Angelman-Syndrom: Forschungsarbeit und klinische Studie. Edwin J Weeber, Ph.D.
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1 Angelman-Syndrom: Forschungsarbeit und klinische Studie Edwin J Weeber, Ph.D.
2
3
4
5 Das UBE3A Gen
6 Synaptische Verbindung
7 Injektion eines Virus mit UBE3A direkt ins Gehirn Ergebnis: Gedächtnisprobleme Lernprobleme Probleme mit der synaptischen Kommunikation
8 Möglichkeiten finden, das Angelman Syndrom zu behandeln 1. Kann das väterliche Gen aktiviert werden? 2. Kann man das Fehlen von UBE3A wettmachen?
9
10 A-T C-G AGGTTCTGAAATTCCGCGTTGCTAGCTTGACGTTAGGCCAAACTTGCACGTTAATTGG TCCAAGACTTTAAGGCGCAACGATCGAACTGCAATCCGGTTTGAACGTGCAATTAACC
11 A-T C-G AGGTTCTGAAATTCCGCGTTGCTAGCTTGACGTTAGGCCAAACTTGCACGTTAATTGG TCCAAGACTTTAAGGCGCAACGATCGAACTGCAATCCGGTTTGAACGTGCAATTAACC
12 Transcription machinery Translation machinery AGGTTCTGAAATTCCGCGTTGCTAGCTTGACGTTAGGCCAAACTTGCACGTTAATTGG AACGUCAAGCUAGCAACGCGC
13
14 Mother s Gene Transcription machinery Translation machinery UBE3A AGGTTCTGAAATTCCGCGTTGCTAGCTTGACGTTAGGCCAAACTTGCACGTTAATTGG TCCAAGACTTTAAGGCGCAACGATCGAACTGCAATCCGGTTTGAACGTGCAATTAACC PW AACGUCAAGCUAGCAACGCGC
15 Father s gene UBE3A AGGTTCTGAAATTCCGCGTTGCTAGCTTGACGTTAGGCCAAACTTGCACGTTAATTGG AAAUUCCGCGUUGCUAGCUUGACGUUAGGCCAAAC AAAUUCCGCGUUGCUAGCUUGACGUUAGGCCAAAC UGCAAGUUUGGCCUAACGUCAAGCUAGCAACGCGC AAAUUCCGCGUUGCUAGCUUGACGUUAGGCCAAAC TCCAAGACTTTAAGGCGCAACGATCGAACTGCAATCCGGTTTGAACGTGCAATTAACC PW AAAUUCCGCGUUGCUAGCUUGACGUUAGGCCAAAC AAAUUCCGCGUUGCUAGCUUGAC UAGCUUGACGUUAGGCCAAAC
16 Mothers Gene UBE3A PW deletion mutation alteration Fathers Gene UBE3A PW
17 Paternal Maternal
18 Paternal Maternal CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3
19 Mothers Gene CH3 CH3 UBE3A CH3 CH3 PW CH3 deletion mutation alteration Fathers Gene UBE3A PW
20 Topoisomerasehemmer Ben Philpot, Ph.D.
21 Topoisomerase wird für die DNA Replikation / Zellteilung benötigt
22
23 Arthur L. Beaudet, M.D. ISIS Pharmacueticals UBE3A AGGTTCTGAAATTCCGCGTTGCTAGCTTGACGTTAGGCCAAACTTGCACGTTAATTGG UGCAAGUUUGGCCUAACGUCAAGCUAGCAACGCGC AACGUCAAGCUAGCAACGCGC AAAUUCCGCGUUGCUAGCUUGACGUUAGGCCAAAC TCCAAGACTTTAAGGCGCAACGATCGAACTGCAATCCGGTTTGAACGTGCAATTAACC PW
24 Die Zinkfinger-Technik David Segal, Ph.D. ATT CCG GGT TTC
25 Zinc Finger technology David Segal, Ph.D. Paternal gene UBE3A AGGTTCTGAAATTCCGCGTTGCTAGCTTGACGTTAGGCCAAACTTGCACGTTAATTGG TCCAAGACTTTAAGGCGCAACGATCGAACTGCAATCCGGTTTGAACGTGCAATTAACC PW
26 Virale Methoden Edwin Weeber, Ph.D.
27 Virale Methoden Edwin Weeber, Ph.D.
28 Entdeckung neuer Medikamente Scott Dindot, Ph.D. Edwin Weeber, Ph.D. UBE3A AGGTTCTGAAATTCCGCGTTGCTAGCTTGACGTTAGGCCAAACTTGCACGTTAATTGG TCCAAGACTTTAAGGCGCAACGATCGAACTGCAATCCGGTTTGAACGTGCAATTAACC PW
29 Entdeckung neuer Medikamente Scott Dindot, Ph.D. Edwin Weeber, Ph.D. UBE3A AGGTTCTGAAATTCCGCGTTGCTAGCTTGACGTTAGGCCAAACTTGCACGTTAATTGG TCCAAGACTTTAAGGCGCAACGATCGAACTGCAATCCGGTTTGAACGTGCAATTAACC PW
30 Weitere Methoden, das Angelman Syndrom zu behandeln Kann man das Fehlen von UBE3A wettmachen?
31 Eric Klann, Ph.D. Zafar Nawaz, Ph.D. Gary Lynch, Ph.D.
32 Besserung der Symptome bei der Angelman Syndrom Maus Proteinaustausch. (protein replacement) CaMKII Mutation. (CamKII mutation) Natrium /Kalium ATPase. (Na/K ATPase) Ampakine. Reelin.* *Unveröffentlicht
33 Potenzielle von der FDA genehmigte Medikamente als Therapeutika für das Angelman Syndrom Potential FDA Approved Drugs as Therapeutics for Angelman Syndrome
34 Kriterien Von der FDA genehmigt. Positive Wirkung bei anderen humanen kognitiven Störungen. Wirksam in Bereichen, die bei AS verändert sind. FDA Approved. Beneficial effects in other human cognitive disorders. Work on sites shown to be altered in AS.
35 Minocyclin Anwendung / bzw. klinische Studien zu: o Schizophrenie o Chronische Polyarthritis o Huntington Krankheit o Verletzungen der Wirbelsäule o Fragiles X Syndrom Schizophrenia Rheumatoid Arthritis Huntington's Disease Spinal Cord Injury Fragile X Mental Retardation
36 Minocyclin Tetrazyklin mit breitem Wirkspektrum Kann aufgrund seiner Eigenschaften ins Gehirn eindringen Wird vor allem zur Behandlung von Akne verwendet Kaum Nebenwirkungen Seit 1972 in Gebrauch Broad spectrum tetracycline antibiotic Properties allow it to penetrate the brain Primarily used to treat acne Very few side effects Used since 1972
37
38 Studienbeginn Woche 1 Studienende Woche 8 Rückkehr Woche 16 Kein Medikament Tägliche Medikamentengabe April 2012 Start 21. September Ende erste 12 Patienten März 2013 Ende 24 Patienten / jede Woche 2 Patienten Einarmige Studie: Bericht
39 Studienbeginn Woche 1 Studienende Woche 8 Rückkehr Woche 16 Tägliche MedikamentengabeKein Medikament
40 Schlussfolgerungen Wie das Mausmodell zeigt, ist das Angelman Syndrom anscheinend ein biochemischer, kein entwicklungsbezogener Defekt. Die Besserung des kognitiven Defekts bei ausgewachsenen AS Mäusen deutet darauf hin, dass bei Patienten mit der Diagnose AS eine therapeutische Intervention von Nutzen sein kann. Therapeutika, die die synaptische Funktion verbessern, können bei der Behandlung von AS von Nutzen sein. Angelman Syndrome, supported by the mouse model, appears to be a biochemical, not a developmental, defect. Recovery of the cognitive defect in adult AS mice suggest that therapeutic intervention may be beneficial for diagnosed AS patients. Therapeutics that enhance synaptic function may be useful in the treatment of AS.
41 Stiftung für Therapeutika für das Angelman-Syndrom NINDS Jerome-Lejeune-Stiftung
42 Danksagung Erasmus-Universität Ype Elgersma UCLA Alcino Silva Baylor College of Medicine Art Beaudet UTSW in Dallas Joachim Herz, Ph.D. Uwe Beffert, Ph.D. University of Alabama J. David Sweatt, Ph.D. Duke University Yong-Hui Jiang Texas A&M Scott Dindot
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