NZ625624B2 - Humanized antibodies that recognize alpha-synuclein - Google Patents

Humanized antibodies that recognize alpha-synuclein Download PDF

Info

Publication number
NZ625624B2
NZ625624B2 NZ625624A NZ62562412A NZ625624B2 NZ 625624 B2 NZ625624 B2 NZ 625624B2 NZ 625624 A NZ625624 A NZ 625624A NZ 62562412 A NZ62562412 A NZ 62562412A NZ 625624 B2 NZ625624 B2 NZ 625624B2
Authority
NZ
New Zealand
Prior art keywords
antibodies
occupied
chain variable
variable region
methods
Prior art date
Application number
NZ625624A
Other versions
NZ625624A (en
Inventor
Tarlochan S Nijjar
Jose Saldanha
Original Assignee
Prothena Biosciences Limited
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 Prothena Biosciences Limited filed Critical Prothena Biosciences Limited
Priority claimed from PCT/US2012/062290 external-priority patent/WO2013063516A1/en
Publication of NZ625624A publication Critical patent/NZ625624A/en
Publication of NZ625624B2 publication Critical patent/NZ625624B2/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/567—Framework region [FR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2835—Movement disorders, e.g. Parkinson, Huntington, Tourette
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6854—Immunoglobulins
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease

Abstract

Disclosed are humanised forms of the mouse 9E4 antibody which comprise the CDRs as defined in the specification and the use of said antibodies for treating synucleinopathy and reducing Lewy body formation.

Description

WO 63516 Humanized Antibodies that ize Alpha-Synuclein CROSS—REFERENCE TO RELATED APPLICATION This application claims ty to US. Provisional Patent Application No. 61/553,131, filed October 28, 2011, and US. Provisional Patent Application No. 61/711,208, filed October 8, 2012, each of which is incorporated by reference in the entirety for all purposes.
REFERENCE TO A SEQUENCE LISTING The Sequence Listing written in file SEQLIST.txt is 34 kilobytes and was created on October 24, 2012. The information contained in this file is hereby incorporated by reference.
BACKGROUND Synucleinopathies also known as Lewy body diseases (LBDs), are terized by degeneration of the dopaminergic system, motor alterations, cognitive impairment, and formation of Lewy bodies (LBS) and/or Lewy es.
(McKeith et al., Neurology (1996) 47:1113—24). Synucleinopathies include Parkinson's disease (including idiopathic Parkinson’s disease), Diffuse Lewy Body e (DLBD) also known as Dementia with Lewy Bodies (DLB), Lewy body variant of Alzheimer’s disease (LBV), Combined Alzheimer's and Parkinson disease, pure autonomic failure and multiple system atrophy (MSA; e.g., Olivopontocerebellar Atrophy, Striatonigral Degeneration and Shy—Drager Syndrome). Several nonmotor signs and symptoms are thought to be gers for synucleinopathies in the mal phase of the diseases (i.e, the presymptomatic, subclinical, preclinical, or or period). Such early signs include, for example, REM sleep behavior disorder (RBD), loss of smell and constipation (Mahowald et al., Neurology (2010) 75:488—489). Lewy body diseases continue to be a common cause for movement disorders and cognitive deterioration in the aging population (Galasko eta1., Arch.
Neurol. (1994) 51:888-95).
Alpha—synuclein is part of a large family of proteins including beta— and gamma— synuclein and synoretin. Alpha—synuclein is expressed in the normal state associated with synapses and is ed to play a role in neural plasticity, learning and memory. Several studies have implicated alpha-synuclein with a central role in PD pathogenesis. The protein can ate to form insoluble fibrils in pathological conditions. For example, synuclein accumulates in LBS (Spillantini et al., Nature (1997) 388:839-40; Takeda et al., J. Pathol. (1998) 152:367-72; Wakabayashi et al., Neurosci. Lett. (1997) 239:45—8). Mutations in the alpha—synuclein gene regate with rare familial forms of parkinsonism (Kruger et al., Nature Gen. (1998) 18:106—8; Polymeropoulos, et al., Science (1997) 276:2045—7). Over expression of alpha synuclein in transgenic mice (Masliah et al., Science (2000) 287: 1265—9) and Drosophila (Feany et al., Nature (2000) 404:394-8) mimics several pathological aspects of Lewy body disease. In addition, it has been suggested that soluble oligomers of synuclein may be neurotoxic (Conway KA, et al., Proc Natl Acad Sci USA (2000) 97:571—576; VollesMJ, Lansbury PT, Jr mistry (2003) 4227871— 7878). The accumulation of alpha-synuclein with similar morphological and neurological tions in species and animal models as diverse as humans, mice, and flies ts that this molecule contributes to the development of Lewy body disease.

Claims (1)

  1. SUMMARY OF THE CLAIMED INVENTION The invention provides dies comprising a mature humanized heavy chain variable region comprising the three Kabat CDRs of SEQ ID NO:11, and being at least 90% identical to SEQ ID NO:11, and a humanized light chain comprising the three Kabat CDRs of SEQ ID NO:4, and being at least 90% identical to SEQ ID NO:4. In some antibodies, the mature heavy chain variable region is at least 95%, 96%, 97%, 98%, or 99% cal to SEQ ID NO:11 and mature light chain variable region is at least 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:4. In some antibodies position L36 (Kabat numbering) can be occupied by Y or F, position L83 (Kabat numbering) can be ed by F or L, position H73 (Kabat ing) can be occupied by N or D and on H93 (Kabat numbering) can be occupied by A or S. In some of such antibodies the amino acid sequence of the mature heavy chain variable region is otherwise that of SEQ ID NO:11 and the amino acid sequence of the mature light chain variable region is otherwise that of SEQ ID NO:4. In some antibodies, the mature heavy chain variable region has an amino acid sequence designated SEQ ID NO:8 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO:3. In some antibodies, the mature heavy chain variable region has an amino acid sequence designated SEQ ID NO:8 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO:4. In some antibodies, the mature heavy chain variable region has an amino acid sequence designated SEQ ID N028 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO:5. In some antibodies, the mature heavy chain variable region has an amino acid sequence ated SEQ ID NO:9 and the mature light chain variable region has an amino acid ce designated SEQ ID N0:3. In some antibodies, the mature heavy chain variable region has an amino acid sequence designated SEQ ID NO:9 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO:4. In some antibodies, the mature heavy chain variable region has an amino acid sequence designated SEQ ID N029 and the mature light chain le region has an amino acid sequence designated SEQ ID N025. In some antibodies, the mature heavy chain variable region has an amino acid sequence designated SEQ ID N0:10 and the mature light chain variable region has an amino acid sequence designated SEQ ID N0:3. In some antibodies, the mature heavy chain variable region has an amino acid sequence designated SEQ ID N0210 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO:4. In some antibodies, the mature heavy chain le region has an amino acid sequence designated SEQ ID N010 and the mature light chain variable region has an amino acid sequence designated SEQ ID N0:5. In some antibodies, the mature heavy chain variable region has an amino acid sequence designated SEQ ID N0:ll and the mature light chain variable region has an amino acid sequence designated SEQ ID N0:3. In some antibodies, the mature heavy chain variable region has an amino acid sequence designated SEQ ID N021 l and the mature light chain variable region has an amino acid sequence designated SEQ ID NO:4. In some antibodies, the mature heavy chain variable region has an amino acid sequence designated SEQ ID N0: 11 and the mature light chain variable region has an amino acid sequence designated SEQ ID N0:5. The invention further provides an dy comprising a humanized heavy chain sing the three Kabat CDRs of SEQ ID N0:ll and a humanized light chain comprising the three CDRs of SEQ ID N024 provided that position L36 (Kabat numbering) is occupied by F or Y and/or position L83 (Kabat numbering) is occupied by L or F and/or position H73 (Kabat numbering) is ed by D or N, and/or position H93 (Kabat numbering) is occupied by S or A. In some such antibodies, position L36 (Kabat ing) is occupied by F and position H73 (Kabat numbering) is occupied by D, and position H93 (Kabat numbering) is occupied by S. In some such antibodies, position L36 is occupied by F. In some such antibodies, position L83 is occupied by L. In some such antibodies position H73 is occupied by D. In some such antibodies, on H93 is occupied by A. In some such antibodies, position L36 is ed by F and position L83 is occupied by L. In some such antibodies, position L36 is occupied by F and position H73 is occupied by D. In some such antibodies, position L36 is occupied by F and position H93 is occupied by A. In some such dies, position L36 is occupied by F, position L83 is occupied by L and position H73 is occupied by D. In some such antibodies, position L36 is occupied by F, position L83 is occupied by L and position H93 is ed by A. In some such antibodies, position L 36 is occupied by F, position L83 is occupied by L, position H73 is occupied by D and on H93 is occupied by A. In some such antibodies, residues at positions L36, L83, H73 and H93 (Kabat numbering) are occupied by amino acids as indicated in Table 1 is occupied by F and position H73 (Kabat numbering) is occupied by D, and position H93 (Kabat numbering) is ed by A. In some such antibodies, position L36 (Kabat numbering) is occupied by F and position H93 (Kabat numbering) is ed by S. In some such antibodies, position H73 (Kabat numbering) is occupied by D and position H93 (Kabat numbering) is occupied by S. In some such antibodies, position H73 (Kabat numbering) is ed by D and position H93 (Kabat numbering) is occupied by A. In some such antibodies, on H93 (Kabat numbering) is occupied by S. In some such dies, position H73 (Kabat numbering) is ed by N. In some such antibodies,,position L36 (Kabat numbering) is occupied by F, on L83 (Kabat numbering) is occupied by L, position H73 (Kabat numbering) is occupied by D, and position H93 (Kabat numbering) is occupied by S. In some such antibodies, position L36 (Kabat numbering) is occupied by F ,position L83 (Kabat numbering) is occupied by L and position H93 (Kabat numbering) is occupied by S. In any of the above antibodies, the mature heavy chain variable region can be fused to a heavy chain constant region and the mature light chain nt region can be fused to a light chain constant region. In any of the above antibodies, the heavy chain constant region can be a mutant form of natural human constant region which has reduced binding to an Fcy receptor relative to the natural human constant region. In any of the above antibodies, the heavy chain constant region can be of human IgG1 isotype. In some antibodies the allotype is G1m3. In some antibodies, the pe is Glml. The invention further provides a nucleic acid encoding any of the above— mentioned mature heavy chain variable s and/or any of the above-mentioned mature light chain variable region, e.g., SEQ ID NO: 15, 17, 18, 19, and 20. The invention further es a host cell comprising a vector comprising any of the nucleic acids described above. The invention further provides a method of treating a patient having or at risk of a Lewy body disease, comprising administering to the patient an effective regime of any of the mentioned antibodies. In some s, the disease is Parkinson’s disease. In some methods, decline of cognitive function in the patient is inhibited. In some methods, neuritic and/or axonal alpha synuclein aggregates are reduced. In some methods, neuritic dystrophy in the t is reduced. In some methods, synaptic and/or dendritic density is preserved. In some methods, the method preserves synaptophysin and/or MAP2 in the patient. The invention further provides a method of treating a patient having or at risk of synucleinopathy, comprising administering to the patient an effective regime of any of the above-mentioned antibodies. In some methods, the disease is Parkinson’s disease. In some methods, the disease is REM sleep or disorder (RBD). In some methods, the disease is Dementia with Lewy Bodies (DLB) or multiple system atrophy (MSA). In some methods, decline of cognitive function in the patient is inhibited. In some methods, neuritic and/or axonal alpha synuclein aggregates are reduced. In some methods, ic dystrophy in the patient is d. In some methods, synaptic and/or dendritic density is preserved. In some s, the method preserves synaptophysin and/or MAP2 in the patient. The invention further provides methods of detecting Lewy bodies in a t having or at risk of a Lewy body e, comprising administering to the patient an effective amount of any of the above—mentioned antibodies, wherein the antibody binds to Lewy bodies and bound antibody is detected. In some methods, the disease is Parkinson’s disease. In some methods, the disease is Dementia with Lewy Bodies (DLB) or multiple system atrophy (MSA). In some methods, the dy is labeled. The invention further provides a method of reducing Lewy body formation in a t having or at risk of a Lewy body disease, comprising administering to the t an ive amount of any of the above—mentioned antibodies. In some methods, the disease is Parkinson’s disease. In some methods, the disease is Dementia with Lewy Bodies (DLB) or multiple system atrophy (MSA). In some methods, decline of cognitive function in the patient is inhibited. In some methods, neuritic and/or axonal alpha synuclein aggregates are reduced. In some methods, neuritic dystrophy in the patient is reduced. In some methods, synaptic and/or dendritic density is preserved. In some methods, the method preserves synaptophysin and/or MAP2 in the patient. The invention further provides a method of inhibiting synuclein aggregation or ng Lewy bodies or synuclein aggregates in a patient having or at risk of a Lewy body disease, comprising administering to the patient an effective amount of any of the above-mentioned antibodies. In some s, the disease is Parkinson’s disease. In some methods, the disease is Dementia with Lewy Bodies (DLB) or multiple system atrophy (MSA). In some methods, decline of cognitive function in the patient is inhibited. In some methods, neuritic and/or axonal alpha synuclein aggregates are reduced. In some methods, ic dystrophy in the patient is d. In some methods, synaptic and/or dendritic density is preserved. In some methods, the method preserves synaptophysin and/or MAP2 in the patient. The invention further provides a ceutical composition comprising any of the above—mentioned antibodies. The invention further provides a method of producing an antibody, comprising culturing cells transformed with nucleic acids encoding the heavy and light chains of the antibody, so that the cell secrete the dy; and purifying the antibody from cell culture media; wherein the antibody is any of the antibodies bed above. The ion further provides a method producing a cell line producing an antibody, comprising introducing a vector encoding heavy and light chains of an antibody and a selectable marker into cells; propagating the cells under conditions to select for cells having increased copy number of the vector; ing single cells from the selected cell; and banking cells cloned from a single cell selected based on yield of antibody; wherein the antibody is any of the antibodies described above. Some such methods further comprises propagating the cells under selective conditions and ing for cell lines naturally expressing and secreting at least 100 mg/L/ 106 cells/24 h. [0020a] According to a first aspect the invention provides an antibody comprising a mature heavy chain variable region comprising the three Kabat CDRs of SEQ ID NO:11, and being at least 95% identical to SEQ ID NO:11, and a light chain comprising the three Kabat CDRs of SEQ ID NO:4, and being at least 95% identical to SEQ ID NO:4 except provided that on L36 (Kabat numbering) is ed from Y or F, position L83 (Kabat numbering) is selected from F or L, position H73 (Kabat numbering) is selected from N or D and position H93 (Kabat numbering) is selected from by A or S. [0020b] According to a second aspect the invention provides a c acid encoding a mature Lewy chain variable region and/or a mature light chain variable region according to the antibody of the first aspect of the invention. [0020c] According to a third aspect the invention provides an isolated host cell comprising a vector comprising the nucleic acid according to the second aspect of the invention. ] According to a fourth aspect the invention provides a pharmaceutical composition sing an antibody as defined by the first aspect of the invention. [0020e] According to a fifth aspect the invention provides a method of producing an antibody according to the first aspect of the invention, comprising culturing cells ormed with nucleic acids encoding the heavy and light chains of the dy, so that the cell secrete the antibody; and purifying the antibody from cell culture media. [0020f] According to a sixth aspect the invention provides a method of producing a cell line producing an antibody according to the first aspect of the invention, comprising ucing a vector encoding heavy and light chains of an antibody and a selectable marker into cells; propagating the cells under conditions to select for cells having increased copy number of the vector; ing single cells from the selected cell; and banking cells cloned from a single cell selected based on yield of antibody; wherein said cell or said cells are not within a human. 11323585 [0020g] According to a seventh aspect the present invention provides the use of an antibody according to the first aspect of the invention in the cture of a medicament for the treatment of a patient having or at risk of a synucleinopathy. [0020h] According to an eighth aspect the present invention es the use of an antibody according to the first aspect of the invention in the manufacture of a medicament for reducing Lewy body formation in a patient having or at risk of a Lewy body disease. [0020i] According to a ninth aspect the present invention provides the use of an antibody according to the first aspect of the invention in the manufacture of a medicament for inhibiting synuclein aggregation or reducing Lewy bodies or synuclein aggregates in a t having or at risk of a Lewy body disease. [0020j] According to a tenth aspect the t invention es the use of an dy according to the first aspect of the invention in the manufacture of a medicament for the detection of Lewy bodies in a patient having or at risk of a Lewy body disease. 11323585
NZ625624A 2011-10-28 2012-10-26 Humanized antibodies that recognize alpha-synuclein NZ625624B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201161553131P 2011-10-28 2011-10-28
US61/553,131 2011-10-28
US201261711208P 2012-10-08 2012-10-08
US61/711,208 2012-10-08
PCT/US2012/062290 WO2013063516A1 (en) 2011-10-28 2012-10-26 Humanized antibodies that recognize alpha-synuclein

Publications (2)

Publication Number Publication Date
NZ625624A NZ625624A (en) 2016-06-24
NZ625624B2 true NZ625624B2 (en) 2016-09-27

Family

ID=

Similar Documents

Publication Publication Date Title
US10875910B2 (en) Antibodies recognizing alpha-synuclein
US10875909B2 (en) Humanized antibodies that recognize alpha-synuclein
AU2017276296B2 (en) Humanized antibodies that recognize alpha-synuclein
KR20150018555A (en) Use of semaphorin-4d binding molecules to promote neurogenesis following stroke
JP2022529009A (en) Neurogenesis
NZ625624B2 (en) Humanized antibodies that recognize alpha-synuclein
Stewart et al. PTEN knockout using retrogradely transported AAVs restores locomotor abilities in both acute and chronic spinal cord injury
Highley et al. The neuropathology of the motor neurone diseases
JP2014508745A (en) Use of ICAM-1 for prevention or treatment of neurological diseases
ALTINTAŞ et al. Cell Transplantation in Multiple Sclerosis: Experiences, Questions and Problems