of Neurotrophic Factors and the Neurophysiological Evaluation we applied.

Studies are being made for consistency and power analysis relating to events, this is a test that evaluates the answers or voltages generated by each region of the brain when performing a task or activity that requires cognitive effort.

The neurophysiological evaluation includes the following studies:

Electroencephalogram (EEG)

-Frequency analysis of EEG

- EEG coherence Analysis

-EVOKED POTENTIALS RELATED TO EVENTS INCLUDING P300

- Topographical visual Potential -

- Audio Potential for Long-Latency

- Coherence Analyses of related events

Next is a brief description of the different neurophysiological tests that can be applied to the patient.

P300: The P300 wave (P3) is a power related to a cognitive event obtained by an infrequent stimulus, relevant to a task. It is considered as a potential endogenous because its occurrence is due to the subject’s reaction to the stimulus and not the physical attributes of the stimulus. To be more specific, the P300 reflects processes involved in stimulus evaluation and categorization. A typical procedure is the oddball paradigm, in which a target stimulus (target or goal) occurs from more frequent background stimuli. A distractor stimulus can also be used to ensure that the response is due to the target in place rather than a change in the background pattern. We use an audio stimulus for the frequent and distracting stimuli. When recording using an electroencephalogram (EEG), this wave appears as a positive voltage deflection with latency (delay between stimulus and response) of about 300 to 600 ms. The presence, magnitude, topography and time of this signal are used to measure cognitive function.

ATTENTION (Contingent CPT): This test is a visual continuous performance task in which the answer depends on the appearance of two consecutive letters (S-T). Conditional execution tests have a long and rich history in the evaluation process trials (Rosvold, 1955). Certain parameters of this task, such as stimulus characteristics, number of trials and blocks and external triggers are controlled by the subject. In the continuous subject tested the patient is presented with random letters. The patient’s goal is to press a button on the mouse only when a specified letter appears to be used as a target.

MEMORY SPACE NOTICE: The test based on a visual spatial memory is a task that can be configured at various levels of difficulty. The number of location of the objects can be changed, the time between the presentation of the stimulus (simultaneously or sequentially) and the time between stimulus presentation and response. The visual memory test requires that the patient retains the location of the objects presented on the screen.

MENTAL FLEXIBILITY (CARDS): The card sorting test is inspired by the Wisconsin Card Sorting Test (Berg. 1948, D.A. Grant and Berg, 1948) which was designed to analyze the “abstract behavior” and “mental flexibility”. The test is sensitive to frontal lobe damage shown by the difficulty to classify according to a category (Drewe, 1974) and a non-specific brain damage, according to persistent errors (Robinson, 1980).

< DOWNLOAD the Complete Clinical Report HERE >

Peptide for Rheumatoid Arthritis

The painful inflammation and debilitating joint damage characteristic of rheumatoid arthritis may be reduced or prevented with a new approach using small-molecule enzyme mimetics, according to research published in the journal Arthritis & Rheumatism.

The preclinical study conducted by researchers at MetaPhore Pharmaceuticals, Inc.® and the University of Messina, Italy showed that a superoxide dismutase (SOD) mimetic, substantially reduced the erosion of cartilage and bone, and the chronic inflammation of rheumatoid arthritis in a standard animal model.

The SOD mimetic was also shown to markedly reduce elevated levels of two pro-inflammatory cytokines (immune regulating substances produced by immune cells). These are tumor necrosis factor alpha (TNF-á) and interleukin-1â (IL-1â), which are intricately involved in the development of arthritis in humans.

As part of the body’s oxidative chemistry, SOD enzymes regulate normal levels of superoxide. Certain disease states like rheumatoid arthritis, however, promote an overproduction of superoxide and the natural enzymes are overwhelmed. For example, excessive amounts of superoxide have been shown to contribute to inflammatory processes, inhibit certain disease fighting mechanisms, and affect mechanisms involved in regulating vascular pressure.

Rheumatoid arthritis, the most common chronic inflammatory disease, is an autoimmune disease, where elements of the body’s immune system attack specific points in the body itself, such as the joints. These pro-inflammatory immune response factors include TNF-á, IL-1â, and superoxide, a free radical that, in excess, is a significant mediator of tissue and cell damage and regulates cytokine release.

To determine the potential of selective removal of superoxide in treating rheumatoid arthritis, researchers tested the SOD mimetic M40403. This mimetic is a small-molecule SOD mimetic designed to replicate the action of natural SOD enzymes, and selectively remove excess superoxide.

SOD mimetics are promising drug candidates because they have a low molecular weight, are highly stable and do not appear to elicit an immune response in the body. Furthermore, the chemical structure of the metal-based compounds can be easily optimized for application to different diseases and conditions.

In the study, researchers evaluated the effects of daily doses of M40403 on the development and progression of arthritis in rats. In animals treated with M40403 results showed inflammation was reduced by up to 56%, joint erosion was reduced by at least 70%, and TNF-a and IL-1b levels were reduced, at two of the doses tested, to those typical of normal, non-arthritic rats.

“The findings of this study suggest a potentially novel therapeutic for rheumatoid arthritis, combining anti-inflammatory and disease-modifying properties into a single drug,” said Daniela Salvemini, Ph.D., MetaPhore’s Vice President of Pharmacology and the principal investigator. “The SOD mimetic possesses both of these properties because superoxide plays a dual role, in acting both as a direct inflammatory molecule as well as stimulating the release of the inflammatory cytokines, TNF-á and IL-1â. This contrasts with the current generation of disease-modifying arthritis drugs which attempt to control the cytokines after their release.”

Article Source: http://www.prohealth.com/library/showarticle.cfm?libid=855

Six years ago, the UC San Diego School of Medicine research team discovered the cause of the excess fibrous tissue growth that leads to liver fibrosis and cirrhosis, and developed a way to block excess scar tissue in mice. At that time, the best hope seemed to be future development of a therapy that would prevent or stop damage in patients suffering from the excessive scarring related to liver or lung disease or severe burns.

In their current study, Martina Buck, Ph.D., assistant professor of medicine at UCSD and the Veterans Affairs San Diego Healthcare System, and Mario Chojkier, M.D., UCSD professor of medicine and liver specialist at the VA, show that by blocking a protein linked to overproduction of scar tissue, they can not only stop the progression of fibrosis in mice, but reverse some of the cell damage that already occurred.

In response to liver injury – for example, cirrhosis caused by alcohol – hepatic stellate cell (HSC) activated by oxidative stress results in large amounts of collagen. Collagen is necessary to heal wounds, but excessive collagen causes scars in tissues. In this paper, the researchers showed that activation of a protein called RSK results in HSC activation and is critical for the progression of liver fibrosis. They theorized that the RSK pathway would be a potential therapeutic target, and developed an RSK inhibitory peptide to block activation of RSK.

The scientists used mice with severe liver fibrosis – similar to the condition in humans with cirrhosis of the liver – that was induced by chronic treatment with a liver toxin known to cause liver damage. The animals, which continued on the liver toxin, were given the RSK-inhibitory peptide. The peptide inhibited RSK activation, which stopped the HSC from proliferating. The peptide also directly activated the caspase or “executioner” protein, which killed the cells producing liver cirrhosis but not the normal cells.

“All control mice had severe liver fibrosis, while all mice that received the RSK-inhibitory peptide had minimal or no liver fibrosis,” said Buck.

Buck explained that the excessive collagen response is blocked by the RSK-inhibitory peptide, but isn’t harmful to the liver. “The cells continue to do their normal, healing work but their excess proliferation is controlled,” Buck said. “Remarkably, the death of HSC may also allow recovery from liver injury and reversal of liver fibrosis.”

The researchers found a similar activation of RSK in activated HSC in humans with severe liver fibrosis but not in control livers, suggesting that this pathway is also relevant in human liver fibrosis. Liver biopsies from patients with liver fibrosis also showed activated RSK.

The study expands on work reported in 2001 in the journal Molecular Cell announcing that a team led by Buck had found that a small piece of an important regulatory protein called C/EBP beta was responsible for fibrous tissue growth, or excessive scar tissue following injury or illness. When normal scarring goes awry, excessive build-up of fibrous tissue can produce disfiguring scars or clog vital internal organs and lead to serious complications. Buck and colleagues developed a mutated protein that stopped this excessive fibrous tissue growth.

“Six years ago, we showed a way to prevent or stop the excessive scarring in animal models,” said Buck. “Our latest finding proves that we can actually reverse the damage.”

Worldwide, almost 800,000 people die from liver cirrhosis each year. Excessive tissue repair in chronic liver disease induced by viral, toxic, immunologic and metabolic disorders all result in excessive scar tissue, and could benefit from therapy developed from the UCSD researchers’ findings.

The research was supported by grants from the National Institutes of Health, the Department of Veterans Affairs and UCSD’s Medical Research Foundation. Buck is the recipient of a Howard Temin Award from the National Cancer Institute.

Article Source: http://scienceblog.com/15104/researchers-halt-reverse-cirrhosis-of-the-liver/

From http://www.ucsd.edu