EP2566882A1 - Médicaments pour le traitement de la maladie d'alzheimer - Google Patents

Médicaments pour le traitement de la maladie d'alzheimer

Info

Publication number
EP2566882A1
EP2566882A1 EP11726321A EP11726321A EP2566882A1 EP 2566882 A1 EP2566882 A1 EP 2566882A1 EP 11726321 A EP11726321 A EP 11726321A EP 11726321 A EP11726321 A EP 11726321A EP 2566882 A1 EP2566882 A1 EP 2566882A1
Authority
EP
European Patent Office
Prior art keywords
sequence
peptide
alzheimer
dementia
protein
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP11726321A
Other languages
German (de)
English (en)
Inventor
Susanne Aileen Funke
Luitgard Nagel-Steger
Dirk Bartnik
Olexandr Brener
Torsten Sehl
Katja Wiesehan
Dieter Willbold
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Forschungszentrum Juelich GmbH
Original Assignee
Forschungszentrum Juelich GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Forschungszentrum Juelich GmbH filed Critical Forschungszentrum Juelich GmbH
Publication of EP2566882A1 publication Critical patent/EP2566882A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4711—Alzheimer's disease; Amyloid plaque core protein
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to agents for the treatment of Alzheimer's dementia.
  • AD Alzheimer's disease
  • Aß peptide Aß peptide
  • neurofibrillary deposits from the tau protein.
  • the A ⁇ peptide is formed by the activities of at least two different proteases from a precursor protein, the amyloid precursor protein (APP), which is localized in the cell wall of neurons, and the proteolytic degradation of APP and subsequent modification produces A ⁇ fragments
  • APP amyloid precursor protein
  • the amyloid cascade hypothesis was postulated in the 1990's and postulated that deposition of A ⁇ in the form of plaques is the cause of the disease symptoms Freely diffusible A ⁇ oligomers are more toxic than the A ⁇ fibrils deposited in the plaques. According to recent work, the plaques can be considered as a reservoir for oligomeric Aß, which colocalizes with the destruction of synapses and neurons.
  • a ⁇ i Aggregating intraneuronal A ⁇ (A ⁇ i) is considered to be a significant factor in early AD pathogenesis. Whether A ⁇ i, which consists for the most part of A ⁇ 1-42, is not secreted A ⁇ or reinter- nalized A ⁇ , could not yet be conclusively clarified. However, the clues for the second possibility are piling up.
  • D3 peptide modulates A ⁇ aggregation.
  • the D3 peptide interacts with soluble A ⁇ oligomers.
  • Surface Plasmon Resonance Studies indicate that D3 preferentially binds soluble A ⁇ oligomers.
  • D3 reduces the number of senile plaques in the brain and the associated inflammatory processes.
  • Substances are needed which i) reduce in vivo toxic, soluble A ⁇ oligomers and ii) which are effective not only outside but also within neurons.
  • Sequence No. 1 L3 peptide, which binds according to the invention to Aß oligomers.
  • Sequence # 2 Exemplified inventive peptide comprising sequence # 1, but additionally comprising a sequence portion that causes secretion to occur through a cell membrane.
  • Sequence # 3 DNA sequence encoding peptide # 1.
  • Sequence # 4 DNA sequence encoding peptide # 2.
  • Sequence No. 5 Sequence coding for a vector containing Sequence No. 3 and coding for a structural unit that fluoresces.
  • Sequence No. 6 Sequence coding for a vector containing Sequence No. 4 and coding for a structural unit which fluoresces.
  • the peptides of the invention are preferably L-enantiomers.
  • the DNA sequences and vectors coding for them preferably also code for L-enantiomers.
  • the peptide according to sequence no. 1 binds to the A ⁇ peptide, in particular to Aß oligomers. It is therefore a medicine for the treatment of Alzheimer's dementia.
  • the drug for treating Alzheimer's dementia may therefore consist of the peptide of Sequence No. 1 or a substance containing the peptide of Sequence No. 1.
  • the peptide of Sequence No. 1 has better binding properties to the A ⁇ peptide than the peptide D3. It enables intracellular and extracellular use for the treatment of Alzheimer's dementia.
  • the peptide according to Sequence No. 1 can be produced synthetically, for example by Merryfield synthesis, and expression of a DNA coding for Sequence 1.
  • the peptide of Sequence No. 1 can be further used for the manufacture of a medicament for the treatment of Alzheimer's dementia.
  • the peptide of Sequence No. 1 binds to A ⁇ oligomers both intracellularly and extracellularly.
  • Alzheimer's dementia can be treated by both intracellular and extracellular action.
  • a protein which contains a sequence section according to sequence no. 1, but which comprises a sequence section which codes for the function that the peptide is capable of secretion, ie can pass through a cell membrane. These proteins can be exported from the cell.
  • the peptide of Sequence No. 1 has better binding properties to A ⁇ than the peptide D3. It allows for intracellular and extracellular treatment of Alzheimer's dementia.
  • the secretion-causing sequence sections are known in the art.
  • a peptide according to sequence no. 2 can be given, which has the properties mentioned.
  • a sequence-causing sequence portion of human origin or identical to a human sequence is used. This has the advantage that in the treatment of humans an undesirable immune response against the secretion section can be prevented or suppressed.
  • the secretion-capable peptides containing a sequence segment according to sequence no. 1 cause them to be able to pass through cell membranes and thereby also have a site of action that is beyond the cell membrane.
  • the secretion-capable peptides can likewise be prepared by a Merryfield synthesis or by expression of the corresponding DNA.
  • These secretory peptides are drugs. Furthermore, they can be used for the manufacture of a medicament for the treatment of Alzheimer's dementia.
  • the secretory peptides can be used intracellularly or extracellularly.
  • the peptides according to the invention according to sequences no. 1 and no. 2 as well as other secretible peptides which contain sequence parts according to sequence 1 bind to the monomeric, oligomeric but also the fibrillar or plaque-like Aß peptide.
  • the peptides according to the invention bind particularly well to soluble, oligomeric A ⁇ peptides. A particularly large effect was observed for A ⁇ peptides of structure length A ⁇ 1-42.
  • a DNA which codes for a peptide according to sequence no.1.
  • the DNA can be expressed intracellularly to produce a sequence no. 1 peptide suitable for the treatment of Alzheimer's dementia. This DNA is therefore suitable for gene therapy.
  • the DNA coding for a peptide according to sequence 1 is a drug which can be used in particular for the treatment of Alzheimer's dementia. It can also be used in the manufacture of a medicament for the treatment of Alzheimer's dementia.
  • a DNA which codes for a peptide containing Sequence No. 1 which comprises a sequence segment which functionally encodes a secretibility of the peptide. Also, this DNA can be expressed intracellularly to give a peptide of Sequence No. 2 which is capable of secreting and contains a portion of Sequence No. 1 suitable for the treatment of Alzheimer's dementia.
  • This DNA is therefore suitable for gene therapy.
  • the portion of the DNA responsible for secretion encodes a human secretory sequence.
  • the DNA coding for such a peptide is a drug which can be used in particular for the treatment of Alzheimer's dementia. It can also be used for the manufacture of a medicament for the treatment of Alzheimer's dementia.
  • a DNA according to sequence no. 4 is provided.
  • vectors which contain a DNA segment which codes for a protein according to sequence no.
  • the vectors may also contain a DNA segment encoding a protein of Sequence No. 1 which comprises a DNA sequence which functionally effects secretion of the expressed DNA segment or protein.
  • peptides according to sequence no. 1 as well as secretible derivatives thereof, such as peptides according to sequence no. 2 can be expressed intracellularly.
  • the vectors may contain sections that functionally code for fluorescent moieties.
  • vectors according to sequences 5 or 6 can be provided.
  • the vectors according to the invention can be prepared starting from commercially available vectors by methods known to the person skilled in the art. They are drugs especially for the treatment of Alzheimer's dementia and can be used for the manufacture of a medicament for the treatment of Alzheimer's dementia. Particularly suitable are viral vectors, since they can be used particularly well for gene therapy in humans but also other animals, such as animals.
  • the deoxyribonucleic acids coding for a peptide according to Sequence No. 1 the deoxyribonucleic acids coding for a peptide according to Sequence No. 1, which comprise a sequence section for the receptivity, for example for a peptide according to Sequence No. 2, and the Vectors comprising the corresponding nucleic acids can be used.
  • a DNA and a vector according to sequences 3 to 6 can be used. These are introduced into the body.
  • L3 is expressed in cells of the central nervous system, for example in neurons or in cells, and subsequently secreted and thus leads specifically to a reduction of the particularly toxic Aß oligomers. This can be done using special, viral vectors. Experiments were carried out in cell culture. The expression of L3 was both intra- and extracellular. Experimental results:
  • Fig. 1 Comparison of the binding preferences of L3 and D3 for Aß oligomers
  • Fig. 2 Comparison results of the density gradient centrifugation of A ⁇ -42 without peptide, with L3 and with D3
  • Fig. 4 Thioflavin T test and turbidity test for the analysis of
  • Figure 1 shows the comparison of the binding preferences of L3 and D3 for A ⁇ I-42 oligomers.
  • L3 is shown in figure section A and D3 is shown in figure section B.
  • L3 shows a stronger binding than D3.
  • a ⁇ 1-42 monomers (dashed lines), oligomers (solid lines) and fibrils (dotted lines) were immobilized on a CM5 biosensor chip. Interaction analyzes were carried out using surface plasmon resonance.
  • RU Resonance Units. In each case 25 .mu. ⁇ peptide solution (100 ug / ml) were injected. Both peptides show the strongest binding to Aßl-42 oligomers, L3 generally shows a higher maximum resonance than D3. The same results are also obtained for A ⁇ I-40 oligomers.
  • Figure 2 shows comparative results of density gradient centrifugation of A ⁇ 1-42 without peptide, with L3 and with D3.
  • L3 precipitates A ⁇ oligomers from complex mixtures of different A ⁇ forms.
  • the size distributions of A ⁇ in solution and A ⁇ -peptide mixtures were examined by sedimentation analysis on an iodixanol gradient (5-50%).
  • the mixtures contained 125 ⁇ A ⁇ and 125 mM each peptide.
  • 14 140 ⁇ fractions were obtained from the surface by sequential pipetting and analyzed by denaturing polyacrylamide gel electrophoresis SDS-PAGE followed by silver staining.
  • the results show that peptides contain the content of Aß oligomers significantly reduce L3 at the time point to a greater extent than D3. This results in large aggregates, which are described in further subsequent experiments as amorphous, non-fibrillar and not amyloidogenic.
  • Figure 3 shows the results of experiments comparing the hydrodynamic radius of A ⁇ 1-42 particles with and without L3 at different times. Dynamic light scattering is used to determine the hydrodynamic radius of particles in solution or suspension. A 5 ⁇ sample of A ⁇ 1-42 oligomeric particles was firstly added by adding a 50 ⁇ L3 sample, on the other with buffer (50 mM
  • Figure 4 shows results for a thioflavin T test and a turbidity test for analyzing the aggregation behavior of A ⁇ in the presence of L3. Both assays were prepared from common stock solutions of 25 ⁇ A ⁇ (light bars) and 25 ⁇ A ⁇ with 1 mM L3 (dark bars).
  • ThT is a dye that has higher fluorescence when bound to regular fibrils and thus serves as a measure of fibrillation.
  • the turbidity of the solution was measured as a measure of the aggregation as absorption at 355 nm in the UV / VIS spectrometer.
  • L3 promotes the rapid formation of large A ⁇ aggregates that have no fibrillar structure and are therefore negative in the thioflavine T (ThT) test.
  • FIG. 5 shows results on the amyloidogenic properties of A ⁇ -L3 aggregates, measured by means of ThT fluorescence intensity.
  • Amyloidogenic aggregation nuclei are particles that act as "germ cells” and thereby accelerate the aggregation process.As for the aggregation of A ⁇ , it is known that already existing Aß oligomers / germs are the aggregate considerably accelerate the onsrea of monomers. For the experiment germs were made which consisted of Aß (triangles) and those consisting of Aß and L3 (squares). After incubation of A ⁇ and A ⁇ -L3 mixtures for 5 days, the seeds were centrifuged off and washed.
  • Germs (20% v / v) were added to freshly prepared A ⁇ in the ThT test. As a control Aß was measured without germs (diamonds). Shown is the ThT fluorescence over time. The germs containing L3 do not accelerate aggregation compared to non-germ A ⁇ solutions. This is an indication that A ⁇ -D3 aggregates no longer have amyloid structures. Aggregation nuclei consisting of A ⁇ and L3 do not accelerate the A ⁇ aggregation process unlike A ⁇ aggregation nuclei.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Neurology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Toxicology (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Hospice & Palliative Care (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

L'invention concerne des médicaments pour le traitement de la maladie d'Alzheimer. La présente invention concerne un peptide selon la séquence n° 1, lequel se lie à des oligomères Aß et permet donc d'obtenir une guérison ou un ralentissement de la maladie d'Alzheimer. Dans d'autres configurations, la présente invention concerne la préparation de peptides, lesquels contiennent une séquence n° 1, et qui disposent toutefois de segments de séquence en amont, qui permettent une sécrétion du peptide. Aux fins de la thérapie génique, des séquences d'ADN et des vecteurs correspondants, en particulier selon les séquences 3 à 6, sont fournis.
EP11726321A 2010-05-05 2011-04-09 Médicaments pour le traitement de la maladie d'alzheimer Withdrawn EP2566882A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102010019336A DE102010019336A1 (de) 2010-05-05 2010-05-05 Mittel zur Behandlung der Alzheimerschen Demenz
PCT/DE2011/000389 WO2011137886A1 (fr) 2010-05-05 2011-04-09 Médicaments pour le traitement de la maladie d'alzheimer

Publications (1)

Publication Number Publication Date
EP2566882A1 true EP2566882A1 (fr) 2013-03-13

Family

ID=44281080

Family Applications (1)

Application Number Title Priority Date Filing Date
EP11726321A Withdrawn EP2566882A1 (fr) 2010-05-05 2011-04-09 Médicaments pour le traitement de la maladie d'alzheimer

Country Status (6)

Country Link
US (1) US20130143822A1 (fr)
EP (1) EP2566882A1 (fr)
JP (1) JP2013527757A (fr)
CA (1) CA2795596A1 (fr)
DE (1) DE102010019336A1 (fr)
WO (1) WO2011137886A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9591845B2 (en) * 2012-04-05 2017-03-14 Forschungszentrum Juelich Gmbh Method for treating blood, blood products and organs
JP6434903B2 (ja) 2012-04-05 2018-12-05 フォルシュングスツェントルム ユーリッヒ ゲゼルシャフト ミット ベシュレンクテル ハフツングＦｏｒｓｃｈｕｎｇｓｚｅｎｔｒｕｍ Ｊｕｅｌｉｃｈ ＧｍｂＨ 多価アミロイドβに結合するＤ−ペプチド含有ポリマー及びその使用
DE102012102998B4 (de) * 2012-04-05 2013-12-05 Forschungszentrum Jülich GmbH Polymere, enthaltend multivalente Amyloid-Beta-bindende D-Peptide und deren Verwendung
DE102014003262A1 (de) 2014-03-12 2015-09-17 Forschungszentrum Jülich GmbH Amyloid-Beta-bindende Peptide und deren Verwendung für die Therapie und die Diagnose der Alzheimerschen Demenz
US10995118B2 (en) 2013-09-26 2021-05-04 Forschungszentrum Juelich Gmbh Amyloid-beta-binding peptides and the use thereof for the treatment and diagnosis of alzheimer's disease

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10061872A1 (de) * 2000-12-12 2002-06-20 Lichtenberg Frate Hella Hefestamm zur Prüfung der Geno- und Zytotoxizität komplexer Umweltkontaminationen
DE10117281A1 (de) 2001-04-06 2002-10-24 Inst Molekulare Biotechnologie Peptid zur Diagnose und Therapie der Alzheimer-Demenz

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2011137886A1 *

Also Published As

Publication number Publication date
JP2013527757A (ja) 2013-07-04
CA2795596A1 (fr) 2011-11-10
DE102010019336A1 (de) 2011-11-10
US20130143822A1 (en) 2013-06-06
WO2011137886A1 (fr) 2011-11-10

Similar Documents

Publication Publication Date Title
EP2566882A1 (fr) Médicaments pour le traitement de la maladie d'alzheimer
EP3260865B1 (fr) Procédé de traitement du sang, produits sanguins et organes
EP3346273B1 (fr) Nouveau peptide d'énantiomère dérivé de d3 et son utilisation
WO2016150416A1 (fr) Peptides se liant spécifiquement aux bêta-amyloïdes et leur utilisation dans le traitement et le diagnostic de la démence d'alzheimer
EP3797787B9 (fr) Peptides cycliques se liants aux bêta-amyloïdes et leur utilisation
EP3747454B9 (fr) Peptides liants amyloïdes-bêta et ces peptides pour leur utilisation pour le traitement et le diagnostic de la maladie d'alzheimer
EP3296315A1 (fr) Peptide pour le traitement et le diagnostic précoce de la maladie d'alzheimer et d'autres tauopathies
EP2991664A1 (fr) Agents de prévention et de traitement des infections par le vih et d'autres infection virales
EP2914616B1 (fr) Peptides se liant au peptide amyloïde bêta raccourci dans la partie n-terminale et leur utilisation
WO1999042088A2 (fr) Procede pour le traitement de maladies ou de troubles de l'oreille interne
EP3271374B1 (fr) Peptides se liant spécifiquement à des espèces a-bêta pour la thérapie et/ou le diagnostic de la démence d'alzheimer
EP1156811B1 (fr) Agoniste du cuivre qui se lie au site de fixation de cuivre de la proteine precurseur de l'amyloide (app) et/ou exerce une action d'inhibition sur la liberation du peptide beta-amyloide
DE60219925T2 (de) Methode zur induzierung neurofibrillärer tangles in transgenen tieren
DE69026275T2 (de) Verfahren zur herstellung von ribonuklease-dimeren
DE102012108599B4 (de) A-Beta-Oligomer-bindende Peptide und deren Verwendung
EP3019870B1 (fr) Procédé de caractérisation quantitative de peptides et/ou de protéines amyloïdes et/ou agrégés dans un échantillon
DE202007007542U1 (de) Aminosäure-Mineral-Peptid-Komplex, insbesondere quantenmechanisch modifiziert, als Arzneimittel zur Behandlung von Demenzerkrankungen
WO2005004887A1 (fr) Principe actif pharmaceutique pour traiter des cancers du colon et d'autres types de tumeurs
DE19654623A1 (de) Behandlung neurodegenerativer Erkrankungen
DE10339727A1 (de) Verfahren zur Bestimmung der adulten Neurogenese

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20120929

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20131204

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Effective date: 20140603