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The enormous advancement in the biological sciences that is taking place has begun to change the traditional way of practicing medicine. Far-reaching biological products are being approved and news about breakthroughs are occupying the media headlines. However, selecting the biotechnology firms... More
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    When breakthroughs surface, there is no way of missing them, or continuing demeaning their importance and impact on the future of medical practice. This time, using the biotechnology company SanGamo’s SGMO zinc finger nuclease (ZFN) technology has, indeed, created the first genetically modified mammals. The breakthrough was the result of efforts by scientists from various institutions and firms, including The Medical College of Wisconsin in Milwaukee, Sangamo Biosciences, the firm that created the zink finger nuclease (ZFN) technology, Sigma-Aldrich Corporation (NASDAQ:SIAL), Open Monoclonal Technology, Inc. (OMT) and INSERM. Together, they announced the scientific breakthrough and, in the mean time, validated SanGamo’s technology.

    In a paper published in the July 24, 2009 issue of Science, the researchers described the novel application of ZFNs to generate rats having permanent, heritable gene mutations. Yes,  we mean it, permanent and heritable gene mutations. This breakthrough is expected to lead to the development of novel genetically modified animal models of human disease. ZFN technology is expected to generate such animals faster and create new opportunities in species other than mice.

    In the study titled "Knockout Rats via Embryo Microinjection of Zinc Finger Nucleases," (Geurts, et al.) scientists used ZFNs to knock out an inserted reporter gene and two native rat genes without causing measurable effects on other genes. Importantly, offspring of the ZFN-mutated rats also carried the modifications, demonstrating the genetic changes were permanent and heritable. Together, these results demonstrate the ability to deliver engineered ZFNs into early-stage embryos and rapidly generate heritable, knockout mutations in a whole organism.

    This outstanding successful experiment is considered a breakthrough as it is the first capable of knocking out, or mutating specific rat genes, which is important, as rats are physiologically more similar to humans than are mice for many traits and are ideal subjects for modeling human diseases. Approximately 90 percent of the rat's 25,000-30,000 estimated genes are analogous to those in humans and mice. Their larger size makes them a superior model for drug evaluation studies using serial sampling. Generating rats with knockout mutations, however, has been a major challenge.  Howard Jacob, Ph.D. Director of the Human and Molecular Genetics Center at the Medical College of Wisconsin said, "Until now, rat geneticists lacked a viable technique for 'knocking out,' or mutating, specific genes to understand their function. This study demonstrates that SanGamo’s ZFN technology bypasses the current need to conduct cumbersome experiments involving nuclear transfer (cloning) or embryonic stem cells and allows rapid creation of new animal models."

    Dr. Jacob's team hopes to use knockout rats to gain a better understanding of disease proc-esses related to hypertension, heart disease, kidney failure and cancer.

    ZFNs are engineered proteins that induce double strand breaks at specific sites in an organism's DNA. Such double-strand breaks stimulate the cell's natural DNA-repair pathways and can result in site-specific changes in the DNA sequence. Previously, ZFNs were used to knock out specific genes in fruit flies, worms, cultured human cells and zebrafish embryos and are now in human clinical trials for the treatment of HIV/AIDS. This is the first example of successful gene editing in mammalian embryos using this technology.

    Philip Gregory, D.Phil., Sangamo's vice president of research stated, "Our ZFN technology is widely applicable across species. Used in conjunction with standard laboratory techniques, ZFNs provide a powerful solution to the challenge of making gene knockouts in cells and in whole organisms. We believe that this technology will become the method of choice for genome engineering in cells, plants and transgenic animals."

    In the first commercial application of this technique, OMT, a private biotechnology company developing a new rat-based human antibody platform, used Sangamo's ZFNs to knock out the gene encoding rat immunoglobulin M (IgM). This is  an important gene for rat antibody production. Inactivation of rat IgM expression is the first step in generating rats that exclusively express human antibodies encoded by transgenic human immunoglobulin genes. Dr. Roland Buelow, CEO of OMT and a senior author of the paper said that the biggest challenge the firm had faced was creating a knockout rat, which ZFN technology has solved. He believes that ZFN technology has the potential to revolutionize genetic engineering of animals."

    Dr. David Smoller, President of Sigma-Aldrich's Research Biotech business unit said that the firm has invested its time and resources to develop the CompoZr platform because it sees enor-mous potential in a technology that can precisely manipulate the genome of living organisms.” Dr. Smoller continued, "We are proud to be part of the public-private collaboration developing the proof-of-concept for this technique, which we believe will become the standard for the creation of genetically engineered research animals."

    Sigma-Aldrich, the sole source of commercial zinc finger nucleases for the research community, markets Sangamo's ZFN technology through its CompoZr™ line of products and services. To get more information, please visit

    Prohost Comments: The reason for our enthusiasm and willingness to invest in the biotechnology industry is based on our confidence that some biotech firms are capable of using the abundant information into creating breakthroughs that take the practice of medicine and aggriculture into the future. As a matter of fact, thanks to some biotech firms, we are beginning to see  the future, today.

    Sigma-Aldrich is a leading Life Science and High Technology company with biochemical and organic chemical products and kits that are used in scientific and genomic research, biotechnology, pharmaceutical development, the diagnosis of disease and as key components in pharmaceutical and other high technology manufacturing. The Company has custom-ers in life science companies, university and government institutions, hospitals, and in industry. Over one million scientists and technologists use its products. Sigma-Aldrich operates in 38 countries and has 7,800 employees providing excellent service worldwide. Sigma-Aldrich is committed to Accelerating Customer Success through innovation and Leadership in Life Science, High Technology and Service. For more information about Sigma-Aldrich, please visit its award-winning Web site at

    Sangamo Biosciences focuses on the research and development of novel DNA-binding proteins for thera-peutic gene regulation and modification. The most advanced ZFP Therapeutic™ development program is currently in Phase 2 clinical trials for evaluation of safety and clinical effect in patients with diabetic neuropa-thy and ALS. Sangamo also has a Phase 1 clinical trial to evaluate safety and clinical effect of a ZFP Thera-peutic for the treatment of HIV/AIDS. Other therapeutic development programs are focused on cancer, neu-ropathic pain, nerve regeneration, Parkinson's disease and monogenic diseases. Sangamo's core compe-tencies enable the engineering of a class of DNA-binding proteins known as zinc finger DNA-binding pro-teins (ZFPs). By engineering ZFPs that recognize a specific DNA sequence Sangamo has created ZFP transcription factors (ZFP TF(NYSE:TM)) that can control gene expression and, consequently, cell function. San-gamo also is developing sequence-specific ZFP Nucleases (ZFN(TM)) for gene modification. Sangamo has established strategic partnerships with companies in non-therapeutic applications of its technology including Dow AgroSciences, Sigma-Aldrich Corporation and several companies applying its ZFP technology to engi-neer cell lines for the production of protein pharmaceuticals. For more information about Sangamo, visit the company's web site at

    The Medical College of Wisconsin in Milwaukee,, is a private, freestanding academic insti-tution dedicated to leadership and excellence in advancing the prevention, diagnosis and treatment of dis-ease and injury through education, discovery, patient care and community engagement. A major national research center and academic medical center, its faculty physicians and scientists direct or collaborate on more than 3,000 research studies, publish over 1,300 peer-reviewed scientific papers, and provide care in virtually every specialty of medicine to approximately 350,000 patients annually. For more information on our transgenic services offering, see

    Open Monoclonal Technology ("OMT") is a private biotechnology company developing a new, fully human monoclonal antibody platform based on transgenic rats. The rat is a widely used laboratory animal with a well characterized immune system, a nearly complete genome sequence, and established transgenesis and hybridoma technologies. OMT's antibody platform is the result of an improved understanding of B-cell devel-opment and a novel approach to the inactivation of endogenous antibody expression. The antibody platform is available for all targets, has broad freedom to operate, and uses technology protected by patents. For more information about OMT, contact Roland Buelow at or visit

    NSERM UMR 643 is a French public academic laboratory. Its scientific activity is centered in the analysis of immune responses and in immunointervention strategies in organ transplantation. The rat is an important immunological model, and INSERM routinely generates transgenic rats using DNA or lentiviral vector mi-croinjection. The generation of transgenic rats also is open to the scientific community through an open facil-ity. More information is available at

    Disclosure: No Positions

    Jul 24 10:19 AM | Link | Comment!

    After Insmed announced results from phase 2 clinical trial evaluating Iplex™ (mecaser-min rinfabate) on patients with myotonic muscular dystrophy ("MMD"), investors instigated a hysterical sell off of INSM on a very high volume. Capital is a coward, we know, especially in shaky economies, yet aggressive negative reaction to news based on fear only might not echo reality, which is much better sensed through an honest search for facts.       

    To begin with, investors should not have overlooked the fact that phase 2 clinical trial with Iplex on MMD was exploratory. The objective of this trial was to let researchers learn more about Iplex’™ as a therapeutic. The important polypeptide in Iplex is the insulin-like growth factor IGF-1, which scientists know now that in nature, it is involved, among other tasks, in children’s growth and in sustaining the muscle strength then after, i.e., it has an adult anabolic effect. It also has to do with glucose and lipid metabolisms. Researchers now recognize that using the free IGF-1 as therapeutic is limited by its toxicity at effective doses. That’s why the combination in Iplex of IGF-1 with its predominant binding protein IGFBP-3 has demonstrated much better results than using the free growth factor in short stature children and had promising results in other neurological diseases where other products failed.  

    Myotonic muscular dystrophy ("MMD") has complex symptoms, which comprise progressive muscular weakness and myotonia, cardiac arrhythmias, cognitive defects, endocrine disturbances including insulin sensitivity, testosterone imbalance, as well as deregulated lipid metabolism, gastrointestinal and reproductive deregulations and pain.  

    No rational professional analyst should have expected full accurate confirmatory results from a short-term exploratory trial with Iplex on a few patients suffering from MMD. That’s why the primary endpoint was not predefined. As a matter of fact, the trials were, yes, incapable of demonstrating positive effects of Iplex on the functional measure of endurance, muscle function and muscle strength, but were positive on other MMD complications. So, while investors reacted hysterically against the stock because of the negative side of the results, they totally overlooked the positive results of the drug on other important MMD complications, including, improvement in standard measures of insulin sensitivity - reductions in fasting glucose, fasting insulin, and on cholesterol and triglyceride high levels. They also closed their eyes on the results demonstrating that the use of Iplex rhas esulted in increasing body mass index and testosterone level.  

    These positive results confirm that Iplex has the same effect as the natural body insulin-like growth factor (IGF-1) without toxicity, thus, it can be used in diseases where the natural IGF-1 is deficient, or not sufficiently protective. Needless to repeat that the combination of IGF-1 with its binding protein IGFBP-3 enables administering the drug safely at higher therapeutic doses with no side effects as those produced through the use of free IGF-1 developed by other firms.      

    The data from phase 2 trial also tell scientists that if they wanted to reproduce the same effects as that of the natural IGF-1 in the body, the only current available drug for them is Iplex. We have no doubt that researchers at Insmed and at other firms interested in providing a therapeutic IGF-1 will do their best in finding effective Iplex combinations for debilitating neuromuscular, neurological and other diseases that have yet to find specific effective treatments.

    Insmed is designing a new phase 2 trial that focuses solely on those patients who suffer from severe insulin resistance and are expected to benefit from the drug as seen from the unveiled results. Insmed intends to apply for a grant from the Muscular Dystrophy Association ("MDA"), which has largely supported the exploratory trials. The firm has considered using alternative methods that can demonstrate the effect of Iplex on muscle function.   

    Why do we need a therapeutic IGF-1?  

    The discovery of cytokines and growth factors and the developed of state-of-the-art tools for gene expression analysis have dramatically changed the understanding of many diseases. They handed scientists new tools that help them use natural body growth factors as therapeutics - a task that has been  difficult to achieve.

    Insulin-like growth factor 1, (IGF-1), for example, which was once called somatomedin C, and is part of Insmed’s complex drug Iplex™ is a polypeptide similar in molecular structure to insulin. IGF-1. It plays an important role in childhood growth and continues to have ananbolic effects in adults. IGF-1 activates the AKT signaling pathway, stimulates cell growth and multiplication and inhibits programmed cell death. It affects every cell in the human body, especially muscle cells, nerve cells, cartilage cells,  bone, liver, kidney, skin and lung cells. IGF-1 and promises regulating cell nerve cell growth and development.

    No wonder then why scientists dream of using this polypetide as therapeutic for growth related issues, for neuromuscular diseases and for metabolic diseases, especially diabetes.        

    Why Iplex?

    Developing Iplex™ as a complex of recombinant human insulin-like growth factor-I (rhIGF-I) and IGFBP-3 (rhIGFBP-3) was a genius approach by Insmed. The complex solved the problem of dose restriction, enabled the drug to cross the blood brain barrier, increased its half life and freed it from the side effects that the free IGF-1 (Increlex and Myotrophin) – drugs developed by other firms.  Iplex is given once a day, while free IGF-1 must be administered twice a day in a much lower dose.

    Iplex™ was approved in the United States in December 2005 for the treatment of children with growth failure due to severe primary IGF-I deficiency. The advantages of this drug, however, convinced scientists’ that Iplex™ could be the drug the would play major roles in the treatment of serious neuromuscular diseases such as amyotrophic lateral sclerosis (ALS), myotonic muscular dystrophy (NYSE:MMD), type 1 and type 2 dia-betes, retinal diseases, such as retinopathy of prematurity (NYSE:ROP) and HIV adipose redistribution syndrome (HARS).

    Amyotrophic lateral sclerosis (ALS): Insmed is currently providing Iplex in Italy through Expanded Access Program to physicians for ALS patients with promising re-sults. No other drugs, including free recombinant insulin-like growth factor-I (rhIGF-I), succeeded in inducing any improvement on the symptoms of this deadly disease. Many physicians are now putting their patients on Iplex™ in Italy. When the FDA heard the news about the Italian experience, it gave physicians the green light to use Iplex™ on compassionate basis on ALS patients in the U.S.

    HIV adipose redistribution syndrome (HARS): Preliminary results from a phase 2 study conducted at the University of California, San Francisco on HIV patients suffering from HIV-associated adipose redistribution syndrome (HARS) showed that treatment with Iplex 0.5 mg/kg/day for three months only resulted in increasing IGF-I levels 3-fold.  The administration of Iplex seems to be associated with significant improvements in fasting glucose levels, in the amount of insulin secreted during oral glucose tolerance test, and overall insulin sensitivity. Additionally, there was a significant reduction in patients’ trunk fat and lipid profiles.   

    If such a low dose of Iplex increased IGF-I levels 3-fold and positively impacted abnor-mal glucose metabolism, dyslipdemia and abnormal fat distribution, it is then fair to assume that a higher dose would have a better impact on improving glucose homeostasis. Competitors’ products have failedl to alter glucose homeostasis. It is important to note that abnormal glucose metabolism and dyslipedemia are present in a significant number of HIV patients treated with highly active antiretroviral therapy.

    Retinopathy of prematurity (ROP

    Premacure is developing iplex™ as a potential treatment for Retinopathy of Prematurity (ROP) via a Material Transfer Agreement with Insmed. It seems that IGF-1 predominant binding protein IGFBP-3 (rhIGFBP-3), increased serum IGF-I levels into the normal range in significantly premature infants. These most recent study results were re-ported at the European Society for Pediatric Endocrinology 47th annual meeting, Istan-bul, Turkey, by Investigators from the Harvard Medical School, Boston MA, and the University of Gothenburg, The Karolinska Institute, Stockholm and Lund University, Sweden in a poster entitled "Pharmacokinetic study of recombinant human (rh) insulin-like growth factor/rh IGFBP-3 complex administered to very low birth weight infants. 

    Commenting on the Results

    Lois Smith, Professor of Ophthalmology, Harvard Medical School, Children's Hospital Boston said, "The possibility of preventing ROP and other complications of prematurity by replicating the in utero environment after infants are born prematurely and lose the factors normally provided by the maternal environment is very exciting. This work shows that it is now possible to raise the serum level of IGF-1 and IGFBP-3 to normal in utero levels in these fragile infants with IGF-1/IGFBP-3 deficiency, which is a critical step in the development of interventions that prevent ROP. Since we have shown that low IGF-1 is associated with ROP, this offers the first possible intervention to prevent this blinding disease."

    Ann Hellstrom, Professor in Pediatric Ophthalmology, Sahlgrenska Academy, Gothen-burg, Sweden said, "Our research focuses on promoting neural, vascular and metabolic development in premature infants. While in this study we are attempting to identify the benefits of IGF-I for ROP, our findings are also likely to be applicable to many aspects of complications of premature birth and could provide benefits for a lifespan."

    Prevention of ROP

    Low levels of IGF-I are known to contribute to the occurence of ROP. The objectives of the investigator-sponsored clinical study were to determine whether intravenous admini-stration of rhIGFI/rhIGFBP-3 (IPLEX™ could increase serum levels of these proteins in at-risk infants to levels seen in normal infants, and to evaluate the drug's safety and tol-erability. Due to consistency in response, the study was finalized after five infants. Treatment with IPLEX™ took place on the infant's chronological age day 3 and the investigators reported that the protein complex effectively raised serum IGF-I levels into the physiological range and that the drug's administration was well tolerated, with no acute adverse events.

    With a drug like Iplex™ one cannot be pessimistic by results from trials that are not meant to prove but teach. We do believe that Iplex™ will, indeed, play a role in the treatment of many diseases, alone, or in combination treatments and as adjuvant to other treatments.

    Insmed has agreements with Pharmacia AB’s portfolio of regulatory filings pertaining to rhIGF; and an agreement with NAPO Pharmaceuticals that gives NAPO the right to develop, manufacture, and commercialize masoprocal products for various indications relating to diabetes, cardiac disease, vascular disease, metabolic disease, and syndrome X.

    Insmed also engages in various oncology programs, including INSM-18, an orally available small molecule tyrosine kinase inhibitor that has demonstrated selective inhibition of IGF-1 and human epidermal growth factor receptor; and rhIGFBP-3, which is in early clinical development stage for breast, prostate, liver, ovarian, and colon cancers.

    The firm has around $120 million in cash reserves and is looking forward to continuing to explore Iplex™ possibilities with its strategic financial advisor, RBC Capital Markets.

    ROP is a disease of the eye that affects prematurely born babies. It is thought to be cau-sed by disorganised growth of retinal blood vessels, which may result in scarring and retinal detachment. ROP can be mild, but may lead to blindness in serious conditions. It is one of the most common causes of visual loss in childhood and can lead to lifelong vision impairment and blindness. As such, all preterm babies are at risk for ROP, and very low birth weight is an additional risk factor.

    Premacure AB, based in Sweden is dedicated to the development of diagnosis and prevention of complications in neonates due to premature birth. The first of several indications to be developed is Retinopathy of Prematurity (ROP).   

    What do you think? Do we hope that Iplex succeeds as therapeutic, because we need a safe and effective IGF-1 drug?

    Disclosure: No positions


    Jul 13 3:46 PM | Link | 2 Comments

    It does not require a genius to know that Savient Pharmaceuticals’ gout drug Krystexxa is indispensable to patients who are not helped by all existing current gout treatments. It is no secret that the firm’s study, presentation of data and tackling of all concerns were extremely scientific, logical and trustworthy.    

    Savient has proven to be highly scientific. It is innovative and will bring to the medical community what it really expects from the biotechnology sector considered the executive branch of science, i.e., scientific and industrial power that turns scientific discoveries into breakthrough therapeutic molecules that fulfill unmet needs  

    Gout patients that conventional gout treatments do not help, will have a new drug called Krystexxa. Indeed, Savient’s drug will save them from their pain and misery. Those sufferers  are numerous, estimated to be over 100,000 patients, a number that is increasing as the disease affects almost all age groups. They suffer excruciating  pain, joint destruction, kidney stones and, in some cases kidney failure, in addition to other cardiovascular associated diseases that require special treatments.

    Gout patients can live a normal life when treatments work on them. That’s why Krystexxa represents the hope for those patients who have no help and until yesterday, had no hope.

    With regard to the firm’s stock, investors must know that the committee recommendation of approval has not really rallied the stock from $6 to over $12 as some are claiming. Such a great news was not even capable of recuperating the stock's losses incurred in one day, when unfair and wrong negative speculations on the drug succeeded in knocked its price down by over 70%. Yes, in  one day, October 25, 2008, a sell off in the stock sank it from $11.34 to $3.7. Needless to say that the stock one month before that date was trading at over $19.  

    So, yesterday celebration has not even covered the losses brought up by fear perpetrated by those who are genius at it. We do believe though, that Krystexxa will become a blockbuster, generating revenues that would exceed the best products for inflammation, pain and life threatening conditions.

    If after yesterday’s excellent news the stock would reach $20 (trading now at less than $13), it would have gained only $0.06 over its price on September 23, 2008, i.e., $19.94, before the hype made it tumble. SVNT represents a unique investment opportunity.

    Disclosure: No positions

    Jun 18 11:54 AM | Link | Comment!
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