DOCSLIB.ORG

Myelin Project

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Myelin Project Myelin Project 11/92 “Shaking Pups ”. Remyelination w/in a 3cm radius from implant site. ( Oligodendrocytes and its’ precursors) 12/96- 2 series of human glial cells are cultured providing a continuous supply of transplantable myelin-forming cells 1/97- Oligodendrocytes & precursors have the greatest capacity for myelination following grafting, although cells of neuronal origin may also be used 1/97- Progesterone promotes re-myelination by activating the genes that control the synthesis of important myelin proteins- but side effects on reproductive functions Amgen - Shaker/ Shiverer rats, newly developed mouse model . Monkey Schwann cells into animal optic gene did not work Other researches used Schwann cells & astrocytes mixture to remyelinate rats 11/98 - Phase I human tria l for transplanting Schwann cells in CNS of 5 MS patients, but must demonstrate that it is not harmful in monkeys first Oecs (olfactory ensheathing cells) from pigs into demyelinated & monkeys significant remyelination 6/11/2000-Michaela Odone dies; Lorenzo 22 yrs old 12/2000- OECs can remyelinate axons of CNS in rat model Yale has second thoughts about the already approved Phase I human trial . It was supposed to start 9/2000, but Yale decides to have an independent researcher give final approval. 7/2001- Phase I finally starts ! Schwann cells (1 million) transplanted into a 53 year old woman suffering from progressive MS. Taken from her own nerve and injected into the right frontal lobe of the brain. (Reminder: Phase I trial is meant to prove safety) 4/2003- Patient #3 has Schwann cells injected . Brain stem cells injected into the blood stream of MS model mice can find their way to the CNS and begin remyelinating the lesions. 5/29/03- Lorenzo turns 25. 10/23/03 Highlights from the 14 th annual myelin project meeting: Marmoset trial- Played himself in the testing the ability of movie ☺☺☺ transplanted human neural stem cells to repair myelin damage. Follow-up studies to “Lorenzo’s Oil”: 2 different studies confirms “that the Oil is effective in delaying the onset of ALD in boys w/o symptoms who started the therapy under the age of six.” 2004- Working on remyelination . 2 main areas: 1.) transplantation of myelin forming cells. Experiments with a.) stem cells b.) Schwann cells c.) Olfactory ensheathing cells (OEC’s) Working on controlling blood levels of fat with pharmaceuticals: a.) progesterone derivative b.) statins w/ interferon c.) Lipitor plus (relief in 45 MS patients) 5/04- Lorenzo turns 26 6/7/04- no harmful side effects seen in marmosets due to transplanted neural stem cells or from the immune-suppressing drugs OPC’s (oligodendrocyte progenitor cells) given to rats traveled 23mm in both directions and produced extensive remyelination . 6/05 - conclusion of 13 year study on the effectiveness of Lorenzo’s Oil in preventing symptoms in 89 ALD boys . Late 05- Development of a new method that makes it more likely that infants will be able to be screened for ALD. Working to perfect the technique . 9/06 Summer update for the myelin project: Robin Franklin; (Cambridge,UK)- observed that aging brains don’t clean up damaged myelin well, which inhibits remyelination . Macrophages are normally in charge of this clean-up. Hypothesized that promoting inflammation (increasing macrophages)would allow transplanted precursor cells to be more effective. Did one transplant and found hypothesis to be true. Jeffrey Kocsis (Yale)- transplants OEC & Schwann cells into injured spinal cord. Result: axonal regeneration and axons formed Nodes of Ranvier with proper sodium and potassium channels. Increase in function noted. Also used an IV injection of gene-modified human mesenchymal stem cells (hMSCS) in a cerebral lesion which resulted in a functional increase. Johannes Berger (Medical Univ. of Vienna brain research Inst .)- gene for defective protein in ALD boys is ABCD1. There’s a very closely related gene that makes a similar protein (ALDRP- adrenoleukodystrophy related protein) called ABCD2. An increase in ALDRP can substitute for the loss of ALDP. Perhaps this could be an alternative for a future therapy. The promoter for ABCD2 is a sequence just prior to the gene but this promoter also affects many other genes. Work must be done to analyze specific elements of the ABCD2 promoter. Hugo Moser (John Hopkins) aka Dr. Nikolais- Follow-up to 2002 results with 89 boys. Yes, there is a decrease in VLCFAs. Boys who stayed on the diet reduce the risk of ALD by a factor of 2 or more. Growth and cognitive development were normal. No serious side effects. New study with 60 boys is underway to see if positive results are repeatable. Lorenzo died at his home in Fairfax, Virginia on May 30, 2008, one day after his 30th birthday due to complications of aspiration pneumonia, with his father Augusto and his life long friend Oumouri at his side. [3] November 2009- Reported in the journal Science: Gene therapy useful in the treatment of ALD ! 2 boys tested and both show healthy cells 2 years after gene therapy. Gene is delivered via an HIV-derived virus vector. This vector is significant b/c it infects dividing cells, so their derivitives should have the proper genome from that point on. This therapy is important for boys who could not get a bone marrow transplant due to a lack of donor (no match). The results of the gene therapy are similar to that of bone marrow transplants: remyelination (not 100%) which leads to increased neurological function. Gene therapy does carry the risk that the biology of the cells is disrupted and the patients end up with leukemia. gene therapy science daily.com In the study, blood stem cells were removed from the patients and genetically corrected in the lab, using a lentiviral vector to introduce a working copy of the ALD gene into the cells. The modified cells were then infused back into the patients' after they had received a treatment that destroyed their bone marrow . Two years later, healthy ALD proteins were still detectable in both patients' blood cells . Encouragingly, both patients showed neurological improvement and a delay in disease progression comparable to that seen with bone marrow transplants. The healthy ALD protein was expressed in about 15 percent of blood cells, yet surprisingly this low level was sufficient to slow brain disease in ALD. "This percentage of correction will not be sufficient for all diseases," warns Aubourg. "There is a lot of work to be done to make this gene therapy vector more powerful, less complicated, and less expensive. This is only the beginning," he said. New Data from Adrenoleukodystrophy (ALD) Pilot Study Presented at American Society of Gene and Cell Therapy Show Three-Year Disease Stabilization of Patients CAMBRIDGE, Mass. & WASHINGTON--(BUSINESS WIRE)-- May 20, 2010 - Nathalie Cartier-Lacave, M.D., study investigator and a director of research at the National Institute of Health and Medical Research in France (INSERM), and collaborator of Genetix Pharmaceuticals, Inc., today presented additional data from a pilot study treating X-linked adrenoleukodystrophy (ALD) at the American Society of Gene and Cell Therapy's 13 th Annual Meeting. The findings demonstrate continued stable expression of ALD protein and disease stabilization at three years in two ALD patients. Initial data on a third patient show stable expression of the protein at 20 months; however, current data are insufficient to determine disease stabilization. Genetix, an emerging leader in developing breakthrough gene therapies for severe genetic disorders, plans to initiate larger clinical studies in ALD in both the United States and Europe in 2011. 2010 News from the Laboratory: • Dr. Jeff Kocsis (Yale University) has shown that mesenchymal stem cells derived from adult human bone marrow when transplanted into experimental demyelinating lesions, produce a significant improvement in functional outcome. They do this by stimulating new myelin formation. • In Milan, Italy Dr. Luigi Naldini ( San Raffaele TelethonInstitute for GeneTherapy ) and his group have been working on gene therapy for the treatment of two severe leukodystrophies, metachromatic leukodystrophy and Krabbe’s disease. Their work is based on using lentiviral vectors in combination with hematopoietic stem cells and is heading into Phase I/II clinical trials. • Also in Milan, Dr. Gianvito Martino’s lab (San Raffaele Hospital) has been working in the field of stem cell biology, particularly neural stem cells. They have shown that these cells, when transplanted into models of MS, have marked effects on the immune system and help protect against neurodegeneration. The goal is to take this approach into clinical trials. • Dr. Robin Franklin’s group at the University of Cambridge have been working on the idea that the brain contains a population of endogenous stem cells or progenitors that can be recruited to become myelinating cells in MS, and possibly other myelin disorders. They have identified some key molecules that might be used in future clinical trials, to promote ‘host’ repair. • Dr. Wolfgang Brück (Universityof Göttingen ) has been studying the immunopathology of MS lesions in attempts to unravel the mechanisms behind endogenous remyelination . It appears that in MS lesions, sufficient myelin-forming precursor cells are present but they do not differentiate into mature cells. • In Paris, Dr. Anne Baron Van Evercooren (L' hopital de la Salpetriere) and her colleagues have been involved in studying remyelination, both by transplanted cells (exogenous) and by host cells (endogenous). They have worked both with myelinating cells from the peripheral nervous system and central nervous system. They have shown activation of neural stem cells from key areas of the CNS in animal models and in the brain of MS patients. They have also evaluated the biological properties of human fetal neural precursors on transplantation into animals. • Dr. Ian Duncan at the University of Wisconsin-Madison and his colleagues have worked extensively on the cells that could be used for transplant repair including human embryonic and neural stem cells.
Load more

Recommended publications
  • Macrophages Counteract Demyelination in a Mouse Model of Globoid Cell Leukodystrophy
    3610 • The Journal of Neuroscience, March 9, 2011 • 31(10):3610–3624 Neurobiology of Disease Macrophages Counteract Demyelination in a Mouse Model of Globoid Cell Leukodystrophy Yoichi Kondo,1 Jessica M. Adams,1 Marie T. Vanier,2 and Ian D. Duncan1 1Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53706, and 2Institut de la Sante´et de la Recherche Me´dicale Unit 820 and Lyon 1 University, Lyon, France Whether microglia and macrophages are beneficial or harmful in many neurological disorders, including demyelinating diseases such as multiple sclerosis and the leukodystrophies, is currently under debate. Answering this question is of special interest in globoid cell leukodystrophy (GLD), a genetic fatal demyelinating disease, because its rapidly progressive demyelination in the nervous system is accompanied by a characteristic accumulation of numerous globoid macrophages. Therefore, we cross-bred the twitcher (twi) mouse, a bona fide model of GLD, with the macrophage-deficient osteopetrotic mutant and studied the resultant macrophage-deficient twitcher twi؉op) mouse. The twi؉op mouse had few microglia and macrophages in the white matter and, interestingly, showed a more severe) clinical phenotype compared to the twi mouse. The number of nonmyelinated axons in the spinal cord was significantly higher in twi؉op mice than in twi mice at 45 d old. The difference appeared to be due to impaired remyelination in twi؉op mice rather than accelerated demyelination. Quantitative reverse transcription PCR and immunohistochemical studies revealed that the recruitment of oligodendro- cyte progenitor cells in response to demyelination was compromised in twi؉op mice.
    [Show full text]
  • HOUSE RESOLUTION Session of No
    PRINTER'S NO. 4421 THE GENERAL ASSEMBLY OF PENNSYLVANIA HOUSE RESOLUTION Session of No. 1011 2020 INTRODUCED BY CRUZ, YOUNGBLOOD, BOBACK, SCHLOSSBERG, KINSEY, HOWARD, GALLOWAY, DRISCOLL, BURNS, BROWN, SAYLOR, MILLARD, LONGIETTI, HEFFLEY, MALAGARI, FARRY AND DEASY, SEPTEMBER 25, 2020 INTRODUCED AS NONCONTROVERSIAL RESOLUTION UNDER RULE 35, SEPTEMBER 25, 2020 A RESOLUTION 1 Designating the month of September 2020 as "Leukodystrophy 2 Awareness Month" in Pennsylvania. 3 WHEREAS, Leukodystrophy is a rare and terminal disease 4 presenting itself in multiple manifestations that attack the 5 central nervous system, severely impacting physical abilities, 6 mental capacity and quality of life; and 7 WHEREAS, The group of rare disorders known as 8 leukodystrophies destroys the central nervous system by 9 disrupting the growth and maintenance of myelin, a sheath that 10 insulates nerve cells and destroys white matter in the brain; 11 and 12 WHEREAS, Leukodystrophies are progressive, with symptoms that 13 worsen throughout the life of the patient; and 14 WHEREAS, There are more than 50 identified leukodystrophies, 15 yet nearly half of patients with leukodystrophy remain 16 unclassified; and 1 WHEREAS, As research advances, scientists will continue to 2 discover and classify new variations in this family of diseases; 3 and 4 WHEREAS, Alone, each leukodystrophy may be considered rare, 5 but as a group these diseases affect approximately 1 in 7,000 6 individuals; and 7 WHEREAS, Infants born with leukodystrophy appear normal at 8 birth, yet, symptoms
    [Show full text]
  • Merchiston's Arms
    THE MERCHISTONIAN 2017 CLUB MAGAZINE Highland Experience Michael Bremner shares his journey to tourism triumph Savills. Teamwork is one of our core values. Across every area of property, Savills has the right people, the right advice and the right knowledge and our teams work together to ensure that our clients are “Ready Ay Ready” for whatever ball is passed to them. Evelyn Channing Ben Fox Scotland Farms & Estates Edinburgh Residential Savills Edinburgh Savills Edinburgh 0131 247 3704 0131 247 3736 Jamie Macnab Nick Green (Merchistonian 93-98) Scotland Country Houses Rural, Energy and Projects Savills Savills Edinburgh Perth 0131 247 3711 01738 477 518 savills.co.uk 170x240mm Merchistonian A Dec17.qxp_Layout 1 04/12/2017 18:32 Page 3 Welcome From the Merchistonian Office It is with great pleasure that we present to you the 2017 Merchistonian Club Magazine. We have thoroughly enjoyed working on this year’s edition, and hope that you enjoy reading it as much as we enjoyed putting it together. Having edited all of your stories, one thing is clear: the friendships created at Merchiston are strong and lifelong. Thank you for sending us your news, without which there would be no magazine. Please continue to get in touch with any stories throughout the year. A special ‘thank you’ goes out to our advertisers, who make the Left to Right David Rider, Gill Imrie and Louise Pert publication possible, and to our proof readers, who scrupulously check each page. find your nearest rep and remember to send us photos This year has seen the launch of the Club’s new of your get-togethers.
    [Show full text]
  • Lack of Adrenoleukodystrophy Protein Enhances Oligodendrocyte Disturbance and Microglia Activation in Mice with Combined Abcd1/Mag Deficiency
    Lack of Adrenoleukodystrophy protein enhances oligodendrocyte disturbance and microglia activation in mice with combined Abcd1/Mag deficiency Dissertation submitted for the academic qualification Doctor of Medical Science at the Medical University of Vienna Dr. Martina Dumser August 2007 1 This work was conducted under the supervision of Ao. Univ. Prof. Dr. Johannes Berger at the Center for Brain Research Medical University of Vienna Department of Neuroimmunology Spitalgasse 4, 1090 Vienna between January 2005 and June 2007 Supervisors: Ao. Univ. Prof. Dr. Johannes Berger Univ. Prof. Dr. Hans Lassmann Univ. Prof. Dr. Klaus-Armin Nave The work was financed by the European Adrenoleukodystrophy Association (ELA)/ The Myelin Project 2 We shall not cease from exploration And the end of all our exploring will be To arrive where we started And know the place for the first time. (T.S. Eliot, nobel price for literature 1948; Four quartets, quartet No. 4: “Little Gidding”) 3 Danksagung DANKSAGUNG Schon während der Schulzeit hat mich die komplexe und geniale Bauweise biologischer Systeme, speziell die des Wesens „Mensch“, fasziniert. Nach Abschluss des Studiums der Humanmedizin bin ich durch Zufall zur Medizinischen Wissenschaft gekommen. Die Zeit, die ich seither hier am Zentrum für Hirnforschung verbracht habe, war eine interessante und lehrreiche, die mich persönlich sehr bereichert und geprägt hat. Dass die vorliegende Arbeit überhaupt möglich wurde und letztendlich auch zu einem Abschluss gebracht werden konnte, verdanke ich einer Reihe von Personen, die hier nun Erwähnung finden sollen: An erster Stelle möchte ich mich bei meinen Eltern und Großeltern für ihre umfassende seelische, emotionale und finanzielle Unterstützung bedanken.
    [Show full text]
  • First International Congress of the ELA Research Foundation
    First International Congress of the ELA Research Foundation October 5-7, 2006 Paris, France The 1st International Congress of the ELA Research Foundation & The Myelin Project entitled "The vital function of myelin development and maintenance" took place in Paris from October 5 to 7, 2006. The Scientific Committee in charge of the meeting organization was composed of Prs. Aubourg, Dubois-Dalcq, Boespflug-Tanguy, Lacaze and Baron-Van Evercooren. Over 200 participants (M.D., Ph.D, Postdocs and Ph.D. students) from around the world specialized in leukodystrophies and myelin repair attended the meeting and presented their last results. The congress was divided in four different scientific sessions: Scientific Session I: Myelin development and repair Co-chairs: Robin Franklin, Anne Baron-Van Evercooren Jean-Léon Thomas, Ph.D. (INSERM U711, Paris, France) A role of vascular growth factor on the development, proliferation and migration of mouse myelin-forming cells has been elucidated. Vittorio Gallo, Ph.D. (Center for Neuroscience Research, Washington DC, USA) The kinase cdk2 plays an important role in the control of myelin-forming cells progenitors and Sox 17, a transcription factor, is as a key regulator of myelin-forming cells proliferation and differentiation in mouse. Pascale Durbec, Ph.D. (IBDML, Marseille, France) Transplantation of adult stem cells from mouse into myelin-deficient adult mice showed that grafted cells perform long distance migration along white matter tracts and are able to differentiate into mature myelin-forming cells. Also, exercise in rodents with multiple sclerosis promoted cell proliferation and increased the number of cells recruited into demyelinated structures. Hans S.
    [Show full text]
  • Moser Center for Leukodystrophies Factsheet
    Moser Center for Leukodystrophies at Kennedy Krieger Institute Who We Are For more than 30 years, Kennedy Krieger Institute has been internationally recognized as an authority on the study and care of patients with leukodystrophies, thanks in large part to the visionary thinking and enduring legacy of the late Dr. Hugo W. Moser. Considered one of the world’s foremost leaders in the field, Dr. Moser believed that innovative research and collaboration were the keys to enhancing clinical care, advancing patient outcomes, and improving the lives of individuals with leukodystrophies worldwide. Today, that commitment lives on through the Moser Center for Leukodystrophies, where leading-edge techniques in neuroimaging, genomics, biomedical engineering, and nanotechnology are helping our experts enhance understanding, diagnosis, and treatment of leukodystrophies. The center’s interdisciplinary approach brings together the fields of neurogenetics, genetic counseling, neurorehabilitation, endocrinology, and urology, along with physical, occupational, speech, and aquatic therapy to provide comprehensive care for patients. Alongside our clinicians, our investigators are exploring the most promising research, while collaborating with other leukodystrophy centers across the country and around the world. Who We Serve Examples of leukodystrophies include: Our interdisciplinary team of experts treats patients from infancy to adulthood who have been diagnosed with, or are suspected of • Adrenoleukodystrophy having, a leukodystrophy. • Alexander disease Leukodystrophies are diseases in which a gene defect leads to • Canavan disease abnormalities of either the axon, the myelin, or the cells that • Cerebrotendinous xanthomatosis provide nutrients to the axon. Currently, over 40 different • Krabbe disease (globoid cell leukodystrophy) leukodystrophies have been described. They are progressive • Metachromatic leukodystrophy diseases, meaning that the disease gets worse throughout a • Pelizaeus-Merzbacher disease lifetime.
    [Show full text]
  • Photo Pleine Page
    ELA FOUNDATION – MYELIN PROJECT (Paris Congress – October 2006) A recent survey among EUROPEAN LEUKODYSTROPHY ASSOCIATION (ELA) patients and families showed that 80% of them consider medical research as the main objective, a priority that needed all of our attention and support. To respond to this massive expectation the ASSOCIATION created in early 2005 a foundation, the ELA FOUNDATION, fully dedicated to medical research. Thanks to the financial support of the FRENCH MINISTRY OF RESEARCH and to the continuous financial commitment of the ELA ASSOCIATION, the ELA FOUNDATION has been able to address right away the broad spectrum of myelin affections beyond the mere although numerous leucodystrophy forms. The core challenge of the ELA FOUNDATION is quite clear and demanding at the same time: repair myelin and restore impaired functions, thereby sharing the major concern of its MYELIN PROJECT friends and as a matter of fact of all concerned patients and families. In order to reach this ambitious goal and make progress in the most balanced and effective fashion, the ELA FOUNDATION has formed a Supervisory Board made of patient related members and well known people strongly involved in our cause, all of them distant from the medical field. This Board operates side to side with a Scientific Committee made of international experts. Its specific mission is twofold: provide guidance for research orientations and select projects to be financed. This model, with precisely defined respective responsibilities between its two main acting bodies, has rapidly demonstrated its merits and we are now all quite enthused and looking forward to developing the ELA FOUNDATION into a major international and global institution to successfully help fight and eradicate myelin diseases.
    [Show full text]